| Title: |
Increasing the Response of Mismatch Repair Proficient Rectal Cancer to Immunotherapy with Particle Radiation and DNA Damage Response Inhibitors—Preclinical Evidence |
| Authors: |
Cristian J. Salazar-Vilches; Daniel K. Ebner; Jake A. Kloeber; Sonja Dragojevic; Jasvinder Singh; Michael Haddock; Yasamin Sharifzadeh; Alexander D. Sherry; Krishan R. Jethwa; Christopher L. Hallemeier; Kenneth W. Merrell; Robert W. Mutter; Zhenkun Lou; Cameron M. Callaghan |
| Source: |
Cancers ; Volume 18 ; Issue 4 ; Pages: 682 |
| Publisher Information: |
Multidisciplinary Digital Publishing Institute |
| Publication Year: |
2026 |
| Collection: |
MDPI Open Access Publishing |
| Subject Terms: |
rectal cancer; particle therapy; immunotherapy; DNA damage response inhibitors |
| Description: |
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. |
| Document Type: |
text |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
Methods and Technologies Development; https://dx.doi.org/10.3390/cancers18040682 |
| DOI: |
10.3390/cancers18040682 |
| Availability: |
https://doi.org/10.3390/cancers18040682 |
| Rights: |
https://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.777ECF52 |
| Database: |
BASE |