MMR-d tumours commonly display high TMB and MSI-H status due to progressive accumulation of mutations that, once transcribed and translated, engender novel neoantigens and a subsequent CPI-responsiveness. Unfortunately, most human cancers, including most colorectal tumours, are MMR-p and unresponsive to CPI therapy.
Thus, there is a strong rationale to develop a therapeutic intervention against key components of the MMR pathway. Treatment with MMR inhibitors in combination with CPI immunotherapies could provide clinical benefit by reawakening the patients’ anti-tumour immune response by effectively turning immunologically ‘cold’ tumours ‘hot’.