Costimulatory domains (CSD) of 4-1BB and CD28 are most widely used in chimeric antigen receptor-engineered T (CAR-T) cells. These CAR-T cells have shown encouraging efficacy in the treatment of hematologic malignancies but have limited efficacy in solid tumors. The herpes virus entry mediator (HVEM) is a costimulatory molecule with a novel downstream signaling pathway. In response to target cells, CAR-T cells with a HVEM CSD (HVEM-CAR-T) displayed more robust cytokine release and cytotoxicity than 4-1BB- or CD28-CAR-T in vitro. Furthermore, HVEM-CAR-T showed superior therapeutic efficacy in several mouse tumor models. Mechanistically, the HVEM CSD endowed CAR-T cells with attenuated exhaustion, improved function and persistence, and enhanced metabolic activities in tumor tissue compared with 4-1BB- or CD28-based CAR-T cells. These studies establish that the HVEM CSD has the potential to improve the therapeutic efficacy of CAR-T cells against solid tumors.

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