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  3. SLC5A11 mediates metformin-induced PD-L1 suppression to enhance cancer immunotherapy through AMPK-IRF1 signaling

SLC5A11 mediates metformin-induced PD-L1 suppression to enhance cancer immunotherapy through AMPK-IRF1 signaling

  • Cancer Lett. 2026 Apr 28:644:218311. doi: 10.1016/j.canlet.2026.218311.
Yarui Ma 1,  Xue Wang 1,  Zhewen Wei 2,  Qi Zhang 1,  Fangqing Yuan 1,  Chungui Xu 1,  Chang Liu 3,  Xiaobing Wang 1,  Lin Li 4,  Yuchen Jiao 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China.
  • 2 Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 3 Amsterdam UMC location Vrije Universiteit Amsterdam, Pulmonary Medicine, De Boelelaan, 1117, Amsterdam, the Netherlands; Amsterdam Institute for Infection and Immunity, Cancer Center Amsterdam, Amsterdam, the Netherlands.
  • 4 Department of Medical Oncology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, 100730, China.
  • 5 State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China; Institute of Cancer Research, Henan Academy of Innovations in Medical Science, Zhengzhou, Henan, China. Electronic address: [email protected].
PMID: 41690450 DOI: 10.1016/j.canlet.2026.218311
Abstract

Metformin exhibits immunomodulatory properties in Cancer treatment, but the underlying mechanisms remain elusive. Using genome-wide CRISPR screening, we identified SLC5A11 as an essential mediator of metformin sensitivity. Molecular docking and dynamics simulations revealed direct metformin-SLC5A11 binding at the pocket containing Asn78 and Glu102 residues. Metformin suppressed PD-L1 expression across multiple Cancer models through SLC5A11-dependent activation of AMPK and subsequent JAK2-STAT1-IRF1 downregulation. SLC5A11 knockout abolished these effects, while reconstitution restored metformin responsiveness. In syngeneic mouse models of lung and pancreatic Cancer, combining metformin with anti-PD1 therapy produced synergistic antitumor effects, enhanced T cell infiltration, and potentiated immunotherapy efficacy. Metformin pretreatment significantly enhanced PBMC-mediated cytotoxicity against tumor cells and patient-derived organoids in ex vivo co-culture systems. Our findings establish the SLC5A11-AMPK-PD-L1 axis as a novel mechanism linking metformin to tumor immunity, providing a molecular rationale for combining metformin with checkpoint inhibitors in Cancer Immunotherapy.

Keywords

CRISPR screen; Immune checkpoint blockade; Metformin; PD-L1; SLC5A11.

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