Stereotactic ablative radiotherapy and immunotherapy in metastatic colorectal cancer: overcoming immune resistance through immune priming

Immune checkpoint inhibitors (ICIs) are effective in the approximately 5% of metastatic colorectal cancers (mCRC) that are microsatellite instability-high or mismatch repair-deficient (MSI-H/dMMR), whereas microsatellite-stable or mismatch repair-proficient (MSS/pMMR) disease rarely responds to ICI monotherapy. Stereotactic ablative radiotherapy (SABR) has been proposed to prime antitumor immunity in MSS disease. Preclinical studies show that high-dose-per-fraction radiation can induce immunogenic cell death, release tumor antigens and activate the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, which may increase T-cell infiltration and, in some models, cause regression of non-irradiated lesions (the abscopal effect). Clinical data come mainly from small, single-arm, early-phase studies that report acceptable safety but modest response rates, and no colorectal-specific randomized trial has shown a survival benefit from adding SABR to immunotherapy. This review summarizes the biological rationale, critically appraises the clinical evidence, including chemo-immuno-radiotherapy in rectal cancer, and discusses toxicity, patient selection, dose-fractionation and sequencing. PubMed/MEDLINE, Embase and ClinicalTrials.gov were searched from January 2000 to February 2026. SABR-induced immune priming in MSS mCRC is biologically plausible but should be tested in biomarker-stratified randomized trials.