Immune checkpoint blockade(ICB)therapy continues to face limitations due to tumor resistance linked to suppressed interferon(IFN)signaling.This suppression can be attributed to multiple mechanisms,among which viral pa...Immune checkpoint blockade(ICB)therapy continues to face limitations due to tumor resistance linked to suppressed interferon(IFN)signaling.This suppression can be attributed to multiple mechanisms,among which viral pathogens represent a compelling though not yet fully elucidated factor.Here,we demonstrate that exogenous Epstein-Barr virus-encoded EBNA1 drives immunosuppression via enhanced RNA-editing enzyme ADAR1-mediated RNA editing.Comparative tumor model analyses revealed that EBNA1 overexpression reduced CD8+T-cell infiltration,inhibited IFN responses,polarized macrophages toward the M2 phenotype,and accelerated tumor growth.Mechanistically,EBNA1 forms a trimeric complex with insulin-like growth factor 2 mRNA-binding protein 3(IGF2BP3)and eukaryotic translation initiation factor 4G1(EIF4G1),enhancing ADAR1 translation.Elevated ADAR1 further increased A-to-I editing of dsRNA,particularly within SINE elements near IFN-associated genes.This editing masked immunostimulatory signals,impairing RNA sensor activation and blunting IFN pathways.Notably,combining the EBNA1-targeting PROTAC degrader EP-1215 with anti-PD-1 effectively restored IFN signaling,enhanced T-cell infiltration,and suppressed EBNA1+tumors in humanized mice.This viral exploitation of RNA editing suggests that targeting EBNA1 could be a strategy to convert“cold”tumors into“hot”targets amenable to ICB therapy.展开更多
基金collectively supported by the National Nature Science Foundation of China(No.82472797 and 82273134 to X.Li,No.82503331 to C.Liu,No.82373706 to J.C.)the Shenzhen Medical Academy of Research and Transcription(SMART)(No.B2402038 to X.Li)+4 种基金the Shenzhen Key Laboratory of Viral Oncology(No.ZDSYS201707311140430 to X.Li)the Provincial Key Laboratory of Immune Regulation and Immunotherapy(No.2022B1212010009 to X.Li)the Shenzhen Science and Technology Plan Projects(No.JCYJ20220530154200002 and No.JCYJ20230807091701004 to C.Cheng)the Longgang District Medical and Health Technology R&D Projects(No.LGKCYLWS2023027 to C.C.)the Shenzhen Key Medical Discipline Construction Fund(No.SZXK039 to C.Cheng).
文摘Immune checkpoint blockade(ICB)therapy continues to face limitations due to tumor resistance linked to suppressed interferon(IFN)signaling.This suppression can be attributed to multiple mechanisms,among which viral pathogens represent a compelling though not yet fully elucidated factor.Here,we demonstrate that exogenous Epstein-Barr virus-encoded EBNA1 drives immunosuppression via enhanced RNA-editing enzyme ADAR1-mediated RNA editing.Comparative tumor model analyses revealed that EBNA1 overexpression reduced CD8+T-cell infiltration,inhibited IFN responses,polarized macrophages toward the M2 phenotype,and accelerated tumor growth.Mechanistically,EBNA1 forms a trimeric complex with insulin-like growth factor 2 mRNA-binding protein 3(IGF2BP3)and eukaryotic translation initiation factor 4G1(EIF4G1),enhancing ADAR1 translation.Elevated ADAR1 further increased A-to-I editing of dsRNA,particularly within SINE elements near IFN-associated genes.This editing masked immunostimulatory signals,impairing RNA sensor activation and blunting IFN pathways.Notably,combining the EBNA1-targeting PROTAC degrader EP-1215 with anti-PD-1 effectively restored IFN signaling,enhanced T-cell infiltration,and suppressed EBNA1+tumors in humanized mice.This viral exploitation of RNA editing suggests that targeting EBNA1 could be a strategy to convert“cold”tumors into“hot”targets amenable to ICB therapy.
