Breaching the immune-cold barrier in pMMR/MSS metastatic colorectal cancer: emerging strategies beyond standard care

Mismatch repair–proficient (pMMR) or microsatellite stable (MSS) metastatic colorectal cancer (mCRC) remains largely refractory to immunotherapy due to its intrinsically immunologically cold tumor microenvironment. Although frontline chemotherapy combined with immune-induction strategies can improve progression-free survival, these benefits have not translated into overall survival gains. Importantly, late-line trials such as LEAP-017 suggest that biologically meaningful immune activity may be masked by dilution effects in unselected populations. This review advocates a shift from empirical treatment approaches toward mechanism-driven precision stratification in refractory pMMR/MSS mCRC. We highlight two complementary immune activation strategies: tumor microenvironment remodeling via tyrosine kinase inhibitor-mediated vascular normalization, and intensified immune priming through cytotoxic T-lymphocyte-associated protein 4 blockade. To address persistently low response rates, we propose an integrated precision framework incorporating genomic repurposing, anatomical filtering, and multimodal synergy, aiming to translate transient immune activation into durable survival benefit.