Mechanisms and Emerging Strategies to Overcome Immunotherapy Resistance in Cold Tumours of Colorectal Cancer

Immunotherapy in colorectal cancer (CRC) presents a striking dichotomy. MSS/pMMR tumors account for approximately 95% of metastatic CRC cases, representing a substantial global health burden. While immune checkpoint inhibitors (ICIs) have revolutionized treatment for mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) metastatic CRC—achieving durable responses in tumors with high mutational burden and a T-cell-inflamed microenvironment—the majority of microsatellite stable (MSS) cases remain resistant. The MSS tumor microenvironment is typically “cold”, featuring low neoantigen load, poor T-cell infiltration, and dominant immunosuppressive networks. To overcome this resistance, extensive research is focused on combination strategies (ICIs with anti-angiogenic agents, targeted therapies, chemotherapy, radiotherapy) and next-generation modalities (adoptive cell therapies, bispecific antibodies, cancer vaccines). This review examines the biological basis for this dichotomy, summarizes clinical evidence in dMMR/MSI-H CRC, and critically assesses emerging strategies for MSS disease. We propose that future progress will likely depend on mechanism-based, biomarker-driven approaches that match specific immune evasion patterns with rationally designed interventions, with the goal of extending immunotherapy benefits to broader CRC populations. This narrative review synthesizes peer-reviewed literature from PubMed and clinical trial registries (2015– 2025), prioritizing Phase II/III trials and mechanistic studies.