Repeated Phase 3 failures have framed proficient mismatch repair/microsatellite stable colorectal cancer as 'cold' and immunotherapy-resistant. We argue that this resistance is conditional, shaped by disease stage, metastatic anatomy, spatial immune architecture, and therapeutic mechanism. Recognizing these principles can guide patient selection, biomarker stratification, and drug development to realize immunotherapy's clinical potential.
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Beiter et al. (2026) studied this question.
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