Immune checkpoint blockade (ICB) therapy only benefits a small subset of colorectal cancer (CRC) patients and identification of CRC-intrinsic events modulating ICB efficacy is an unmet need. Here, we revealed AlkB Homolog 5 (ALKBH5), an RNA N6-methyladenosine (m6A) eraser, drives immunosuppression and is a molecular target to boost ICB therapy in CRC.