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Background CAR-T therapy has demonstrated curative potential against hematological malignancies, but its success in solid tumors is limited by factors such as immunosuppressive cells in the tumor microenvironment. DR5 (TRAILR2) is a death receptor that induces apoptosis in myeloid-derived suppressor cells, tumor-associated macrophages (TAMs), and sensitive tumor cells.Methods We engineered CAR-T cells to express a membrane-bound DR5 agonist (aDR5) lacking intracellular signaling capabilities to induce apoptosis in these populations.Results aDR5-expressing CAR-T cells killed DR5-sensitive tumor cells independently of CAR engagement, enhancing unarmored CAR-T tumor control both in vitro and in xenograft models. In vitro coculture of TAMs with aDR5-expressing cells reduced TAM recovery compared to non-aDR5 T cells, while having no effect on normal lymphoid or myeloid populations. Additionally, expressing a murine anti-DR5 agonistic antibody on the surface of CAR-T cells resulted in the depletion of myeloid cells in a syngeneic 4T1 mouse model.Conclusions By decoupling DR5 activity from T cell function, this strategy ensures selective depletion of myeloid suppressive cells and tumor cells without exacerbating CAR-T cytokine responses, and does not rely on T cell fitness.Ethics Approval All animal experiments were conducted in a facility accredited by the Association for Assessment of Laboratory Animal Care (AALAC) under Institutional Animal Care and Use Committee (IACUC) guidelines and appropriate animal research approval.