2. Academic Validation
  3. MTAP deficiency confers resistance to cytosolic nucleic acid sensing and STING agonists

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

  • Science. 2025 Oct 9;390(6769):eadl4089. doi: 10.1126/science.adl4089.
Jung-Mao Hsu # 1 2,  Chunxiao Liu # 3 4,  Weiya Xia 2 4 5,  Chung-Yu Chen 2 5,  Wei-Chung Cheng 2 6,  Junwei Hou 7,  Mien-Chie Hung 1 2 4 5 8
Affiliations

Affiliations

  • 1 Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.
  • 2 Cancer Biology and Precision Therapeutics Center, China Medical University, Taichung, Taiwan.
  • 3 Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
  • 4 Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 5 Center for Molecular Medicine, China Medical University, Taichung, Taiwan.
  • 6 Ph.D. Program for Cancer Molecular Biology and Drug Discovery, China Medical University, Taichung, Taiwan.
  • 7 Department of Otolaryngology Head and Neck Surgery and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University; Otolaryngology Major Disease Research Key Laboratory of Hunan Province, Changsha, Hunan, China.
  • 8 Department of Biotechnology, Asia University, Taichung, Taiwan.
  • # Contributed equally.
PMID: 41066563 DOI: 10.1126/science.adl4089
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 MTAP 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 MTAP-deleted tumors.

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