Medicinal mushrooms and the hallmarks of cancer: mechanistic insights for complementary chemotherapy

1 Introduction

Cancer progression is governed by a series of interconnected cellular and molecular processes collectively described as the “Hallmarks of Cancer”. Defined in 2011, these included sustained proliferative signaling, evasion of growth suppressors, resistance to cell death, replicative immortality, angiogenesis, invasion and metastasis, altered metabolism, immune evasion, genome instability and mutation, and tumor-promoting inflammation (1). Recent refinements expanded the framework to 14 hallmarks, adding phenotypic plasticity, non-mutational epigenetic reprogramming, senescent cells, polymorphic microbiomes, and additional microenvironmental influences, reflecting a more comprehensive understanding of tumor biology (2). Understanding these hallmarks at a mechanistic level provides a foundation for integrating therapeutic interventions that target not only tumor cells but also the surrounding microenvironment.

Since the original submission, an updated conceptual framework of the hallmarks of cancer has been proposed (3), distinguishing between hallmark capabilities, enabling characteristics, and systemic interactions. While the present review was initially structured according to the earlier classification, the revised manuscript aligns its conceptual mapping with this updated framework (3).

Conventional chemotherapeutic agents primarily target proliferative and survival pathways within tumor cells. Beyond cytotoxicity, chemotherapeutics can modulate the tumor microenvironment, influence immune responses, and perturb key metabolic signaling pathways such as AMPK/mTOR, ROS balance, and glucose metabolism (4, 5). These pleiotropic effects can significantly affect treatment outcomes and suggest opportunities for combination strategies with adjunctive agents that modulate complementary pathways.

Medicinal mushrooms have been extensively investigated for their biologically active compounds, particularly β-glucans, polysaccharopeptides, and secondary metabolites (6, 7). These molecules engage innate immune receptors, including Dectin-1, complement receptor 3, and Toll-like receptors, leading to activation of macrophages, dendritic cells, natural killer (NK) cells, and T lymphocytes (6). Additionally, fungal polysaccharides influence inflammatory signaling, angiogenesis, oxidative stress responses, and metabolic regulation within immune and tumor cells, establishing a mechanistic rationale for their potential integration into oncology care (7–9).

Clinical and translational studies of mushroom-derived compounds, including Trametes versicolor extracts (PSK/PSP) and Lentinula edodes preparations (lentinan), indicate improvements in immune parameters, quality of life, and, in some contexts, treatment response, although study heterogeneity and methodological limitations preclude definitive conclusions (9–14).

This review aims to synthesize mechanistic and clinical evidence linking chemotherapy effects and the hallmarks of cancer with the immunometabolic actions of medicinal mushrooms. Specifically, we map pathway-level overlaps, highlight plausible synergistic interactions, and discuss the implications for integrative oncology research. This work adopts a narrative, mechanism-oriented approach. Relevant literature was identified through targeted searches in PubMed, Scopus, and Web of Science (2000–2025) using keywords including “medicinal mushroom,” “β-glucan,” “PSK,” “lentinan,” “chemotherapy,” and “hallmarks of cancer.” Studies were selected based on their relevance to mechanistic pathways and clinical context, with emphasis on translational integration rather than exhaustive systematic coverage.

2 Overview of cancer hallmarks (Hanahan and Weinberg)

Cancer progression is orchestrated through a series of interconnected cellular and molecular traits, collectively described as the “Hallmarks of Cancer” (1, 2). Initially defined in 2011, the classic hallmarks included sustained proliferative signaling, evasion of growth suppressors, resistance to cell death, replicative immortality, angiogenesis, invasion and metastasis, altered metabolism, immune evasion, genome instability and mutation, and tumor-promoting inflammation (1). The updated framework in 2022 expanded to 14 hallmarks, incorporating phenotypic plasticity, non-mutational epigenetic reprogramming, senescent cells, polymorphic microbiomes, and additional microenvironmental influences (2). Together, these traits provide a comprehensive blueprint of tumor biology and potential therapeutic vulnerabilities. The 2026 update characterized the hallmarks by their functional interconnection; Acquired functional capabilities; Core cellular mechanisms driving tumor growth and survival.

Enabling phenotypic characteristics; Traits of cancer cells and their microenvironment that facilitate acquisition of hallmark capabilities.

Hallmark-facilitating / hallmark-conveying cells in the tumor microenvironment (TME); recruited non-cancer cells in the tumor microenvironment that actively contribute to the acquisition or maintenance of hallmark capabilities.

Systemic factors; broader host-level influences such as age, obesity, or metabolic status, which affect tumor development but are not hallmarks themselves (3).

2.1 Sustaining proliferative signaling

Cancer cells sustain chronic proliferative signaling through both autocrine and paracrine mechanisms, as well as constitutive activation of key growth-promoting pathways. This includes overexpression or mutation of growth factor receptors such as EGFR and HER2, leading to ligand-independent activation. Downstream, signaling cascades including the RAS/MAPK and PI3K/AKT/mTOR pathways become persistently active, promoting cell cycle progression, protein synthesis, and metabolic adaptation.

In addition to receptor-level alterations, mutations in intracellular signaling components (e.g., RAS, PI3K) or loss of negative regulators (such as PTEN) further amplify proliferative signaling. These changes collectively enable cancer cells to bypass normal dependence on external mitogenic cues.

From a therapeutic perspective, this hallmark is a central target of multiple anticancer strategies, including tyrosine kinase inhibitors and monoclonal antibodies directed against growth factor receptors. Disruption of these pathways can reduce tumor growth and restore sensitivity to growth-regulatory signals (1, 2).

2.2 Evading growth suppressors

Cancer cells acquire the ability to evade growth suppressive signals that normally regulate cell cycle progression and maintain tissue homeostasis. Central to this process is the functional inactivation of tumor suppressor pathways, particularly those governed by TP53 and RB.

The RB pathway controls the G1/S checkpoint by regulating E2F transcription factors. In many cancers, RB is inactivated either directly or indirectly through cyclin D overexpression or CDK4/6 hyperactivation, resulting in unchecked progression through the cell cycle. Similarly, TP53, often referred to as the “guardian of the genome”, is frequently mutated, impairing its ability to induce cell cycle arrest, DNA repair, or apoptosis in response to genomic stress.

Additional mechanisms include disruption of contact inhibition, alterations in TGF-β signaling, and epigenetic silencing of tumor suppressor genes. Collectively, these changes remove critical constraints on proliferation.

Therapeutically, restoration of growth control is approached through strategies such as CDK4/6 inhibitors and agents that aim to reactivate p53 signaling or exploit vulnerabilities created by its loss (1, 2).

2.3 Resisting cell death

A defining feature of cancer cells is their ability to resist programmed cell death, particularly apoptosis, even under conditions of cellular stress or therapeutic intervention. This is achieved through multiple mechanisms that disrupt both intrinsic (mitochondrial) and extrinsic (death receptor-mediated) apoptotic pathways.

On the intrinsic side, cancer cells frequently upregulate anti-apoptotic members of the BCL-2 family (e.g., BCL-2, BCL-XL) while downregulating pro-apoptotic proteins such as BAX and BAK. This imbalance stabilizes mitochondrial integrity and prevents cytochrome c release, thereby inhibiting caspase activation. On the extrinsic side, alterations in death receptors (e.g., Fas) and downstream signaling components impair apoptosis induced by immune cells.

In addition, cancer cells may engage alternative survival pathways, including autophagy modulation and activation of pro-survival signaling via NF-κB and PI3K/AKT.

This hallmark has significant therapeutic implications, as many anticancer treatments rely on the induction of apoptosis. Accordingly, targeted therapies such as BH3 mimetics (e.g., BCL-2 inhibitors) have been developed to restore apoptotic sensitivity and enhance treatment efficacy (1, 2).

2.4 Enabling replicative immortality

A hallmark of cancer cells is their ability to proliferate indefinitely by overcoming the natural limits of cellular senescence. Normal somatic cells experience replicative senescence primarily due to progressive telomere shortening at chromosome ends during each cell division. Cancer cells bypass this barrier through activation of telomerase (TERT), which elongates telomeres and maintains chromosomal integrity. Additionally, some tumors utilize Alternative Lengthening of Telomeres (ALT), a telomerase-independent homologous recombination-based mechanism, to sustain telomere length.

Beyond telomere maintenance, alterations in tumor suppressor pathways such as p53 and RB allow cells to ignore DNA damage checkpoints, preventing senescence induction despite genomic stress. Collectively, these mechanisms enable continuous cell division, genomic instability, and accumulation of mutations that fuel tumor progression.

Therapeutically, targeting telomerase with small-molecule inhibitors or immunotherapies is being investigated as a strategy to limit the proliferative capacity of cancer cells and sensitize tumors to cytotoxic treatments (1, 2).

