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Translational relevance:Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide, with around 1.3 million cases diagnosed each year. Efforts to develop biomarkers of prognosis and response to chemotherapy in CRC have resulted in stratification systems based on components of the tumour microenvironment (TME), highlighting the importance of characterising both molecular and pathological features. The DNA Damage Immune Response (DDIR) transcriptional assay was developed as a predictive biomarker for identifying breast cancer (BC) patients that benefit from DNA-damaging chemotherapy, based on signalling associated with defective homologous recombination DNA repair. Here we show that the DDIR signature does not predict outcomes from oxaliplatin based chemotherapy for localised or metatastic CRC patients in clinical trials. We show that although this predictive assay identifies tumours enriched for defects in the DNA mismatch repair machinery, it primarily identifies immune-rich, albeit exhausted, CRC tumours with competent repair signalling that may respond to immune checkpoint blockade.

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