Background: A small proportion of patients with metastatic colorectal cancer (CRC) who might respond well to immune checkpoint inhibitors (ICIs) can be identified based on the biomarker of high microsatellite instability. Genes involved in homologous recombination repair (HRR) have been linked to response to such therapy. Methods: HRR mutations in CRC were explored by analyzing genomic data from patients in The Cancer Genome Atlas (TCGA) (n=377), from a Chinese cohort (n=6106) and from our

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... tal in China (n=50). The impact of HRR mutations on prognosis of CRC patients was explored in the cohort from TCGA. A cohort of patients treated with ICIs from Memorial Sloan Kettering Cancer Center (MSKCC) (n=110), and two patients from our hospital were studied to characterize the impact of the HRR mutation in prognosis of CRC treated with ICIs.Results: HRR genes were mutated in all the cohorts examined, with frequencies ranging from 22.44% in our hospital to 52.78% in TCGA. Frequencies of HRR mutations were 43.69-50.47% among patients showing microsatellite stability. HRR mutations were associated with higher tumor mutational burden and high microsatellite instability. HRR mutations correlated with higher neoantigen and increased CD8+ T cell infiltration in the cohort from TCGA. HRR mutations were associated with significantly better overall survival in patients treated with ICIs of MSKCC cohort, particularly among patients with microsatellite stability. Conclusion: HRR mutations may be associated with stronger response to ICIs in CRC patients with microsatellite-stable, and may be useful for identifying CRC patients likely to benefit from immunotherapy.