Colorectal cancer (CRC) shows variable response to immune checkpoint blockade, which can only partially be explained by high tumour mutational burden (TMB). We conducted an integrated study of the cancer tissue and associated tumour microenvironment (TME) from patients treated with Pembrolizumab (KEYNOTE 177 clinical trial) or Nivolumab to dissect the cellular and molecular determinants of response to anti-PD1 immunotherapy.