2.5 Inducing angiogenesis

For tumors to grow beyond a minimal size (~1–2 mm), they require a dedicated blood supply. Cancer cells secrete pro-angiogenic factors, prominently VEGF (vascular endothelial growth factor), FGF (fibroblast growth factor), and angiopoietins, which act on endothelial cells to stimulate proliferation, migration, and tube formation. Hypoxia within the tumor microenvironment stabilizes HIF-1α (hypoxia-inducible factor 1-alpha), a transcription factor that upregulates these pro-angiogenic genes.

The angiogenic switch involves remodeling of the extracellular matrix by matrix metalloproteinases (MMPs) and recruitment of supporting stromal cells. This newly formed vasculature not only delivers oxygen and nutrients but also provides routes for metastatic dissemination.

From a therapeutic perspective, inhibitors of VEGF signaling, such as bevacizumab, and tyrosine kinase inhibitors targeting VEGF receptors, have been developed to starve tumors of their blood supply and complement conventional chemotherapies (1, 2).

2.6 Activating invasion and metastasis

Cancer progression involves not only local tumor growth but also invasion into surrounding tissues and distant metastasis. Cells acquire motility through epithelial-to-mesenchymal transition (EMT), characterized by loss of E-cadherin, upregulation of N-cadherin, and cytoskeletal remodeling via Rho/ROCK signaling.

Invasion requires degradation of the extracellular matrix, mediated by enzymes such as MMP-2 and MMP-9, which break down collagen and other matrix proteins. Integrins and other adhesion molecules coordinate cell attachment and migration. At distant sites, metastatic cells interact with the microenvironment to establish pre-metastatic niches, often co-opting stromal and immune cells.

Therapeutic interventions targeting EMT, MMPs, or integrin signaling are being explored to prevent metastatic spread, although clinical translation remains challenging (1, 2).

2.7 Deregulating cellular energetics

Cancer cells reprogram their metabolism to meet the demands of rapid proliferation. A well-characterized feature is the Warburg effect, where cells pre-ferentially convert glucose to lactate via glycolysis even under aerobic conditions. Key enzymes involved include hexokinase 2 (HK2), pyruvate kinase M2 (PKM2), and lactate dehydrogenase A (LDHA).

Signaling pathways such as PI3K/AKT/mTOR and MYC drive increased nutrient uptake, glycolytic flux, and biosynthesis of macromolecules. Mitochondrial metabolism is also adapted to support redox balance and production of anabolic intermediates. These changes provide energy and substrates for proliferation, while contributing to an acidic tumor microenvironment that can facilitate invasion and immune evasion.

Targeting metabolic pathways is an emerging therapeutic approach, including glycolysis inhibitors, mTOR inhibitors, and modulators of mitochondrial function, aiming to selectively impair cancer cell survival (1, 2).

2.8 Avoiding immune destruction

A defining feature of cancer is its ability to evade immune surveillance, allowing tumor cells to persist despite host immune defenses. Tumors achieve this through multiple mechanisms:

Immune checkpoint activation: tumor cells upregulate ligands such as PD-L1 and PD-L2, which engage PD-1 receptors on T cells, inhibiting cytotoxic activity and inducing T cell exhaustion.

Secretion of immunosuppressive cytokines: factors like TGF-β, IL-10, and VEGF dampen effector immune responses and promote recruitment of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs).

Downregulation of antigen presentation: loss or reduction of MHC class I molecules prevents recognition by CD8+ T cells.

Modulation of innate immunity: tumor cells can inhibit natural killer (NK) cell activity through downregulation of activating ligands or secretion of inhibitory factors.

Therapeutically, immune checkpoint inhibitors targeting PD-1/PD-L1 or CTLA-4 can restore T cell function, representing a transformative approach in cancer therapy (1, 2).

2.9 Tumor-promoting inflammation

Chronic inflammation in the tumor microenvironment acts as a fertile soil for tumor development. Immune cells, stromal components, and cytokines create a milieu that enhances tumor progression via:

DNA damage: reactive oxygen and nitrogen species produced by inflammatory cells increase mutation rates.

Growth and survival signaling: cytokines such as IL-6, TNF-α, and IL-1β activate STAT3, NF-κB, and MAPK pathways, promoting proliferation and survival.

Angiogenesis: pro-inflammatory mediators stimulate VEGF and other angiogenic factors.

Extracellular matrix remodeling: inflammatory enzymes like MMPs facilitate invasion and metastasis.

Chronic tumor-promoting inflammation represents both a hallmark of cancer and a therapeutic target, with strategies including anti-inflammatory agents, cytokine blockade, or modulation of immune cell recruitment (1, 2).

2.10 Genome instability and mutation

Genomic instability is a driving force in cancer evolution, providing a substrate for selection and adaptation. Key mechanisms include:

Defective DNA repair: loss of function in pathways such as mismatch repair (MMR), homologous recombination (HR), or non-homologous end joining (NHEJ) increases mutation rates.

Replication stress: oncogene activation (e.g., MYC, RAS) accelerates replication, leading to DNA breaks and chromosomal abnormalities.

Chromosomal instability: aneuploidy, translocations, and deletions generate diversity in gene copy number, affecting oncogenes and tumor suppressors.

This hallmark underpins heterogeneity and adaptation in tumors, and also creates vulnerabilities exploited by therapies like PARP inhibitors in DNA repair-deficient cancers (2).

2.11 Non-mutational epigenetic reprogramming

Cancer cells undergo epigenetic alterations that modulate gene expression independently of DNA sequence changes. Mechanisms include:

DNA methylation changes: hypermethylation of tumor suppressor promoters or global hypomethylation affecting genomic stability.

Histone modifications: altered acetylation, methylation, or phosphorylation of histones can either repress or activate gene transcription.

Chromatin remodeling: changes in nucleosome positioning and chromatin accessibility influence transcriptional programs governing differentiation, proliferation, and survival.

Epigenetic reprogramming cooperates with genetic mutations to support tumor initiation, progression, and therapy resistance. Therapeutic strategies include DNA methyltransferase inhibitors (e.g., azacitidine) and histone deacetylase inhibitors (e.g., vorinostat), aiming to reverse aberrant transcriptional states (2).

2.12 Polymorphic microbiomes

Emerging evidence suggests that interactions between tumors and the host microbiome can significantly influence cancer progression. Diverse microbial populations can modulate local and systemic inflammation, affecting cytokine signaling (e.g., IL-6, TNF-α) and immune cell recruitment. Certain microbial metabolites, such as short-chain fatty acids, can alter epigenetic regulation and metabolic pathways within tumor cells, impacting proliferation, differentiation, and survival. Dysbiosis may enhance tumor-promoting inflammation, whereas beneficial microbiota can support anti-tumor immunity. Therapeutically, microbiome modulation through probiotics, pre-biotics, or fecal microbiota transplantation is being explored as a complementary strategy to improve responses to immunotherapy and chemotherapy (2).

2.13 Senescent cells

Senescent cells accumulate in aging tissues and within the tumor microenvironment. These cells secrete a range of pro-inflammatory cytokines, chemokines, growth factors, and proteases collectively termed the senescence-associated secretory phenotype (SASP). SASP factors, including IL-1, IL-6, IL-8, and MMPs, can promote proliferation of nearby pre-malignant or malignant cells, remodel the extracellular matrix, and enhance angiogenesis. While senescence initially acts as a tumor-suppressive mechanism by arresting cell cycle progression, chronic accumulation of senescent cells paradoxically supports tumor development. Targeting senescent cells pharmacologically (“senolytics”) or modulating SASP represents a potential therapeutic avenue to reduce tumor-promoting inflammation (2).

2.14 Phenotypic plasticity

Cancer cells can dynamically transition between epithelial, mesenchymal, and stem-like states, a phenomenon contributing to heterogeneity, therapy resistance, and metastasis. This plasticity is regulated by transcription factors (e.g., SNAIL, TWIST, ZEB1/2), epigenetic modifications, and signaling pathways including TGF-β, Wnt/β-catenin, and Notch. By adopting mesenchymal-like or stem-like phenotypes, tumor cells gain motility, invasiveness, and the ability to survive hostile microenvironments, such as hypoxia or chemotherapy exposure. Phenotypic plasticity enables reversible adaptation, allowing tumors to evade therapeutic pressure and seed metastases. Therapeutically, interventions targeting EMT regulators or stemness pathways are being investigated to limit plasticity-driven progression (2).

2.15 New categories division 2026

Following the 2026 update of the Hallmarks framework (Hanahan, 2026), the 14 hallmarks discussed above can be conceptually grouped into four categories. Functional capabilities represent the classical hallmarks intrinsic to cancer cells, such as sustaining proliferation or resisting cell death. Enabling phenotypic characteristics are traits that support or enhance these capabilities, including genome instability and epigenetic reprogramming. Hallmark-conveying cells in the tumor microenvironment (TME) are non-cancerous cells that facilitate hallmark functions, such as immune cells, fibroblasts, or endothelial cells promoting angiogenesis. Finally, systemic interactions refer to organism-level processes that influence tumor behavior, for example metabolic dysregulation or chronic inflammation. This categorization provides a conceptual bridge to the updated taxonomy without altering the detailed discussion of each hallmark presented above (3).

