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Background The gold standard treatment for locally advanced rectal cancer is total mesorectal excision after preoperative chemoradiotherapy. Response to chemoradiotherapy varies, with some patients completely responding to the treatment and some failing to respond at all. Identifying biomarkers of response to chemoradiotherapy could allow patients to avoid unnecessary treatment-associated morbidity rate. While previous studies have attempted to identify such biomarkers, none have reached clinical utility, which may be due to heterogeneity of the cancer. In this study, potential human gene and microbial biomarkers were explored in a cohort of rectal cancer patients who underwent chemoradiotherapy. Methods RNA sequencing was carried out on matched tumour and adjacent normal rectum biopsies from patients with rectal cancer with varying chemoradiotherapy responses treated between 2016 and 2019 at two institutions. Enriched genes and microbes from tumours of complete responders were compared with those from tumours of others with lesser response. Results In 39 patients analysed, enriched gene sets in complete responders indicate involvement of immune responses, including immunoglobulin production, B cell activation and response to bacteria (adjusted P values Conclusion These results identify potential genetic and microbial biomarkers of response to chemoradiotherapy in rectal cancer, as well as suggesting a potential mechanism of complete response to chemoradiotherapy that may benefit further testing in the laboratory.