Tumor Antigen–Independent Targeting of Solid Tumors by Armored 1 Macrophage-Directed anti-TREM2-CAR T Cells

Chimeric antigen receptor (CAR) T cell therapy has shown remarkable clinical efficacy in hematological malignancies and, more recently, in autoimmune diseases. However, its application in solid tumors has been limited by tumor antigen heterogeneity, antigen escape, and the immunosuppressive tumor microenvironment (TME), which is particularly shaped by tumor associated macrophages (TAMs). To overcome these barriers, we developed a novel CAR T cell strategy targeting human TREM2⁺ immunosuppressive TAMs. Macrophage-directed anti- TREM2-CAR T cells demonstrated potent anti-TREM2 activity in both in vitro assays and in solid tumor models in vivo. To further enhance intratumoral T cell function, we incorporated a CAR T cell responsive synthetic DNA biosensor comprising NFAT motifs that enable localized secretion of interleukin-12 upon CAR activation. In murine tumor models, this “armored” TREM2-targeted CAR-T cell approach led to robust remodeling of the TME and tumor-draining lymph nodes, characterized by TREM2⁺ TAM depletion, enhanced T and NK cell infiltration and activation, and complete tumor eradication, independent of tumor antigen expression.