Immunotherapy resistance in colorectal cancer: therapeutic strategies and biomarker-guided approaches

Overcoming immunotherapy resistance remains a major challenge in colorectal cancer (CRC), particularly because most tumors are microsatellite stable/proficient mismatch repair (MSS/pMMR) and respond poorly to immune checkpoint inhibitors (ICIs). In contrast, deficient mismatch repair/high microsatellite instability (dMMR/MSI-H) tumors show greater sensitivity to PD-1/PD-L1 and CTLA-4 blockade due to high tumor mutational burden, neoantigen generation, and immune-inflamed tumor microenvironments. However, both primary and acquired resistance continue to limit durable clinical benefit. Resistance arises from tumor-intrinsic mechanisms, including impaired antigen presentation, MHC-I downregulation, oncogenic signaling, and chromatin remodeling defects, as well as tumor-extrinsic mechanisms such as immune suppression, stromal exclusion, inhibitory cytokines, metabolic stress, and gut microbiome dysbiosis. This review distinguishes itself by linking specific resistance barriers to therapeutic strategies rather than discussing immunotherapy approaches in isolation. We summarize emerging strategies, including rational ICI combinations, targeted therapies, adoptive cell therapies, CAR-T cells, BiTEs, cancer vaccines, oncolytic viruses, microbiome-modulating approaches, and cytokine/adjuvant-based therapies. We also highlight clinically relevant biomarkers, including MSI/MMR status, tumor mutational burden, immune contexture, Immunoscore, circulating tumor DNA, microbiome profiles, and spatial or AI-assisted multi-marker models. This review summarizes emerging strategies to enhance therapeutic efficacy in CRC and maps each modality to the tumor-intrinsic or tumor-extrinsic resistance barriers it is most likely to overcome.