Understanding these hallmarks provides a mechanistic framework to interpret how therapeutic interventions can influence tumor biology. Conventional chemotherapeutic agents exert effects far beyond direct cytotoxicity: they modulate immune responses, reshape the tumor microenvironment, trigger metabolic stress through pathways such as AMPK/mTOR and ROS signaling, and affect inflammatory networks including NF-κB and COX-2. These multifaceted actions intersect with multiple hallmarks, offering opportunities for synergistic strategies, including the integration of adjunctive agents like medicinal mushrooms. The following section examines how chemotherapy interacts with hallmark-associated mechanisms, emphasizing immunogenic cell death, microenvironmental modulation, metabolic stress, and inflammation.

3 Chemotherapy and hallmark modulation

Although traditionally defined by their cytotoxicity, chemotherapeutic agents exert a wide spectrum of actions that intersect directly with the cancer hallmarks described by Hanahan and Weinberg. These mechanisms include induction of apoptosis, interference with DNA replication and repair, metabolic stress, inhibition of angiogenesis, reshaping of the tumor microenvironment, and activation of immunogenic pathways. Mapping chemotherapy effects onto the hallmark framework provides a mechanistic rationale for combination strategies and helps contextualize the potential synergy with non-cytotoxic agents such as medicinal mushroom polysaccharides.

3.1 Induction of cell death and damage responses

Hallmarks: resisting to cell death, genome instability and mutation, replicative immortality.

Most chemotherapies, including alkylating agents, platinum compounds and topoisomerase inhibitors, exert their primary effect by inducing overwhelming DNA damage. This activates intrinsic and extrinsic apoptotic pathways, engages p53-dependent transcription, and force cells into mitotic catastrophe. By re-sensitizing tumor cells to apoptosis, chemotherapy directly counteracts the hallmark of resisting cell death. In parallel, the DNA damage response amplifies genomic instability, pushing tumor cells beyond tolerable thresholds of mutation accumulation (15–21).

Cisplatin, as a presentative to platinum-based drugs, is clinically proven treatment for various types of cancer including sarcomas, cancers of soft tissue, bones, muscles and blood vessels. Cisplatin becomes activated once it enters the cell, primarily through direct interaction with DNA, forming intra- and inter-strand crosslinks that obstruct replication and transcription. This DNA damage activates the DNA damage response (DDR), engages checkpoint pathways, and promotes apoptotic signaling through p53 and related effectors. Beyond DNA adduct formation, cisplatin increases reactive oxygen species (ROS) production, disrupts mitochondrial function, and interferes with RNA transcription, cumulatively driving tumor cell death. However, the therapeutic efficacy of cisplatin is often limited by the development of resistance mechanisms and dose-limiting toxicities (15).

It is important to distinguish between platinum-based drugs: oxaliplatin is considered ICD-competent, meaning it can induce immune response, whereas cisplatin is not ICD-competent. This distinction is relevant when combining cytotoxic therapies with β-glucans and other immunomodulatory agents (16).

Doxorubicin, a widely used anthracycline chemotherapeutic, exerts its anticancer activity through multiple interrelated mechanisms. It intercalates into DNA and inhibits topoisomerase II, stabilizing the cleavage complex and causing double-strand breaks that disrupt replication and transcription. In addition, doxorubicin generates reactive oxygen species (ROS), leading to oxidative damage of DNA, proteins, and cellular membranes, further promoting apoptotic signaling. Emerging evidence also implicates doxorubicin in pathways of senescence, autophagy, ferroptosis, and immunomodulation, reflecting its pleiotropic impact on tumor cells and the tumor microenvironment (17).

Etoposide (VP-16) targets topoisomerase II by stabilizing the transient DNA cleavage complexes, preventing re-ligation of double-stranded breaks. This accumulation of DNA lesions disrupts replication and transcription, leading to cell cycle arrest and apoptosis in rapidly dividing tumor cells. In addition to direct cytotoxicity, Etoposide induces apoptosis and can promote release of certain DAMPs (including HMGB1), but is not considered a canonical immunogenic cell death inducer according to current ICD definitions. (18). Irinotecan and Topotecan act similarly on topoisomerase I, inducing DNA damage, apoptotic signaling, and immunogenic cell death, thereby complementing the effects observed with etoposide (19, 20).

Cyclophosphamide (CP) is an alkylating chemotherapeutic prodrug that requires metabolic activation in the liver by cytochrome P450 enzymes to form 4-hydroxycyclophosphamide (OHCP), which exists in equilibrium with its tautomer aldophosphamide (ALDO). In vivo, aldophosphamide is enzymatically cleaved to generate phosphoramide mustard (PAM), the DNA-alkylating metabolite responsible for cytotoxicity, and hydroxypropanal (HPA), which enhances apoptosis. PAM forms interstrand and intrastrand crosslinks at guanine N-7 positions in DNA, blocking replication and transcription and triggering cell cycle arrest. If DNA damage cannot be repaired, p53-mediated pathways initiate apoptosis. Unique to CP is the enhancement of apoptosis by HPA through inhibition of anti-apoptotic proteins (e.g., Bcl-2, Bcl-xL) and suppression of NF-κB activation, as well as stimulation of MAPK signaling via increased JNK and p38 phosphorylation, further driving cytotoxic apoptosis in tumor cells (21).

3.2 Disruption of proliferation signaling and cell-cycle progression

Hallmarks: sustaining proliferative signaling, evading growth suppressors.

Chemotherapeutic agents disrupt cell proliferation not only by direct DNA damage but also by perturbing the tightly regulated progression through the cell cycle and by inducing replication stress. These effects lead to checkpoint activation, arrest at defined cell-cycle phases, and prevention of successful DNA replication and mitosis, thereby limiting tumor cell expansion and sensitizing cells to downstream death pathways (22).

Antimetabolites such as 5-fluorouracil (5-FU) and methotrexate interfere with DNA synthesis during S phase by inhibiting thymidylate synthase and dihydrofolate reductase, respectively. This results in depletion or imbalance of deoxynucleotide pools, replication fork stalling, and activation of intra-S-phase checkpoints, ultimately preventing progression through the cell cycle and promoting replication stress–induced arrest (23, 24).

Microtubule-targeting agents, including docetaxel and vinblastine, primarily affect mitotic progression. Docetaxel stabilizes microtubules, whereas vinblastine disrupts microtubule polymerization, in both cases impairing mitotic spindle assembly. This leads to persistent activation of the spindle assembly checkpoint and arrest at the G2/M transition, preventing chromosome segregation and completion of mitosis (25, 26). Prolonged mitotic arrest frequently culminates in cell death or irreversible proliferative failure.

Topoisomerase inhibitors such as etoposide contribute to replication stress by stabilizing topoisomerase II–DNA cleavage complexes, thereby blocking DNA unwinding and replication fork progression. This accumulation of unresolved DNA lesions activates checkpoint kinases and enforces S and G2 phase arrest, linking interference with replication dynamics directly to impaired cell-cycle progression (18, 19).

Collectively, these mechanisms demonstrate that many chemotherapeutic agents suppress tumor growth by targeting key regulatory nodes of DNA replication and cell-cycle control. By enforcing arrest at S phase or G2/M, chemotherapy directly undermines the hallmark of sustained proliferative signaling and reinforces antiproliferative barriers within cancer cells.

3.3 Inhibition of angiogenesis hallmark: inducing angiogenesis

Tumor progression beyond a minimal size requires angiogenesis to ensure adequate oxygen and nutrient supply, a process largely driven by VEGF signaling and hypoxia-responsive pathways. In addition to their cytotoxic effects, several chemotherapeutic agents interfere with angiogenesis by targeting endothelial cell function and suppressing pro-angiogenic signaling within the tumor microenvironment (1).

Metronomic administration of cyclophosphamide exerts a pronounced anti-angiogenic effect by selectively inhibiting endothelial cell proliferation, reducing circulating endothelial progenitor cells, and suppressing VEGF-mediated neovascularization, independently of direct tumor cell killing (27, 28). This shifts chemotherapy activity toward vascular targeting rather than exclusive cytotoxicity.

Microtubule-stabilizing agents such as paclitaxel and docetaxel further inhibit angiogenesis by impairing endothelial cell migration, tube formation, and mitotic progression, resulting in reduced microvessel density within tumors (29, 30).

In addition, chemotherapeutic agents previously discussed, including cisplatin and doxorubicin, indirectly suppress angiogenesis by downregulating tumor-derived VEGF expression and interfering with hypoxia-inducible signaling, thereby weakening angiogenic support within the tumor microenvironment (31).

Together, these findings indicate that chemotherapy can counteract the angiogenesis hallmark through both direct endothelial targeting and indirect modulation of tumor-derived angiogenic signals, reinforcing its role as a multi-hallmark modulator rather than a purely cytotoxic intervention.

3.4 Modulation of invasion, metastasis and plasticity

Hallmarks: activating invasion and metastasis, phenotypic plasticity.

