Armored macrophage-targeted CAR-T cells reset and reprogram the tumor microenvironment and control metastatic cancer growth.

Tumor-associated macrophages (TAMs), which commonly express FOLR2 or TREM2, are enriched in solid tumors and keep the tumor microenvironment (TME) immunosuppressed. Here, we introduce IL-12-expressing CAR-T cells targeting FOLR2 or TREM2 to deplete pro-tumor TAMs and reprogram the TME. Treatment with IL-12-armored anti-TAM CAR-T leads to significantly improved survival in metastatic ovarian and lung cancer models. The CAR-T mediates benefit at low cell dose and without lymphodepletion, and remains largely restricted to tumors with no overt toxicity. Spatial transcriptomics reveals that IL-12 anti-TAM CAR-T mediates sustained remodeling of the TME, even after CAR-T contraction, with the expansion of CXCL9+ immunostimulatory macrophages and endogenous tumor-specific cytotoxic T cells. Tumor clearance depends, in part, on FAS expression on cancer cells, revealing an IL-12-FAS axis for IL-12-armored CAR-T activity. These findings position IL-12-producing, myeloid-directed CAR-T as a broad strategy to remodel the TME and drive anti-tumor immunity for solid cancers.