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

## TL;DR

This paper explores new strategies to improve immunotherapy for a type of colorectal cancer that typically responds poorly to treatment.

## Contribution

The paper proposes a precision framework combining immune activation and genomic strategies to enhance treatment outcomes in pMMR/MSS mCRC.

## Key findings

- Frontline chemotherapy with immune-induction strategies improves progression-free survival but not overall survival.
- Late-line trials suggest immune activity may be diluted in unselected patient populations.
- Integrated precision strategies aim to convert transient immune activation into durable survival benefits.

## Abstract

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.