Chemotherapeutic agents can modulate cellular invasion and metastasis programs beyond their cytotoxic effects by altering epithelial-to-mesenchymal transition (EMT), cytoskeletal dynamics, and migration. Cisplatin has been shown to block early EMT programs in breast cancer models, antagonizing TGF-β signaling and suppressing filopodia and migration, thereby reducing metastatic dissemination independent of its cytotoxic action (32).

Paclitaxel, a microtubule-stabilizing agent, can influence invasion by regulating intracellular signaling pathways such as PI3K/AKT, leading to reduced expression of invasion-associated factors like MMP-9 and diminished migratory capacity in breast cancer cells (33). However, taxanes also have complex effects on EMT programs and metastatic traits; in some models paclitaxel-induced EMT markers can be attenuated by co-inhibition of TGF-β signaling, indicating context-dependent plasticity modulation (33, 34).

Doxorubicin has been reported to activate the RhoA/MLC pathway in breast cancer cells, enhancing migration and invasion under certain treatment conditions, emphasizing that chemotherapeutic modulation of invasion can be bidirectional depending on cellular context and dosing (35).

Although Docetaxel is similarly a taxane, evidence from resistant cell populations indicates that acquisition of docetaxel resistance is associated with enhanced EMT features and increased migratory/invasive potential (36).

Collectively, these findings show that chemotherapy influences invasive and plastic behaviors through multiple signaling axes, and that effects on EMT, cytoskeleton, and migration are nuanced and context-dependent, contributing to altered metastatic potential in treated tumors (37).

3.5 Metabolic stress and energetic disruption

Hallmark: deregulating cellular energetics.

Chemotherapeutic agents can impose metabolic stress on tumor cells, perturbing energy homeostasis and making cells more susceptible to apoptosis or cell cycle arrest. Key affected pathways include mitochondrial function, ROS generation, AMPK/mTOR signaling, and nucleotide metabolism. Doxorubicin compromises mitochondrial integrity and elevates ROS levels, promoting oxidative stress-mediated apoptosis (38). Cisplatin reduces ATP production, impairing cellular energy supply and sensitizing tumor cells to cytotoxicity (15). Paclitaxel activates AMPK, leading to inhibition of mTOR signaling and suppression of anabolic processes required for proliferation (39). Methotrexate and 5-fluorouracil interfere with nucleotide biosynthesis, limiting substrates for DNA replication and repair, and driving energetic collapse in rapidly dividing cells (24). Together, these mechanisms illustrate how chemotherapeutics create a metabolically stressed environment that contributes to their anticancer efficacy.

3.6 Immunogenic cell death (ICD) and immune activation

Hallmarks: avoiding immune destruction, tumor-promoting inflammation.

Certain chemotherapeutic agents induce immunogenic cell death (ICD), a regulated form of cell death that activates adaptive antitumor immunity. ICD requires coordinated exposure or release of multiple danger-associated molecular patterns (DAMPs) such as calreticulin (CRT), extracellular ATP, high-mobility group box 1 (HMGB1), and heat shock proteins and cannot be inferred solely from apoptosis or isolated DAMP detection (39). During ICD, the exposure of CRT on the cell surface functions as an “eat-me” signal that promotes dendritic cell (DC) phagocytosis, while ATP and HMGB1 act as chemotactic and maturation signals for DCs and other antigen-presenting cells (40, 41). Once DCs process tumor antigens, they migrate to lymph nodes and prime CD8⁺ cytotoxic T lymphocytes, linking chemotherapy-induced cell death to systemic antitumor immune responses (40, 42).

Among chemotherapeutic drugs, anthracyclines such as doxorubicin are well validated as ICD inducers, causing translocation of CRT to the tumor cell surface and release of ATP and HMGB1, which enhance DC activation and subsequent T-cell responses (40, 42). Oxaliplatin, a platinum derivative, similarly induces ICD with DAMP emission and has been implicated in activating immune recognition in experimental cancer models (40, 42). Cyclophosphamide and bortezomib are also reported to elicit ICD-associated signals, contributing to immune activation in pre-clinical settings (42). In contrast, the ability of cisplatin to induce classical ICD is less consistent across models and may depend on tumor type, dosing, and microenvironment but can still contribute to immune modulation in certain contexts (40, 42).

Overall, ICD represents a mechanistic bridge between cytotoxic chemotherapy and the host immune response, offering a rationale for chemo-immunotherapy combinations that harness both direct tumor cell killing and immune system engagement.

3.7 Tumor microenvironment remodeling

Hallmarks: tumor- promoting inflammation, avoiding immune destruction, activating invasion and metastasis, inducing angiogenesis.

Beyond direct cytotoxicity, conventional chemotherapeutic agents exert significant effects on the tumor microenvironment (TME), modulating immune cell composition, stromal interactions, inflammatory signaling, and immune surveillance. These changes may either enhance antitumor immunity or, in some contexts, contribute to immune suppression and therapy resistance (43).

Low-dose Cyclophosphamide has been shown to selectively deplete regulatory T cells (Tregs), thereby relieving immunosuppression within the TME and enhancing effector T-cell responses. This immunomodulatory effect is mechanistically distinct from its cytotoxic activity and has been explored as a strategy to improve antitumor immune activation (44).

Anthracyclines such as Doxorubicin may modulate the tumor microenvironment by activating innate immune pathways and promoting the recruitment and activation of myeloid cells (45).

Paclitaxel has been reported to modulate extracellular matrix (ECM) remodeling and innate immune signaling through Toll-like receptor 4 (TLR4) activation on immune and stromal cells. These effects contribute to altered cytokine secretion and immune cell trafficking within the tumor niche, although context-dependent pro-tumor effects have also been described (46).

In addition, Cyclophosphamide indirectly remodel the TME via alterations in the gut microbiome. Microbiome changes influence systemic inflammation, myeloid cell function, and responsiveness to anticancer therapies, highlighting an emerging axis linking chemotherapy, host microbiota, and tumor immunity (47).

Collectively, these findings indicate that chemotherapy-induced remodeling of the tumor microenvironment represents a critical, non-cytotoxic component of therapeutic efficacy, intersecting with immune evasion, chronic inflammation, and treatment response.

3.8 Summary of section 3

Although chemotherapeutic agents intersect with many of the classical and expanded hallmarks of cancer, their activity is not uniformly directed toward all fourteen hallmarks. Most cytotoxic drugs primarily target proliferative capacity, genome integrity, apoptotic resistance, and in some regimens, angiogenesis, metabolic stress, or immune activation through immunogenic cell death. Other hallmarks, such as phenotypic plasticity, epigenetic reprogramming, and microbiome-associated influences, remain only indirectly affected by conventional chemotherapy or are not targeted at all.

Despite these limitations, chemotherapy remains one of the most effective modalities in oncology because it strikes at the core vulnerabilities shared by rapidly dividing malignant cells.

Medicinal mushrooms, in contrast, exert their biological effects through a broader spectrum of mechanisms. Their β-glucans and secondary metabolites influence innate and adaptive immunity, inflammation, angiogenesis, oxidative stress, metabolic pathways, the tumor microenvironment, and even hallmarks that chemotherapy only minimally affects. While there is meaningful overlap, especially in pathways involving immunity, apoptosis, angiogenesis, and metabolic stress, mushroom-derived compounds extend into additional hallmarks that chemotherapeutics do not directly modulate.

The next chapter explores these mechanistic dimensions in detail and demonstrates how the immunometabolic and microenvironmental effects of medicinal mushrooms may complement, rather than duplicate, the hallmark-level actions of chemotherapy.

4 Medicinal mushrooms: biochemistry and mechanisms

Medicinal mushrooms have been extensively studied for their bioactive compounds, particularly β-glucans and other polysaccharides, triterpenoids and secondary metabolites, which interact with multiple cellular pathways relevant to cancer biology. These compounds exhibit immunomodulatory, anti-inflammatory, antioxidant, anti-angiogenic, and metabolic regulatory properties, positioning them as potential complementary agents in oncology. Unlike conventional chemotherapeutic drugs that often target one or a few hallmarks of cancer directly, medicinal mushrooms can influence multiple hallmarks simultaneously, modulating tumor cell behavior, the tumor microenvironment, and host immune responses without inducing the severe toxicities associated with chemotherapy (7, 8, 48, 49).

The goal of this chapter is to map the effects of key medicinal mushrooms, such as Ganoderma lucidum (Fr.) Karst (Reishi), Trametes (Coriolus) versicolor (L.) Lioyd (Turkey Tail) and Grifola frondosa (Dicks.) Gray (Maitake), onto the framework of cancer hallmarks, highlighting both molecular mechanisms and evidence from pre-clinical and clinical studies. This approach allows us to compare, contrast, and potentially integrate mushroom-derived compounds with conventional anticancer therapies in a mechanistically informed manner (7, 8, 50).

4.1 Hallmarks linked to modulation of cell death and DNA damage responses

Hallmarks: sustaining proliferative signaling, evading growth suppression, resisting cell death, genome instability and mutation, enabling replicative immortality.

