Tumor-antigen-independent targeting of solid tumors by armored macrophage-directed anti-TREM2 CAR T cells.

Chimeric antigen receptor (CAR) T cell therapy has shown remarkable success in hematologic malignancies and autoimmune diseases but remains limited in solid tumors due to antigen heterogeneity, escape, and an immunosuppressive tumor microenvironment (TME) dominated by tumor-associated macrophages (TAMs). We developed a macrophage-directed CAR T strategy targeting TREM2+ immunosuppressive TAMs, achieving potent in vitro activity and robust antitumor efficacy in vivo. To enhance intratumoral activity, we incorporated synthetic CAR-responsive biosensors containing NFAT, IRF, and AP1 motifs that enable localized IL-12 secretion upon activation. In an immunocompetent human TREM2 transgenic murine model, IL-12-armored hTREM2 CAR T cells remodel the TME and tumor-draining lymph nodes, depleting TREM2+ TAMs, enhancing T and natural killer (NK) cell infiltration and activation, and inducing tumor regression without systemic toxicity. This study highlights the potential for developing universal and efficacious CAR T cell therapies targeting tumor-associated macrophages for the treatment of solid tumors.