Molecular mechanisms of cancer metastasis: Tumor–microenvironment crosstalk and therapeutic opportunities

Cancer metastasis is responsible for nearly 90% of cancer-related deaths and remains one of the greatest challenges in oncology worldwide. Although substantial progress has been made in understanding tumor biology and developing targeted therapies, effective treatment of metastatic disease remains limited by the remarkable complexity and heterogeneity of metastatic tumors and their surrounding microenvironment.Increasing evidence indicates that metastasis is not driven solely by intrinsic genetic and epigenetic alterations within tumor cells but is critically regulated by dynamic interactions between tumor cells and the tumor microenvironment. Immune regulation represents a central component of this crosstalk, influencing nearly every stage of the metastatic cascade, including tumor cell dissemination, metastatic niche formation, immune surveillance and escape, metastatic colonization, dormancy, therapeutic resistance, and disease recurrence. The metastatic microenvironment consists of diverse cellular and extracellular components, including T cells, B cells, natural killer cells, macrophages, neutrophils, myeloid-derived suppressor cells, cancer-associated fibroblasts, endothelial cells, extracellular matrix (ECM), and tissue-specific resident cells. Their interactions can either promote antitumor immunity or create an immunosuppressive environment that supports metastatic progression.Brain, lung, liver, bone, and lymph node metastases originate from tumor cells that detach from a primary tumor, disseminate through blood or lymphatic circulation, and ultimately colonize distant organs. Importantly, the immune landscape differs substantially among these metastatic sites and can determine whether disseminated tumor cells are eliminated, remain dormant, or successfully establish metastatic lesions. Understanding how tumor cells interact with tissue-specific immune and stromal populations is therefore essential for defining the mechanisms underlying organ-specific metastasis. In particular, the brain microenvironment presents unique immunological and cellular characteristics that can influence metastatic colonization, immune surveillance, therapeutic response, and disease progression.Recent technological advances have transformed metastasis research by enabling comprehensive characterization of the tumor–immune ecosystem. Single-cell and spatial transcriptomics, proteomics, metabolomics, epigenomics, advanced imaging, artificial intelligence-driven data analysis, and multi-omics integration have provided unprecedented insights into tumor heterogeneity and the spatial and functional organization of immune cells within metastatic lesions. These approaches are revealing how signaling pathways, stromal cells, ECM remodeling, metabolic alterations, and cell–cell communication shape immune-cell recruitment, localization, activation, exhaustion, suppression, and antitumor function.The role of stromal biology and ECM remodeling is particularly important in regulating immune responses during metastasis. Changes in ECM composition, stiffness, and architecture can influence immune-cell trafficking, infiltration, positioning, and functional activity within metastatic tumors. Similarly, cancer-associated fibroblasts and other stromal populations can regulate chemokine and cytokine signaling, establish physical and biochemical barriers to immune-cell infiltration, and contribute to an immunosuppressive metastatic niche. Understanding these processes may reveal opportunities to remodel the tumor microenvironment and improve responses to immunotherapy.In parallel, tumor-associated signaling pathways and metabolic programs can profoundly influence antitumor immunity. Oncogenic signaling may promote immune evasion and suppress immune-cell function, whereas alterations in nutrient availability, hypoxia, lipid metabolism, and cellular metabolism can determine the functional state of both tumor and immune cells. These mechanisms may contribute to immune dysfunction and resistance to immune-based therapies. Extracellular vesicles and other forms of intercellular communication further contribute to metastatic progression by transferring molecular signals between tumor cells, immune cells, and stromal populations.Innovative experimental platforms, including patient-derived organoids, organ-on-chip systems, patient-derived xenografts, and genetically engineered mouse models, have further accelerated investigation of tumor–immune interactions and metastatic progression. These models provide opportunities to investigate how specific immune and microenvironmental mechanisms contribute to metastatic colonization and to evaluate therapeutic strategies designed to restore antitumor immune responses.Despite these advances, many fundamental questions remain unanswered regarding the mechanisms that regulate organ-specific metastasis, metastatic niche formation, immune-cell trafficking and positioning, immune suppression and dysfunction, metabolic reprogramming, tumor dormancy, and resistance to immunotherapy and other anticancer treatments. Addressing these challenges requires multidisciplinary approaches that integrate cancer biology, immunology, stromal biology, computational biology, pharmacology, translational research, and clinical oncology.This Research Topic aims to provide a comprehensive platform for disseminating cutting-edge discoveries that advance our understanding of immune regulation within the metastatic tumor microenvironment and promote the development of innovative therapeutic interventions. We welcome original research articles, reviews, perspectives, and clinical studies investigating molecular signaling pathways, immune regulation, stromal biology, ECM remodeling, angiogenesis, metabolic adaptation, extracellular vesicle-mediated communication, immune-cell trafficking, immune evasion, metastatic dormancy, biomarkers, and mechanisms of therapeutic resistance.We particularly encourage submissions examining how these processes influence immune-cell infiltration, localization, activation, exhaustion, suppression, and antitumor function, as well as how the tumor microenvironment shapes responses to immunotherapy and combination treatment strategies. Contributions addressing advances in single-cell and spatial biology, multi-omics integration, artificial intelligence, computational modeling, precision oncology, and emerging preclinical models that provide new insights into tumor–immune interactions and metastatic disease are also strongly encouraged.By bringing together researchers from diverse disciplines, this Research Topic seeks to identify novel mechanisms underlying immune–tumor–microenvironment interactions during metastatic progression, foster interdisciplinary collaboration, and accelerate the translation of fundamental discoveries into effective diagnostic, prognostic, and therapeutic strategies. Ultimately, a deeper understanding of how the immune system interacts with tumor and stromal compartments across metastatic sites may enable the development of more effective approaches to prevent metastatic dissemination, overcome immune resistance, and improve outcomes for patients with metastatic cancer.Conflict of interest statement: Topic Editor Prof. Betül Karademir-Yılmaz is co-founder of Cellformatics Biotechnology Ltd. The remaining Topic Editors declare no competing interests with regard to the Research Topic subject. Topic editors: Narendra Kumar, Betul Karademir Yilmaz, JAYSHREE MISHRA Source: https://www.frontiersin.org/research-topics/84700/molecular-mechanisms-of-cancer-metastasis-tumor-microenvironment-crosstalk-and-therapeutic-opportunities