One of the primary mechanisms by which medicinal mushrooms exert anticancer effects is the regulation of cell death pathways and maintenance of genomic integrity. β-glucans from Ganoderma lucidum have been shown to activate apoptotic signaling in cancer cells via p53-dependent pathways, caspase activation, and mitochondrial membrane permeabilization, mimicking some aspects of chemotherapeutic-induced cytotoxicity but in a more selective manner toward tumor cells (51, 52).

Mushroom polysaccharides, particularly from Ganoderma lucidum, have demonstrated the ability to modulate Bcl-2 family proteins, enhance pro-apoptotic Bax expression, and reduce anti-apoptotic Bcl-2, promoting apoptosis in multiple cancer cell lines without affecting normal cells (52, 53). In addition to apoptosis, polysaccharides from Grifola frondosa can induce cell cycle arrest, particularly at the G1/S transition, by regulating cyclin-dependent kinases and checkpoint proteins, thereby limiting uncontrolled proliferation (53–55).

Emerging evidence also indicates that certain mushroom-derived compounds with other co-nutrients, may support genomic stability in normal cells while exerting cytotoxic effects on leukemia cells (56). Some medicinal mushrooms have been shown to possess antigenotoxic and antioxidant properties, which may protect DNA from damage (57). This dual effect, promoting repair in normal cells while inducing stress in tumor cells, distinguishes mushroom-derived compounds from classical chemotherapeutics and underpins their low toxicity profile (50).

4.2 Hallmarks linked to metabolism and angiogenesis

Hallmarks: deregulating cellular energetics, inducing angiogenesis, resisting cell death.

Medicinal mushrooms influence cancer metabolism and angiogenesis, two critical hallmarks that support tumor growth and survival. β-glucans and triterpenoids from Ganoderma lucidum and Trametes versicolor have been shown to modulate PI3K/AKT/mTOR and AMPK signaling pathways, restoring metabolic homeostasis and inhibiting glycolytic flux in tumor cells (50, 58). This metabolic reprogramming not only reduces energy supply to rapidly proliferating cancer cells but also promotes oxidative phosphorylation and mitochondrial function in normal cells, a balance not typically achieved with conventional chemotherapeutics. In addition, compounds derived from Ganoderma lucidum have been shown to modulate lipid metabolism, decreasing fatty acid synthesis while enhancing β-oxidation particularly in diabetes models (59, 60), which further limits biosynthetic resources required for tumor proliferation (61, 62).

In parallel to metabolic effects, mushroom-derived compounds exhibit anti-angiogenic properties. Extracts from Grifola frondosa and Ganoderma lucidum downregulate VEGF expression and inhibit endothelial cell proliferation, migration, and tube formation, effectively suppressing tumor vascularization (7, 63, 64). They also modulate angiogenesis-related signaling pathways such as HIF-1α and MAPK/ERK, which are crucial under hypoxic tumor conditions. By simultaneously restricting energy supply and vascular support, mushrooms create a multi-faceted barrier to tumor growth that complements conventional therapies targeting dividing cells.

4.3 Hallmarks linked to invasion, metastasis and plasticity

Hallmarks: activating invasion and metastasis, tumor-promoting inflammation, avoiding immune destruction, unlocking phenotypic plasticity.

Cancer cell invasion, metastasis, and phenotypic plasticity are major contributors to disease progression and treatment resistance. Polysaccharides and triterpenoids from medicinal mushrooms can suppress epithelial-to-mesenchymal transition (EMT) and downregulate matrix metalloproteinases (MMP-2 and MMP-9), which are essential for extracellular matrix degradation and metastasis (65–70). Ganoderma Lucidum components, for example, inhibit EMT markers such as N-cadherin and vimentin, while enhancing E-cadherin expression, stabilizing epithelial phenotypes and reducing motility (71). Trametes Versicolor and Grifola Frondosa polysaccharides also showed ability to enhance E-cadherin (69). The processes of epithelial-mesenchymal transition and cellular plasticity described above naturally interface with cancer stem cell (CSC) biology, reflecting the capacity of certain tumor cells to self-renew and drive tumor heterogeneity.

Furthermore, mushroom compounds modulate key signaling pathways that govern cellular plasticity, including Wnt/β-catenin, MAPK, and PI3K/AKT, thereby limiting the adaptability of cancer cells to microenvironmental stressors and chemotherapeutic pressure (50, 58, 62). Ganoderma Lucidum compounds also influence cytoskeletal dynamics and focal adhesion kinase (FAK) signaling, reducing migratory capacity and invasive potential (72). By targeting both molecular drivers of invasion and the structural mechanisms underlying migration, medicinal mushrooms offer a multi-level approach to restrain metastasis and maintain tissue integrity.

4.4 Hallmarks linked to immunity and inflammation

Hallmarks: avoiding Immune Destruction, Tumor- promoting Inflammation

Medicinal mushrooms are potent immunomodulators, impacting both innate and adaptive immune responses. β-glucans from Ganoderma lucidum, Trametes versicolor, and Grifola frondosa activate macrophages, natural killer (NK) cells, and dendritic cells, enhancing tumor cell recognition and cytotoxicity (7, 58). This activation includes increased phagocytic activity, enhanced antigen presentation, and stimulation of cytotoxic T lymphocytes. Mushroom polysaccharides also promote cytokine production (IL-12, IFN-γ, TNF-α), supporting a Th1-skewed immune response favorable for anti-tumor activity (62, 73).

In addition, mushrooms mitigate chronic inflammation, which is a hallmark of tumor progression. Triterpenoids and polysaccharides inhibit NF-κB activation and downstream pro-inflammatory cytokines, including IL-6 and TNF-α, while reducing oxidative stress within the tumor microenvironment (7, 50). This dual effect, enhancing anti-tumor immunity while dampening tumor-promoting inflammation, contrasts with many conventional chemotherapeutics, which often suppress immune function, and highlights the potential of medicinal mushrooms as integrative agents in oncology.

4.5 Additional hallmarks

Hallmarks: microbiome dysbiosis, non-mutational epigenetic reprogramming, avoiding cellular senescence.

Medicinal mushrooms can exert significant effects on the gut microbiome, which in turn influences tumor progression, host metabolism, and systemic immune responses. Polysaccharides and other non-digestible compounds from species such as Ganoderma lucidum, Grifola frondosa, and Trametes versicolor serve as prebiotics, promoting the growth of beneficial bacteria such as Lactobacillus and Bifidobacterium (74). These microbial shifts can increase the production of short-chain fatty acids (SCFAs), including butyrate, propionate, and acetate, which have been shown to modulate host epigenetic marks, enhance mucosal barrier integrity, and regulate inflammatory pathways relevant to cancer (75, 76).

Mushroom-derived compounds have been shown to modulate the gut microbiota and increase the production of short-chain fatty acids (SCFAs). While SCFAs are known to function as histone deacetylase (HDAC) inhibitors, their role in promoting tumor-suppressor gene expression and apoptosis in the specific context of mushroom-derived compounds remains to be fully elucidated. (75–77). Promoting the expression of tumor-suppressor genes and enhancing apoptotic signaling. This dual mechanism; microbiome-mediated epigenetic modulation in host tissues and direct effects on tumor cells, represents a unique multi-level approach that complements conventional therapies while minimizing toxicity.

Importantly, these interactions underscore the potential of medicinal mushrooms as integrative agents capable of modulating systemic cancer hallmarks via non-genetic pathways. They contribute to immune surveillance, reduce pro-tumor inflammation, and maintain epithelial integrity, positioning them as promising adjuncts in oncology (74, 76).

Cellular senescence refers to a state of permanent growth arrest triggered by oxidative stress, DNA damage, or other cellular insults, and is a key contributor to tissue aging and dysfunction. Bioactive compounds from medicinal mushrooms, especially triterpenoids derived from Ganoderma lucidum, have demonstrated the ability to reduce markers associated with cellular senescence in experimental models. In vitro and in vivo studies show that ganoderic acid D, a Ganoderma lucidum triterpenoid, can attenuate oxidative stress-induced senescence in human mesenchymal stem cells, reduce reactive oxygen species and senescence markers such as SA-β-gal, p16/INK4a and p21, and activate protective signaling pathways linked to redox homeostasis (78). Additionally, polysaccharides from Ganoderma lucidum have been found to decrease markers of cellular aging in fibroblasts exposed to stress and reduce expression of senescence-associated proteins in aging animal tissues, suggesting a protective effect against senescence-related processes (79, 80). Overall, these findings indicate that medicinal mushroom compounds can modulate cellular stress responses and delay or mitigate senescence-like phenotypes, supporting health span-related mechanisms without directly promoting malignant escape pathways.

4.6 Summary of section 4

In this chapter, we have detailed how medicinal mushrooms, including; Ganoderma lucidum, Grifola frondosa and Trametes versicolor, modulate multiple cancer hallmarks through diverse biochemical mechanisms. From regulating cell death and proliferation, to reprogramming metabolism and angiogenesis, limiting invasion and metastasis, modulating immunity and inflammation, and influencing the gut microbiome and epigenetic processes, these fungi exert broad-spectrum effects with minimal toxicity. Importantly, their multi-targeted actions complement conventional therapies, potentially enhancing efficacy while mitigating adverse effects. Having established the mechanistic rationale and pre-clinical evidence, the next chapter will focus on clinical studies, examining how these mushroom-derived compounds perform in human populations, their safety profiles, and the translational relevance of the laboratory findings discussed here.

