MTAP deficiency confers resistance to cytosolic nucleic acid sensing and STING agonists.

Abstract

Cytosolic nucleic acid-sensing pathways are potential targets for cancer immunotherapy. Although stimulator of interferon genes (STING) agonists have shown substantial antitumor effects in animal models, their clinical efficacy in human tumors remains unclear. Deletion of methylthioadenosine phosphorylase (MTAP) is a common genomic alteration in human tumors but is rare in preclinical syngeneic mouse models. We found that homozygous <i>MTAP</i> deletion in human tumors creates a tumor microenvironment that obstructs cytosolic nucleic acid-sensing pathways by down-regulating interferon regulatory factor 3 (IRF3), leading to resistance to STING agonists. Targeting polyamine biosynthesis reverses IRF3 down-regulation, restoring sensitivity to STING agonists in MTAP-deficient tumors. Our findings suggest that MTAP genetic status may inform patient responses to STING agonist therapy and offer an alternative strategy for boosting antitumor immune responses using STING agonists in <i>MTAP</i>-deleted tumors.