biostudies-literatureUnknown221(7)Hodgins JJNatural Sciences and Engineering Research Council of CanadaTerry Fox Research InstituteRide for DadBioCanRxUniversity of Ottawa Heart InstituteCanadian Institutes of Health ResearchCIHRSchulich Leader ScholarshipCancer Research SocietyCanadian Allergy, Asthma, and Immunology FoundationCharles Best Canada Graduate Scholarships DoctoralTerry Fox FoundationCanadian Fund for InnovationOntario Graduate ScholarshipTaggart-Parkes FellowshipProstate Cancer CanadaUniversity of OttawaCanadian Cancer Society Research InstituteCI3 scholarshipVanier CanadaWhile 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 laThe Journal of experimental medicinee20221721https://www.ebi.ac.uk/biostudies/studies/S-EPMC11176258biostudies-literaturePD-L1 promotes oncolytic virus infection via a metabolic shift that inhibits the type I IFN pathway.PMC11176258Vanderhyden BCPark MMHodgins JJMakinson OJHarper METanese de Souza CBell JCBourgeois-Daigneault MCFong-McMaster CBuchler AAbou-Hamad JKurdieh RRotstein BHMarotel MYakubovich EIlkow CSDhillon HSArdolino MFadel SCrupi MFO'Dwyer CEAuer RCSabourin LAHagerman ARezaei RCook DPfalsePD-L1 promotes oncolytic virus infection via a metabolic shift that inhibits the type I IFN pathway.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 la2024-01-01T00:00:00Z2024 Jul2025-04-04T01:20:38.599Z2025-04-04T01:20:38.599ZS-EPMC111762583886948010.1084/jem.20221721