5 Clinical evidence

Clinical research evaluating medicinal mushrooms in cancer patients has expanded over the past decades, encompassing randomized controlled trials, cohort studies, and systematic reviews. While many studies are small, heterogeneous in design, and focus on different outcomes (e.g., immune parameters, quality of life, survival), consistent patterns emerge suggesting that certain mushroom extracts, particularly polysaccharide-rich preparations such as PSK and other β-glucan formulations, may have clinically meaningful benefits when used as adjuvants to standard cancer treatments. This chapter synthesizes the best-available evidence on clinical outcomes, safety, and therapeutic potential of medicinal mushrooms in oncology.

5.1 Clinical evidence of medicinal mushrooms in oncology

Clinical evidence investigating medicinal mushrooms in oncology suggests beneficial effects primarily in immune modulation, improvement of quality of life, mitigation of chemotherapy-related adverse effects, and, in selected contexts, improved survival outcomes. The strongest clinical evidence originates from protein-bound polysaccharides such as PSK and PSP from Trametes versicolor, lentinan from Lentinula edodes (Berk) Pegler (Shiitake), and polysaccharide fractions from Grifola frondosa, which have been evaluated in randomized trials and meta-analyses as adjuncts to conventional cancer therapies (81–87).

Beyond these well-established agents, a growing body of clinical and translational evidence supports potential supportive roles for Ganoderma lucidum, Cordyceps species (C. militaris and C. sinensis), Pleurotus species, Agaricus blazei, and additional medicinal fungi. Collectively, these studies highlight a broader spectrum of mushrooms with clinically relevant immunomodulatory and supportive effects in oncology (58, 84–98).

5.1.1 Trametes versicolor (PSK/PSP)

Trametes versicolor, commonly known as Turkey Tail, contains bioactive polysaccharides PSK (polysaccharide-K) and PSP (polysaccharopeptide), which are among the most extensively studied medicinal mushroom compounds in clinical oncology. Randomized controlled trials and long-term observational studies in gastric, colorectal, and breast cancer patients demonstrate that PSK administered as an adjuvant to surgery and chemotherapy improves overall survival, disease-free survival, and reduces recurrence rates (81–83).

Mechanistically, PSK enhances immune function by increasing natural killer (NK) cell activity, promoting T-cell proliferation, and elevating Th1-associated cytokines such as IL-2 and IFN-γ, while also supporting hematological recovery during chemotherapy (82). Meta-analyses and multicenter studies confirm consistent clinical benefits, particularly in East Asian oncology practice where PSK has been integrated into standard treatment protocols (83). These findings position Trametes versicolor as a well-tolerated and clinically relevant adjunctive therapy in integrative oncology.

5.1.2 Lentinula edodes (Lentinan)

Lentinan, a β-1,3/1,6-glucan isolated from Lentinula edodes mushrooms, has been evaluated clinically as an adjunct therapy in gastric, colorectal, lung, and pancreatic cancers. Clinical trials report improved response rates to chemotherapy, reduced treatment-related toxicity, and enhanced quality of life, with some studies indicating improved short-term survival outcomes (84).

Mechanistically, lentinan activates dendritic cells, enhances antigen presentation, promotes Th1-biased immune responses, and increases NK-cell cytotoxicity, supporting its role as an immune-supportive agent in integrative oncology (85).

5.1.3 Grifola frondosa (Maitake)

Polysaccharide fractions from Grifola frondosa, particularly the D-fraction, have been investigated in phase I and II clinical studies involving breast, lung, and colorectal cancer patients. These studies demonstrate enhancement of NK-cell activity, modulation of cytokine profiles, and improved immune responsiveness when used alongside conventional therapies (86).

Although robust survival data remain limited, Grifola frondosa extracts are generally well tolerated and show promise as immune-supportive adjuncts in oncology, particularly in patients receiving chemotherapy (87).

5.1.4 Ganoderma lucidum (Reishi)

Clinical studies examining Ganoderma lucidum focus primarily on immune function, fatigue, and quality of life in cancer patients. Small clinical trials in breast cancer populations report increased NK-cell activity, improved T-cell responses, and reductions in cancer-related fatigue and inflammatory markers (88).

While definitive evidence for survival benefit is lacking, Ganoderma lucidum appears safe and may improve tolerability of conventional cancer treatments, supporting its use in integrative oncology settings (89).

5.1.5 Cordyceps spp. (C. militaris and C. sinensis)

Cordyceps militaris (L.) Fr. and Cordyceps sinensis (Berk.) Sacc. are both clinically relevant species in integrative and traditional oncology practice. C. militaris, rich in cordycepin and bioactive polysaccharides, has been evaluated in preliminary clinical and translational studies involving lung and hepatocellular carcinoma patients, demonstrating enhanced NK-cell activity, increased Th1 cytokine production, and improvements in fatigue and overall wellbeing during immunotherapy (90).

Cordyceps sinensis, traditionally used in East Asian medicine, has been investigated in pilot clinical studies for cancer-related fatigue, immune suppression, and treatment tolerance. Findings suggest improvements in immune parameters, exercise capacity, and quality of life in cancer patients receiving conventional therapies (91). Together, these species represent a clinically important category of medicinal mushrooms with supportive roles in oncology.

5.1.6 Pleurotus spp. (Oyster Mushrooms)

Polysaccharides and β-glucans from Pleurotus ostreatus (Jacq.) P. Kumm. (oyster mushroom) have demonstrated immunomodulatory effects that may support immune function in oncology patients. Preclinical and clinical studies indicate that Pleurotus polysaccharides can enhance natural killer (NK) cell activity, modulate cytokine production (including IFN-γ and TNF-α), and improve leukocyte recovery during chemotherapy, suggesting a supportive role in maintaining immune competence (92, 93). In addition, clinical studies show that Pleurotus supplementation may improve mitigate treatment-induced immunosuppression, providing translational evidence for its use as an adjunct in integrative oncology (94). Collectively, these findings support further research into Pleurotus extracts as immune-supportive agents in cancer care.

5.1.7 Agaricus blazei (Murrill)

Agaricus blazei polysaccharides have been evaluated in clinical studies involving cancer patients receiving chemotherapy. Reported outcomes include increased NK-cell activity, improved hematological parameters, reduced fatigue, and enhanced immune responsiveness (95).

While variability exists between preparations, Agaricus blazei demonstrates consistent immune-supportive effects and a favorable safety profile in integrative oncology (96).

5.1.8 Additional Medicinal Mushrooms

Additional medicinal mushrooms, including Hericium erinaceus (Bull.) Pers. (Lion's Mane) (97), Inonotus obliquus (Fr.) Pilat. (Chaga) (98), and other less-studied species (58), have been evaluated in pilot clinical studies and observational trials. These studies suggest potential benefits in immune regulation, mitigation of chemotherapy-induced toxicity, and improvement of neurological or gastrointestinal symptoms in cancer patients. (58).

Despite promising results, many studies are limited by small sample sizes, heterogeneous preparations, and short follow-up periods, highlighting the need for further high-quality clinical trials.

5.2 Safety, tolerability and interactions

Medicinal mushrooms are generally well-tolerated in cancer patients, with most studies reporting only mild and transient adverse effects, such as gastrointestinal discomfort, bloating, or rash. Serious adverse events are rare, particularly when standardized extracts are used at clinically studied doses (89, 99). Importantly, immune-enhancing mushrooms such as Trametes versicolor (PSK/PSP) and Grifola frondosa (Maitake D-fraction) have not been associated with significant hematological or hepatic toxicity in clinical trials (82, 87).

While the safety profile is favorable, caution is advised in certain populations. Patients receiving immunosuppressive therapy, anticoagulants, or chemotherapeutic agents with narrow therapeutic indices should consult healthcare professionals before initiating mushroom supplementation, as potential interactions may alter drug metabolism or immune responses (100, 101). Additionally, individuals with known allergies to fungi or with autoimmune disorders should be monitored carefully when considering immunomodulatory mushroom extracts (102).

The mechanistic evidence of sections 3–5 is summarized in Table 1 providing a conceptual overview of the relationships between cancer hallmarks, signaling pathways influenced by medicinal mushrooms, and conventional chemotherapeutic agents targeting similar biological processes. The table is intended as a visual synthesis of the mechanisms discussed in sections 3–5, allowing readers to easily compare key pathways and therapeutic strategies. Due to the large number of mushroom species reported to influence these pathways, individual species are not listed in the table. Species-specific mechanisms and supporting references are discussed in detail in relevant sections of the text. Information derives primarily from in vitro and in vivo experimental studies. Clinical trials of medicinal mushrooms in oncology have generally focused on clinical outcomes and immune parameters rather than direct validation of specific molecular pathways. Parentheses indicate corresponding 2026 Hallmarks categories [Functional capabilities, Enabling Phenotypic characteristics and Hallmark-facilitating / hallmark-conveying cells in the tumor microenvironment (TME)] providing conceptual alignment with the updated framework.

