# Increasing the Response of Mismatch Repair Proficient Rectal Cancer to Immunotherapy with Particle Radiation and DNA Damage Response Inhibitors—Preclinical Evidence

## TL;DR

This paper reviews preclinical evidence showing that combining high-LET radiation and DNA damage response inhibitors can improve immunotherapy responses in mismatch repair proficient rectal cancer.

## Contribution

The study provides a systematic review of preclinical evidence supporting the use of high-LET radiation and DDRi to enhance immunotherapy in pMMR rectal cancer.

## Key findings

- High-LET radiation increases immunogenic cell death and tumor antigen presentation in pMMR models.
- Combining DDRi with immunotherapy improves local control and systemic antitumor responses in preclinical studies.
- High-LET therapies show manageable toxicity and excellent local control in murine models.

## Abstract

Patients with mismatch repair deficient (dMMR) rectal adenocarcinomas demonstrate significant complete response rates to PD-1 inhibitor monotherapy, potentially allowing them to avoid chemotherapy, radiation, and surgery. However, >95% of patients are mismatch repair proficient (pMMR) and have so far not responded to immunotherapy in clinical trials. There is growing evidence that both high linear energy transfer (LET) particle radiation and DNA damage response inhibitors (DDRis) may increase the response of pMMR rectal cancer to immunotherapy and are ready for clinical translation.

Background/Objectives: We performed a systematic review of preclinical literature on the use of high-LET particle therapy, DDRi, and/or immunotherapy specifically in pMMR colorectal cancer. Methods: A systematic review of the literature published between 2014 and 2025 was conducted across major databases. Studies were included if they examined particle radiotherapy (e.g., proton, alpha, and carbon) or X-ray radiation either alone or in combination with DDRi and/or immune checkpoint inhibitors (ICIs) in pMMR colorectal cancer models. Results: In total, 131 studies met the inclusion criteria, including 70 preclinical studies. These studies consistently demonstrate that high-LET radiation amplifies immunogenic cell death, increases cGAS-STING pathway activation, and enhances tumor antigen presentation, thereby fostering greater immune infiltration and systemic antitumor responses. Concurrent irradiation with DDRi enhances persistent DNA damage and cytosolic DNA accumulation. In murine models, high-LET therapies show excellent local control, with manageable toxicity profiles. Combination regimens with ICIs exhibit improved local control and elicit systemic antitumor immune responses. Conclusions: High-LET particle radiation and/or the use of concurrent DDRi with ICI have significant preclinical evidence of immunostimulatory effects in pMMR rectal adenocarcinoma and increased response rates to immunotherapy. The clinical evidence will be reviewed in the companion manuscript.