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Most colorectal cancers (CRC) are microsatellite stable (MSS) and show little benefit from single-agent immune checkpoint inhibition (ICI). A rapidly expanding body of work now focuses on combination strategies to remodel the tumor microenvironment (TME) and convert immune-“cold” MSS disease into an immune-responsive state. We synthesize (i) biological liabilities that underpin MSS immune resistance; (ii) clinical evidence across key combination classes—anti-angiogenic/VEGFR + ICI (randomized AtezoTRIBE suggests a progression-free survival benefit when atezolizumab is added to FOLFOXIRI + bevacizumab), multikinase TKI + PD-1/PD-L1 (mixed activity and geographic/site heterogeneity; LEAP-017 was negative for overall survival), dual-checkpoint or next-generation CTLA-4 backbones (phase-1 botensilimab + balstilimab with durable responses in heavily pretreated MSS mCRC), EGFR- or HER2-targeted plus ICI (signals in molecularly defined subsets; e.g., CAVE rechallenge), and RT/ablation + ICI (biologically compelling but heterogeneous outcomes in pMMR-dominant settings). We emphasize biomarker-anchored selection—topology of disease (especially active liver metastases), inflammatory gene programs, and ctDNA kinetics—and propose peri-operative/oligometastatic integration frameworks relevant to surgical teams. Conclusions: Converting MSS CRC from cold to hot appears feasible in biologically selected contexts and with rational sequences. The next wave should stratify by liver involvement, embed ctDNA-anchored endpoints, and leverage surgery-embedded window studies to verify on-treatment immune conditioning.
Yao et al. (2026) studied this question.