# Antigen Remodeling in Colorectal Cancer: How Radiotherapy and Chemotherapy Enhance Immunotherapy Responsiveness

## TL;DR

This paper explores how radiotherapy and chemotherapy can make colorectal cancer more responsive to immunotherapy by changing tumor antigens.

## Contribution

The paper introduces the concept of therapy-induced antigen remodeling as a novel mechanism to enhance immunotherapy in colorectal cancer.

## Key findings

- Radiotherapy and chemotherapy induce DNA damage and epigenetic changes that generate new neoepitopes.
- Combining cytotoxic therapies with immunotherapy improves responses in microsatellite-stable colorectal cancer.
- Short-course radiotherapy combined with chemotherapy and ICIs shows encouraging results in neoadjuvant treatment.

## Abstract

Colorectal cancer is often considered a “cold tumor” that responds poorly to immunotherapy. However, tumor antigenicity is not static and can be reshaped by cancer treatments. This review summarizes emerging evidence that chemoradiotherapy and chemotherapy can remodel tumor antigens by inducing DNA damage, transcriptional stress, and epigenetic/epitranscriptomic alterations, including RNA editing. These therapy-induced changes may generate new or unmasked neoepitopes, thereby enhancing immune recognition even in microsatellite-stable colorectal cancer. By integrating mechanistic insights with recent clinical trial data, we highlight how combining cytotoxic therapies with immune checkpoint inhibitors may overcome immune resistance. Understanding therapy-driven antigen remodeling provides a framework for optimizing immunotherapy strategies and identifying biomarkers of response in colorectal cancer.

Colorectal cancer (CRC) is traditionally considered a “cold tumor” characterized by low immunogenicity and limited responsiveness to immune checkpoint inhibitors (ICIs). However, recent findings reveal that cytotoxic modalities can reprogram this immunologically inert landscape. This review integrates these evolving concepts to guide the optimization of future treatments. Radiotherapy induces extensive DNA double-strand breaks, which may generate de novo mutations through error-prone repair while simultaneously exposing cryptic antigens via increased transcriptional instability, alternative splicing, and enhanced proteasomal processing. Chemoradiation also amplifies epigenetic and epitranscriptomic sources of neoepitope diversity, including RNA editing and stress-induced splicing alterations, expanding the immunopeptidome beyond canonical mutation-driven neoantigens. These changes collectively enhance antigen presentation and facilitate T-cell priming. Chemotherapy further reduces immunosuppressive cell populations and promotes dendritic cell activation, creating a permissive milieu for subsequent immune engagement. Clinically, the VOLTAGE studies demonstrated that long-course chemoradiotherapy can sensitize even mismatch repair–proficient rectal cancers to PD-1 blockade, yielding clinically meaningful pathological responses. In contrast, mismatch repair–deficient rectal tumors may respond completely to ICIs alone. Short-course radiotherapy combined with chemotherapy and ICIs has also shown encouraging activity in the setting of total neoadjuvant therapy. Collectively, these findings support a paradigm in which radiotherapy, chemotherapy, and epigenetic/epitranscriptomic alterations—including RNA editing—act as potent modulators of tumor antigenicity. By expanding the neoantigen repertoire and reshaping the tumor microenvironment, these strategies can transform CRC from a cold tumor into one that is increasingly responsive to immunotherapy.