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Overcoming conditional immune resistance in MSS and pMMR colorectal cancer: A sequential gating framework for
Husni Farah1, Djamila Polatova2, Jasur Rizaev3
1Faculty of Allied Medical Sciences, Hourani Center for Applied Scientific Research, Al-Ahliyya Amman University, Amman, Jordan.
Abstract:
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.
Insights
Microsatellite stable colorectal cancer (CRC) is resistant to immunotherapy due to immune cell access issues, not indifference. Addressing these sequential "immune gating" steps is key for effective treatment.
Area of Science:
- Oncology
- Immunology
- Cancer Research
Background:
- Microsatellite stable (MSS) and mismatch repair proficient (pMMR) colorectal cancer (CRC) is the largest patient group receiving immune checkpoint inhibitors (ICIs).
- This MSS/pMMR CRC subtype largely remains refractory to ICIs, with resistance often attributed to low tumor mutational burden or neoantigenicity.
- However, emerging data show immune cell infiltration, antigen expression, and immune signaling in many MSS tumors, challenging intrinsic immune indifference as the sole explanation for resistance.
Purpose of the Study:
- To propose that immunotherapy failure in MSS/pMMR CRC is due to a hierarchical immune gating problem.
- To outline a sequential model of immune resistance involving priming, effector cell access, and suppression.
- To provide a framework for developing combination therapies and treatment strategies for MSS/pMMR CRC.
Main Methods:
- Review of clinical, transcriptional, and spatial profiling data.
- Analysis of mechanisms contributing to immune resistance in MSS/pMMR CRC.
- Synthesis of existing and emerging therapeutic strategies targeting immune evasion.
Main Results:
- A sequential model of immune gating is proposed, where immune priming, physical access, and suppression are rate-limiting steps.
- This model reconciles historical clinical trial outcomes with recent successes in combination therapies.
- Therapeutic strategies like epigenetic priming, stromal remodeling, myeloid reprogramming, and microbiome modulation show promise.
Conclusions:
- Immunotherapy resistance in MSS/pMMR CRC is a dynamically enforced immune state, not intrinsic indifference.
- Relieving sequential immune gating barriers is crucial for ICI efficacy.
- This framework supports rational combination therapy, optimized sequencing, and biomarker development for MSS/pMMR CRC immunotherapy.
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