POLD1 and neoplasm: Although MSI (microsatellite instable)/MSS (microsatellite stable) status, TMB (tumor mutational burden), POLE/POLD1 mutation, and MSI-like gene signature are widely used as indications of whether CRC a patient should receive immunotherapy, these features cannot fully explain anti-PD1 resistance and exhibit limited accuracy in predicting the response to immune checkpoint inhibitor treatment, due to they only directly or indirectly indicate the potential of high quantity of tumor-infiltrating CD8+ T cells in tumor samples while ignoring the exhaustion state of CD8+ T cells (110–112).