Mechanisms of immune resistance in the colorectal cancer tumor microenvironment: Insights from preclinical mouse models and emerging therapeutic strategies

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, with disease progression and treatment outcome tightly coupled to the complexity of its tumor immune microenvironment (TIME). Immune and stromal cells, extracellular matrix, vasculature, and gut microbiota collectively shape antitumor immunity, but also enforce immune evasion and therapeutic resistance, particularly in the predominant microsatellite-stable (MSS) subset that derives limited benefit from current immunotherapies. Preclinical mouse models have been indispensable for dissecting these mechanisms, enabling controlled interrogation of tissue-specific immune circuits, spatial organization, and resistance pathways that are difficult to study in patients. However, many models still incompletely recapitulate human CRC TIME heterogeneity and immune resistance, underscoring the need for integrated efforts that link mechanistic insights in vivo with emerging therapeutic strategies.This Research Topic aims to address the central challenge that most CRCs, especially MSS/proficient mismatch repair tumors, exhibit primary or acquired resistance to immune-based therapies despite the transformative success of immune checkpoint inhibitors in a small microsatellite-instability-high fraction. Resistance arises from modular, interdependent circuits within the TIME that integrate immunosuppressive cell populations, metabolic rewiring, stromal and vascular barriers, and adverse spatial architectures that exclude or exhaust effector T cells. Recent advances—including orthotopic and metastatic mouse CRC models, humanized and PDX systems, and sophisticated immune profiling—now permit high-resolution analysis of colon-specific immune signatures and treatment responses. Parallel progress in combination immunotherapies, macrophage and myeloid targeting, microbiome modulation, oncolytic platforms, and engineered cell therapies offers powerful tools to reprogram the TIME and overcome resistance. By bringing together mechanistic and translational studies in preclinical models, this Research Topic seeks to define actionable pathways of immune resistance and inform rational, multi-modal strategies that can be advanced toward clinical testing.We welcome Original Research, Review, Mini-Review, and Perspective articles that elucidate mechanisms of immune resistance in CRC using preclinical models. Themes of interest include: immune cell circuits (T cells, Tregs, myeloid and innate lymphoid populations), stromal and CAF-mediated immune exclusion, angiogenesis and vascular normalization, immune-metabolic interactions, and spatial organization of the TIME in relation to therapy response. Studies on gut and intratumoral microbiota, MSI-H versus MSS TIME heterogeneity, biomarker discovery, and rational combination strategies that re-sensitize resistant tumors are strongly encouraged. Submissions should integrate robust experimental validation—whether in vivo, ex vivo, or with independent cohorts—and clearly articulate translational relevance, in line with an emphasis on mechanistic insight beyond purely in silico analyses.Please note that manuscripts consisting solely of bioinformatics or computational analysis of public genomic or transcriptomic databases which are not accompanied by robust and relevant validation (clinical cohort or biological validation in vitro or in vivo) are out of scope for this Research Topic. Manuscripts focusing solely on cost-effectiveness studies are also not considered for publication in this journal.Topic Editor Neal Bhutiani declares to be the owner of patent -- 12109249 ("Compositions and methods for treating inflammation and cancer"), based in part upon his work as a PhD student. This has not been licensed or monetized. Also, he is in the scientific and clinical advisory board for Therapyx, Inc, providing scientific and clinical guidance to the company with no compensation of any kind received. Topic editors: Claudia Peitzsch, Neal Bhutiani, Dr. Samantha Sharma Source: https://www.frontiersin.org/research-topics/84704/mechanisms-of-immune-resistance-in-the-colorectal-cancer-tumor-microenvironment-insights-from-preclinical-mouse-models-and-emerging-therapeutic-strategies