biostudies-literatureChen JNational Natural Science Foundation of China1290-1301https://www.ebi.ac.uk/biostudies/studies/S-EPMC9622748biostudies-literatureUnknown19(11)PD-L1⁺ tumor-derived extracellular vesicles (TEVs) cause systemic immunosuppression and possibly resistance to anti-PD-L1 antibody (αPD-L1) blockade. However, whether and how PD-L1⁺ TEVs mediate αPD-L1 therapy resistance is unknown. Here, we show that PD-L1⁺ TEVs substantially decoy αPD-L1 and that TEV-bound αPD-L1 is more rapidly cleared by macrophages, causing insufficient blockade of tumor PD-L1 and subsequent αPD-L1 therapy resistance. Inhibition of endogenous production of TEVs by Rab27a or Coro1a knockout reverses αPD-L1 therapy resistance. Either an increased αPD-L1 dose or macrophage depletion mediated by the clinical drug pexidartinib abolishes αPD-L1 therapy resistance. Moreover, in the treatment cycle with the same total treatment dose of αPD-L1,Cellular & molecular immunologyTumor extracellular vesicles mediate anti-PD-L1 therapy resistance by decoying anti-PD-L1.PMC962274831970845819015718197187131870876Zhang GYang JChen JLu XZhang JWang JWang PWang SHuang XCai ZWang WGuo DZhang CfalseTumor extracellular vesicles mediate anti-PD-L1 therapy resistance by decoying anti-PD-L1.PD-L1⁺ tumor-derived extracellular vesicles (TEVs) cause systemic immunosuppression and possibly resistance to anti-PD-L1 antibody (αPD-L1) blockade. However, whether and how PD-L1⁺ TEVs mediate αPD-L1 therapy resistance is unknown. Here, we show that PD-L1⁺ TEVs substantially decoy αPD-L1 and that TEV-bound αPD-L1 is more rapidly cleared by macrophages, causing insufficient blockade of tumor PD-L1 and subsequent αPD-L1 therapy resistance. Inhibition of endogenous production of TEVs by Rab27a or Coro1a knockout reverses αPD-L1 therapy resistance. Either an increased αPD-L1 dose or macrophage depletion mediated by the clinical drug pexidartinib abolishes αPD-L1 therapy resistance. Moreover, in the treatment cycle with the same total treatment dose of αPD-L1,2022-01-01T00:00:00Z2022 Nov2025-04-04T08:45:12.719Z2025-04-04T08:45:12.719ZS-EPMC96227483622099410.1038/s41423-022-00926-6