Overcoming immune exclusion: remodeling the tumor microenvironment to enhance cancer immunotherapy efficacy

The field of cancer immunotherapy has transformed modern oncology through the implementation of immune checkpoint inhibitors, adoptive cell therapies, and cancer vaccines. Nevertheless, their therapeutic success remains limited across many solid tumors due to the phenomenon of immune exclusion, whereby effector immune cells fail to penetrate or function effectively within the tumor microenvironment (TME). This state of exclusion is driven by multifactorial mechanisms, including architectural barriers formed by a dense extracellular matrix, immunosuppressive cell populations such as Tregs, myeloid-derived suppressor cells, and tumor-associated macrophages, as well as inhibitory signaling molecules like PD-L1, TGF-β, and adenosine. Although efforts to revert such immune exclusion have intensified, the complexity of the TME continues to impede durable immune activation and response. Leveraging novel tools—such as targeted protein degradation, ubiquitination modulation, and advanced biomarker-guided combination regimens—presents transformative potential to remodel the TME and expand immunotherapy benefits to a broader patient population.This Research Topic aims to integrate fundamental, translational, and clinical insights centered on overcoming immune exclusion and reprogramming the TME to enhance cancer immunotherapy. It encourages studies that dissect the molecular, cellular, and stromal mechanisms underlying tumor immune evasion, alongside innovations that repurpose or combine modalities to break TME-imposed barriers. Contributions may highlight novel pharmacological strategies—such as protein degraders (PROTACs, molecular glues), deubiquitinase inhibitors, small molecules, cytokine-based interventions, chemotherapy, or radiotherapy—that restore immune access and functionality. In addition, submissions exploring synergistic frameworks with checkpoint inhibitors, CAR-T or NK-cell therapies, as well as biomarker discovery and clinical translation of TME-targeted interventions, are especially welcomed. Ultimately, this Research Topic seeks to foster cross-disciplinary collaboration to accelerate the bench-to-bedside translation of TME-modulating immunotherapies across tumor types. To gather further insights into strategies that mitigate immune exclusion and remodel the TME across diverse oncologic contexts, we welcome articles addressing, but not limited to, the following themes:• Mechanistic studies defining physical, metabolic, and signaling barriers that restrict immune infiltration in solid and hematologic malignancies• Preclinical and translational research on immunotherapy–TME-targeting combinations (e.g., degraders, inhibitors, cytokines, chemo- or radiotherapy)• Clinical investigations (phase I–II trials, retrospective cohorts, biomarker discovery) evaluating TME remodeling and immunotherapy outcomes• Identification and validation of actionable molecular targets (such as E3 ligases, deubiquitinases, matrix regulators, kinases, and transcription factors) controlling immune infiltration• Advanced omics, high-dimensional imaging, and spatial profiling technologies to characterize immune exclusion and predict therapeutic benefitWe welcome Original Research, Brief Research Reports, Reviews, Mini-Reviews, Clinical Trials, Case Reports, and Perspectives. Both basic mechanistic and clinically oriented manuscripts are strongly encouraged. Please note: Manuscripts consisting solely of bioinformatics or computational analysis of public genomic or transcriptomic databases which are not accompanied by validation (independent cohort or biological validation in vitro or in vivo) are out of scope for this section and will not be accepted as part of this Research Topic. Topic editors: Hongbin Wang, Jing Yang, Shang Xie, Peipei Zhou, Nahum Puebla-Osorio Source: https://www.frontiersin.org/research-topics/84203/overcoming-immune-exclusion-remodeling-the-tumor-microenvironment-to-enhance-cancer-immunotherapy-efficacy