PD-L1 promotes oncolytic virus infection via a metabolic shift that inhibits the type I IFN pathway

J Exp Med. 2024 Jul 1;221(7):e20221721. doi: 10.1084/jem.20221721. Epub 2024 Jun 13.


While conventional wisdom initially postulated that PD-L1 serves as the inert ligand for PD-1, an emerging body of literature suggests that PD-L1 has cell-intrinsic functions in immune and cancer cells. In line with these studies, here we show that engagement of PD-L1 via cellular ligands or agonistic antibodies, including those used in the clinic, potently inhibits the type I interferon pathway in cancer cells. Hampered type I interferon responses in PD-L1-expressing cancer cells resulted in enhanced efficacy of oncolytic viruses in vitro and in vivo. Consistently, PD-L1 expression marked tumor explants from cancer patients that were best infected by oncolytic viruses. Mechanistically, PD-L1 promoted a metabolic shift characterized by enhanced glycolysis rate that resulted in increased lactate production. In turn, lactate inhibited type I IFN responses. In addition to adding mechanistic insight into PD-L1 intrinsic function, our results will also help guide the numerous ongoing efforts to combine PD-L1 antibodies with oncolytic virotherapy in clinical trials.

MeSH terms

  • Animals
  • B7-H1 Antigen* / genetics
  • B7-H1 Antigen* / immunology
  • B7-H1 Antigen* / metabolism
  • Cell Line, Tumor
  • Female
  • Glycolysis
  • Humans
  • Interferon Type I* / immunology
  • Interferon Type I* / metabolism
  • Lactic Acid / metabolism
  • Male
  • Mice
  • Neoplasms / immunology
  • Neoplasms / metabolism
  • Neoplasms / therapy
  • Oncolytic Virotherapy* / methods
  • Oncolytic Viruses* / physiology
  • Signal Transduction


  • B7-H1 Antigen
  • CD274 protein, human
  • Interferon Type I
  • Lactic Acid