Overcoming conditional immune resistance in MSS and pMMR colorectal cancer: A sequential gating framework for immunotherapy.

Microsatellite stable and mismatch repair proficient colorectal cancer (CRC) represents the largest population of patients exposed to immune checkpoint inhibitors, yet remains largely refractory to these therapies. Resistance is commonly attributed to low tumor mutational burden or limited neoantigenicity.

However, this explanation is insufficient in light of accumulating clinical, transcriptional, and spatial profiling data demonstrating the presence of immune cells, antigen expression, and inducible immune signaling in a substantial fraction of MSS tumors. In this Review, we propose that immunotherapy failure in MSS and pMMR CRC reflects a hierarchical immune gating problem rather than intrinsic immune indifference. We outline a sequential model in which immune priming, physical access of effector cells to tumor epithelial compartments, and suppression by stromal, myeloid, and metabolic programs constitute ordered and rate-limiting steps that must be relieved before immune checkpoint blockade can exert clinical activity. This framework reconciles decades of negative clinical trials with emerging conditional successes observed using epigenetic priming, stromal and vascular remodeling, myeloid reprogramming, and microbiome-modulating strategies.

By reframing resistance as a dynamically enforced and therapeutically tractable immune state, this Review provides a decision shaping framework for rational combination therapy, treatment sequencing, and biomarker guided immunotherapy development in MSS and pMMR CRC.