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Significance N 6 -methylation of adenosine (m6 A) RNA modification plays important roles in development and tumorigenesis. The functions and mechanisms of m6 A demethylases during cancer immunotherapy is still unclear. Here we employed melanoma and colon syngeneic mouse models to study the roles of m6 A demethylases ALKBH5 and FTO during anti–PD-1 antibody and GVAX vaccination therapy. We found that ALKBH5 knockout in tumor cells enhances efficacy of immunotherapy and prolonged mouse survival. ALKBH5 modulates target gene expression and gene splicing, leading to changes of metabolite contents, such as lactate in tumor microenvironment, which regulates suppressive lymphocytes Treg and myeloid-derived suppressor cell accumulations. Importantly, by using ALKBH5-specific inhibitor, we observed the similar phenotype, indicating future translational application of our findings.

ALKBH5 regulates anti–PD-1 therapy response by modulating lactate and suppressive immune cell accumulation in tumor microenvironment