biostudies-literatureUnknown7(2)Zhang HShandong Province Natural Science FoundationNational Natural Science Foundation of ChinaLiaoning Provincial Natural Science FoundationChimeric antigen receptor (CAR) cell therapy transforms hematologic cancer treatment but remains limited in solid tumors due to stromal barriers and an immunosuppressive tumor microenvironment that restricts immune cell infiltration. To address these barriers, we develop a cell-free therapeutic platform based on CAR-engineered induced pluripotent stem cell (iPSC)-derived natural killer (NK) extracellular vesicles (CAR-iNEVs), which retain tumor-targeting capability without reliance on live-cell delivery. CAR-iNEV demonstrates potent antitumor activity and excellent tolerability across multiple xenograft and patient-derived models. Mechanistically, CAR-iNEV directly eliminates tumor cells and remodels the tumor microenvironment by promoting pro-inflammatory macrophage polarization, thereby Cell reports. Medicine102545https://www.ebi.ac.uk/biostudies/studies/S-EPMC12923919biostudies-literatureProgrammable iPSC-derived CAR-NK vesicles remodel the immune microenvironment and eradicate tumors.PMC12923919Li HJu CWGongye XZhang HXia PNiu XGuan YLi SZhai XJin BJia WLiu CJi YfalseProgrammable iPSC-derived CAR-NK vesicles remodel the immune microenvironment and eradicate tumors.Chimeric antigen receptor (CAR) cell therapy transforms hematologic cancer treatment but remains limited in solid tumors due to stromal barriers and an immunosuppressive tumor microenvironment that restricts immune cell infiltration. To address these barriers, we develop a cell-free therapeutic platform based on CAR-engineered induced pluripotent stem cell (iPSC)-derived natural killer (NK) extracellular vesicles (CAR-iNEVs), which retain tumor-targeting capability without reliance on live-cell delivery. CAR-iNEV demonstrates potent antitumor activity and excellent tolerability across multiple xenograft and patient-derived models. Mechanistically, CAR-iNEV directly eliminates tumor cells and remodels the tumor microenvironment by promoting pro-inflammatory macrophage polarization, thereby 2026-01-01T00:00:00Z2026 Feb2026-07-16T15:14:40.497Z2026-07-10T03:09:41.166ZS-EPMC129239194165095210.1016/j.xcrm.2025.102545