Advances in immunotherapy for colorectal cancer: overcoming resistance in mismatch repair-proficient tumors

Colorectal cancer (CRC) is the second leading cause of cancer-related mortality worldwide. Immune checkpoint inhibitors (ICIs) have transformed outcomes for the ~ 5% of CRC patients with mismatch repair deficiency or microsatellite instability-high (dMMR/MSI-H) tumors, delivering durable responses in metastatic and early-stage disease. However, the vast majority of CRCs are mismatch repair-proficient and microsatellite stable (pMMR/MSS), characterized by low tumor mutational burden, sparse immune infiltration, and an immunosuppressive tumor microenvironment, features that confer resistance to current immunotherapies. Bridging this efficacy gap requires a translational roadmap focused on “heating up” immune-cold tumors. Promising strategies include combination checkpoint blockade (PD-1 with CTLA-4, LAG-3, or TIGIT inhibitors), tumor microenvironment modulation via VEGF inhibition and anti-angiogenics, integration of targeted therapies (KRAS-G12C, BRAF, MEK inhibitors) with ICIs, neoantigen-based vaccines, oncolytic viruses, and microbiome manipulation. Biomarker-guided patient selection with incorporating circulating tumor DNA, Immunoscore, and Consensus Molecular Subtypes will be critical to optimize therapeutic sequencing and minimize toxicity. Early-phase trials combining these approaches in MSS CRC show encouraging activity, while neoadjuvant and adjuvant immunotherapy in MSI-H disease redefines treatment paradigms, with some patients achieving complete responses without surgery. This review synthesizes the current evidence and emerging innovations in CRC immunotherapy and proposes a structured translational framework to extend immunotherapy benefits beyond the MSI-H subset.