DR5 CAR-T cells target solid tumors and suppress MDSCs with minimal toxicity

Chimeric antigen receptor (CAR) T cell therapies have poor efficacy in solid tumors due to limited target specificity and an immunosuppressive tumor microenvironment. We investigated death receptor 5 (DR5) as a CAR target based on its high expression in both solid tumors and myeloid- derived suppressor cells (MDSCs). We engineered agonistic DR5-specific CAR constructs and evaluated their activity in multiple models, demonstrating DR5-expression-dependent tumor killing, confirmed by knockout and overexpression experiments. DR5-targeting single-chain variable fragments retained their pro-apoptotic activity when expressed on non-effector cells or extracellular vesicles. Among multiple CAR designs, we identified a construct with optimized binding affinity that maintained T cell viability while preserving strong tumor and MDSC-killing potency. To assess safety and efficacy in an immunocompetent setting, we also developed a murine DR5-targeted CAR. In multiple xenograft and syngeneic mouse models, DR5 CAR-T cells reduced tumor growth, prolonged survival, and did not cause detectable toxicity. In patient- derived organoids and tissue slices, DR5 CAR-T cells infiltrated tumor tissues, reduced MDSCs, boosted CD8+ T cell activity, and inhibited tumor growth. These findings support DR5-targeted CAR-T therapy as a promising strategy for treating solid tumors, which combines direct tumor cytotoxicity with immune activation and minimizes off-target effects. Teaser DR5 CAR-T cells eliminate tumor cells and MDSCs and activate tumor-resident CD8+ T cells within the TME.