Table 1. Integrative summary of cancer hallmarks, medicinal mushroom actions and chemotherapeutic mechanisms (Hanahan D. 2026 framework), summarizing mechanisms discussed in Sections 3–5.

The listed mechanisms reflect the bioactivities of multiple medicinal mushrooms across pre-clinical and clinical studies.

Overall, the available clinical data support the use of medicinal mushrooms as adjuncts in oncology, provided that attention is given to standardized dosing, patient comorbidities, and concomitant medications. This foundational understanding of safety and tolerability provides the basis for informed evaluation of mushroom integration with conventional chemotherapeutic regimens, discussed in Chapter 6.

6 Integration of medicinal mushrooms with chemotherapy

Cancer treatment with chemotherapy often leads to significant collateral effects on the immune system, hematopoiesis, mucosal integrity, and overall patient wellbeing. Conventional cytotoxic agents, while targeting rapidly dividing tumor cells, also affect normal proliferative tissues, resulting in immune suppression, (Suppression of NK cell activity, T-cell function, antigen presentation) bone marrow toxicity (neutropenia, leukopenia), and impaired quality of life due to fatigue, nausea, mucositis, and general malaise. These effects can limit dose intensity, delay treatment cycles, and contribute to treatment discontinuation (7, 9, 103).

Medicinal mushrooms, rich in immunomodulatory polysaccharides and other bioactive compounds, have been explored not as direct cytotoxic agents but as supportive care interventions that may help preserve or restore immune function and ameliorate therapy-related adverse effects. The integration of mushrooms with conventional chemotherapy should be understood within the context of supportive care, not as a replacement for cytotoxic therapy, but as a complementary adjunct that may enhance tolerability and maintain host resilience (7, 9, 103).

6.1 Rationale for integration with chemotherapy

Chemotherapy is essential for cytoreduction and tumor control, but its effects extend beyond cancer cells. Immune suppression is a frequent consequence, with reduced NK cell cytotoxicity, impaired T-cell responses, and disrupted antigen presentation pathways, which increase susceptibility to infections and limit anti-tumor immune surveillance. In addition, myelosuppression manifests as leukopenia and neutropenia and represents one of the most common dose-limiting toxicities of chemotherapeutic regimens, often necessitating dose delays or growth factor support. Gastrointestinal mucositis, nausea, altered appetite, and dysbiosis further compromise patient comfort and nutrition. Fatigue, cognitive fog, and general malaise are commonly reported, affecting quality of life and treatment adherence even when tumor response is objectively significant (7, 9, 49, 104).

Medicinal mushrooms, particularly those containing β-glucans and other complex polysaccharides, interact with pattern recognition receptors such as Dectin-1, TLR2 and TLR4, and CR3 on innate immune cells, supporting targeted immune modulation rather than indiscriminate stimulation. This can help maintain immune competence during cytotoxic stress, potentially reducing infection risk and contributing to better overall treatment tolerance (7, 9). By addressing immune suppression and some aspects of treatment-related toxicity, medicinal mushrooms offer a complementary strategy that may enhance patient resilience and optimize the therapeutic window of chemotherapy.

6.2 Immunological support during chemotherapy

The immune system is a key battleground during cancer therapy. Chemotherapy-induced declines in NK activity, Th1 signaling, and antigen presentation reduce immunogenic tumor clearance and impede host defense (9).

Medicinal mushrooms offer immunological support via well-characterized mechanisms:

β-glucans from mushrooms such as Trametes versicolor, Grifola frondosa, and Lentinula edodes engage Dectin-1 and TLR on macrophages and dendritic cells, promoting maturation, cytokine production, and antigen presentation.

Enhanced NK cell activity and modulation of Th1-biased responses have been documented in clinical contexts, often correlating with better infection control and improved host immune surveillance (9, 49).

Rather than causing blind immune stimulation, mushroom β-glucans act as immune response modifiers, fine-tuning cellular immunity to support host resilience under chemotherapeutic stress (49, 105).

Clinical data and systematic reviews suggest that the adjunctive use of mushroom supplements during chemotherapy is associated with favorable trends in immune markers and quality of life metrics, though larger and more rigorous trials are needed to confirm effects on long-term clinical outcomes such as disease-free survival (9, 103, 105).

6.3 Hematological and bone marrow support

Bone marrow suppression is a prime concern during chemotherapy, manifesting as neutropenia, leukopenia, and compromised hematopoiesis. While growth factors (e.g., G-CSF) are standard interventions, supportive agents that can help mitigate cytopenias and enhance hematological recovery remain clinically valuable. (9, 49).

Medicinal mushrooms have shown promise in this area:

Clinical and observational evidence from systematic reviews indicates that mushroom supplementation during chemotherapy is associated with reduced severity of leukopenia and neutropenia, potentially contributing to more consistent treatment delivery and fewer dose delays (9, 105).

Mushroom extracts rich in β-glucans and proteoglycans may support bone marrow cellularity indirectly via immune modulation and reduction of systemic inflammatory stress (7, 49).

Importantly, mushrooms are not replacements for standard hematological support agents (e.g., G-CSF) but may act as complementary agents that promote overall hematologic resilience, potentially easing the severity of blood count declines during cytotoxic therapy (7, 9).

6.4 Gastrointestinal protection and systemic inflammation

Chemotherapy frequently injures the gastrointestinal (GI) mucosa, causing mucositis, increased intestinal permeability and, in some cases, bacterial translocation that promotes systemic inflammation and endotoxemia. These processes contribute to treatment-related morbidity (e.g., severe diarrhea, malabsorption, infection risk) and to systemic symptoms such as fatigue and reduced functional status, which can compromise the ability to complete planned chemotherapy regimens (9, 76).

Medicinal mushroom polysaccharides and related compounds can act on several levels that are mechanistically relevant to chemotherapy-induced GI injury:

• Enhancement of intestinal barrier function. Animal and cellular studies indicate that certain mushroom polysaccharides (e.g., from Ganoderma lucidum) promote epithelial restitution, increase mucin production and upregulate tight-junction proteins (claudin, occludin), thereby reducing permeability after chemical or drug-induced injury. These barrier-protective effects reduce translocation of microbial products that drive systemic inflammation (104, 106).
• Prebiotic modulation of the gut microbiome. Non-digestible mushroom polysaccharides serve as fermentable substrates for beneficial commensals and can increase short-chain fatty acid production (butyrate, propionate). Changes in microbiome composition toward health-associated taxa have been reported after mushroom polysaccharide supplementation, which may attenuate chemotherapy-associated dysbiosis and its downstream pro-inflammatory consequences (76).
• Reduction of systemic inflammation. By strengthening barrier integrity and shifting the microbiome, mushroom extracts can lower circulating inflammatory mediators in pre-clinical models and are associated with improved inflammatory cytokine profiles in some clinical reports. Reduced systemic inflammation may translate into less fatigue, improved appetite, and better overall patient functioning during treatment (9, 76).

Clinical implication. While high-quality randomized trials directly assessing mucosal protection in humans receiving chemotherapy are still limited, the mechanistic data combined with clinical signals for improved GI symptoms and patient wellbeing support the rational, supervised use of standardized mushroom extracts as adjunctive measures to help preserve GI integrity and reduce systemic inflammatory burden during cytotoxic therapy. [See clinical evidence reviews and trials summarized in (9, 99)].

6.5 Quality of life and treatment tolerability

Quality of life (QoL) domains; fatigue, appetite, physical function, and psychological wellbeing, are key determinants of a patient's ability to adhere to and complete chemotherapy. Improvements in QoL can directly affect treatment intensity (fewer dose delays or reductions) and thus potentially influence oncologic outcomes.

Evidence for mushrooms and QoL during chemotherapy:

• Clinical signals of benefit; Several randomized and observational studies report that adjunctive use of medicinal mushroom extracts (notably Trametes versicolor extracts, Ganoderma lucidum preparations and others) is associated with improvements in fatigue, appetite, and patient-reported QoL indices compared with control or baseline measures. Systematic reviews also identify consistent positive trends, though heterogeneity in products, doses and endpoints limits definitive conclusions (9, 99).
• Mechanistic links; The putative mechanisms by which mushrooms improve QoL include immune-modulation (reducing infection and inflammation), antioxidant activity (mitigating oxidative stress induced by chemotherapy), and preservation of gut integrity (reducing GI symptoms that impair nutrition). These mechanisms are complementary to, and distinct from, the cytotoxic mechanisms of chemotherapy, supporting a supportive-care role rather than a competing therapeutic aim (76, 99).
• Clinical implication; For oncologists, the available data support that carefully selected, standardized mushroom extracts can be considered as adjunctive interventions to improve QoL and tolerability during chemotherapy, provided that product quality, dosing and patient comorbidities are taken into account. Larger, well-designed RCTs using standardized QoL instruments are still warranted to quantify effect sizes and to define which patient subgroups derive the most benefit (9, 99).

