# Biomarker guided combination strategies and perioperative integration for immune cold microsatellite stable colorectal cancer

## TL;DR

This paper explores strategies to convert immune-cold microsatellite stable colorectal cancer into immune-responsive states using combination therapies and biomarker guidance.

## Contribution

The paper introduces novel frameworks for biomarker-guided treatment selection and perioperative integration in MSS CRC.

## Key findings

- Combination therapies like anti-angiogenic/VEGFR + ICI show progression-free survival benefits in some MSS CRC cases.
- Dual-checkpoint inhibitors demonstrate durable responses in pretreated MSS mCRC patients.
- Biomarker-anchored selection and perioperative integration may improve outcomes in biologically selected MSS CRC contexts.

## Abstract

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.