6.6 Safety considerations and timing with chemotherapy

When counseling patients and integrating mushroom extracts into chemotherapy care, clinicians should balance potential supportive benefits against safety considerations and practical logistics. Key practical points:

• Prefer standardized preparations with documented composition; Variability between commercial products is substantial; prefer formulations used in clinical studies or from reputable manufacturers with standardized assays of β-glucan content and contaminant testing (9).
• Timing and co-administration; There is no universal rule that applies to all mushroom products; most clinical studies administered extracts continuously during chemotherapy cycles. For agents with known narrow therapeutic windows or that are highly myelotoxic, consider coordinating timing with the oncology team and monitoring blood counts more closely during initial combined use. There is limited evidence that temporary spacing (e.g., taking the supplement on non-infusion days) is necessary, but this may be reasonable as a precaution in complex polypharmacy scenarios (9, 99).
• Drug-supplement interactions; Significant pharmacokinetic interactions between mushroom polysaccharide extracts and conventional chemotherapeutics are not well documented; however, theoretical interactions exist (e.g., modulation of cytochrome P450 enzymes by some secondary metabolites). Clinicians should review concomitant medications (including anticoagulants, immunosuppressants) and monitor for unexpected toxicity. When in doubt, coordinate with the treating oncologist or a clinical pharmacist (9).
• Autoimmune disease and immunotherapy caution; In patients with active autoimmune disorders or those receiving immune-stimulatory biologics, exercise caution, monitor disease activity closely, as case reports describe immune-related exacerbations potentially temporally associated with fungal supplements. For patients on immune checkpoint inhibitors, current data are limited and warrant individualized consideration and close surveillance (7, 9).
• Clinical implication; Safety data from clinical studies are overall reassuring for standardized mushroom extracts in oncology patients, but good clinical practice requires product selection, clear documentation in the medical record, baseline allergy and medication review, and periodic monitoring (CBC, liver enzymes) during combined therapy (9, 99).

6.7 Clinical perspective: integrative oncology approach

Medicinal mushrooms are not an alternative to chemotherapy; rather, they are evidence-supported supportive adjuncts that may improve tolerability, help preserve immune function, reduce some treatment-related symptoms, and enhance patient quality of life. The strongest rationale for integration is mechanistic complementarity (immune and mucosal protection, microbiome modulation, antioxidant activity) together with signals from clinical studies showing improved patient-reported outcomes and immune biomarkers. Practical pathway for integration (recommended clinical checklist):

• Confirm the clinical objective (e.g., reduce fatigue, support leukocyte recovery, mitigate GI symptoms).
• Select a standardized extract with clinical evidence for the intended objective.
• Review patient allergies, autoimmune history, and concomitant medications.
• Document start date, product, dose, and monitoring plan (CBC, LFTs as clinically indicated).
• Communicate the plan with the oncology multidisciplinary team and reassess at scheduled intervals.

This pragmatic, safety-first approach allows oncologists to offer mechanistically rational supportive care without compromising standard oncologic management. The next chapter (Discussion) will synthesize these practical recommendations with the mechanistic evidence and outline research priorities to strengthen the clinical evidence base.

7 Discussion and conclusions

This review integrates mechanistic, pre-clinical, and clinical evidence to contextualize the role of medicinal mushrooms within modern oncology, specifically alongside conventional chemotherapy. By mapping both chemotherapy and mushroom-derived compounds onto the framework of cancer hallmarks, several key insights emerge regarding overlap, complementarity, and translational relevance.

Chemotherapy is not a single-mechanism intervention. As outlined in Chapters 2 and 3, cytotoxic agents exert pleiotropic effects across multiple hallmarks of cancer, including induction of apoptosis, disruption of proliferative signaling, metabolic stress, modulation of angiogenesis, immune activation through immunogenic cell death, and remodeling of the tumor microenvironment. These effects are accompanied by predictable collateral damage to rapidly proliferating healthy tissues, immune suppression, mucosal injury, and systemic inflammation, which collectively limit dose intensity and treatment adherence.

Medicinal mushrooms occupy a fundamentally different therapeutic niche. Rather than directly targeting tumor cell proliferation, mushroom-derived β-glucans, polysaccharopeptides, and secondary metabolites primarily act as immune response modifiers and microenvironmental regulators. Their biological activity spans multiple hallmarks, particularly immune evasion, tumor-promoting inflammation, metabolic deregulation, angiogenesis, and microbiome-related processes, many of which are only partially or indirectly affected by chemotherapy. This distinction underpins the mechanistic rationale for combination rather than substitution.

A central theme emerging from this synthesis is mechanistic complementarity. Chemotherapy induces tumor cell stress and death, including immunogenic cell death in selected regimens, while medicinal mushrooms may support the host's capacity to respond to this stress by preserving innate and adaptive immune function, maintaining mucosal integrity, and limiting excessive systemic inflammation. This complementary interaction is especially evident in immune-related hallmarks: chemotherapy can expose tumor antigens and danger signals, whereas mushroom polysaccharides enhance antigen presentation, NK-cell activity, and Th1-biased responses without indiscriminate immune overstimulation.

From a clinical perspective, the strongest and most consistent evidence for medicinal mushrooms lies not in direct antitumor cytotoxicity, but in supportive outcomes. These include improved immune parameters, mitigation of chemotherapy-induced leukopenia, better gastrointestinal tolerance, reduced fatigue, and enhanced quality of life. Importantly, quality of life should not be viewed as a secondary endpoint; fatigue, mucositis, and systemic inflammation directly influence treatment adherence, dose reductions, cycle delays, and ultimately clinical outcomes. Supportive interventions that preserve host resilience may thus have downstream effects on oncologic efficacy, even without directly shrinking tumors.

The gastrointestinal tract emerges as a particularly relevant interface for integration. Chemotherapy-induced mucosal injury, increased intestinal permeability, dysbiosis, and endotoxemia contribute to systemic inflammation and symptom burden. Mushroom polysaccharides, through barrier-protective, pre-biotic, and anti-inflammatory mechanisms, offer a biologically plausible strategy to attenuate this cascade. Although direct clinical trials focusing on GI endpoints remain limited, converging mechanistic and clinical signals justify further investigation in this domain.

Safety considerations are central to any integrative oncology approach. Available clinical literature indicates that standardized medicinal mushroom extracts are generally well tolerated when used alongside chemotherapy, with low rates of serious adverse events. Nevertheless, heterogeneity in commercial preparations, variability in dosing, and limited pharmacokinetic interaction data necessitate a cautious, clinician-guided approach. Coordination with oncology teams, attention to autoimmune conditions, and preference for standardized products used in clinical trials are essential to responsible integration.

Several limitations of the current evidence base warrant acknowledgment. Many clinical studies are small, heterogeneous, and conducted pre-dominantly in East Asian populations, where specific extracts such as PSK are part of standard care. Outcomes often focus on immune markers or quality of life rather than hard oncologic endpoints, and product standardization remains a challenge. These limitations preclude definitive conclusions regarding survival benefits in most cancer types, but do not negate the consistent signal that mushrooms function as supportive agents rather than antagonists to chemotherapy.

Future research should prioritize well-designed randomized controlled trials that integrate mechanistic biomarkers with clinically meaningful endpoints, including treatment adherence, toxicity profiles, and patient-reported outcomes. Studies examining interactions with modern regimens, such as targeted therapies and immune checkpoint inhibitors, are particularly needed. Additionally, greater attention to microbiome-mediated mechanisms and patient stratification may help identify subgroups most likely to benefit from mushroom-based interventions.

In conclusion, medicinal mushrooms should not be framed as alternatives to chemotherapy, nor as non-specific immune stimulants. Rather, they represent a class of biologically active, mechanism-informed supportive agents that may complement cytotoxic therapy by reinforcing immune competence, preserving mucosal integrity, modulating inflammation, and improving quality of life. Polysaccharide-rich mushroom extracts, including those derived from Trametes versicolor, Lentinula edodes, Grifola frondosa, and Ganoderma lucidum, demonstrate consistent immunomodulatory effects across clinical settings, with favorable impacts on immune parameters, treatment tolerability, and patient-reported outcomes.

When integrated thoughtfully and responsibly, medicinal mushrooms align with the principles of evidence-based integrative oncology. While robust survival benefits have been most clearly demonstrated for PSK and PSP in specific cancer types, the broader body of evidence supports their use to enhance host resilience, optimize the therapeutic window of conventional treatments, and improve treatment adherence and quality of life. The accumulated mechanistic, pre-clinical, and clinical evidence underscores the potential of medicinal mushrooms as a promising adjunctive strategy within contemporary cancer care, warranting continued investigation and standardized clinical integration.

Generative AI statement

The author(s) declared that generative AI was not used in the creation of this manuscript.

Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.

Publisher's note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Footnotes

Edited by: Agustín Sánchez-Cobos, Independent Researcher, Elx/Elche, Spain

Reviewed by: Massimo Tacchini, University of Ferrara, Italy

Vijaya Deshmukh, MGM University, India