IL-10-Targeting SR CAR-M for Solid Tumors
Wang S, Ahmad O, Shui K, et al. Engineered Macrophages With IL-10-TLR9 Signal Switch Receptors for Reprogramming Tumor Microenvironment and Enhancing Antitumor Immunity. Experimental & Molecular Medicine. 2026; (doi: 10.1038/s12276-026-01800-5).
Chimeric antigen receptor (CAR) T-cell therapy is inching closer to clinical success in solid tumors, according to researchers reporting on the performance of a CAR-like signal-switching receptor-macrophage (SR CAR-M) in this setting. The macrophage in question was engineered to recognize IL-10, a cytokine that is highly expressed in solid tumors and that suppresses antitumor immunity by inhibiting dendritic cell (DC) maturation, promoting regulatory T cell differentiation, and polarizing macrophages toward tumor-supportive M2 phenotypes. The SR CAR-M converted immunosuppressive IL-10 signaling into a pro-inflammatory therapeutic pathway in part by supporting DC maturation, enhancing T-cell proliferation and effector function, and preventing T-cell exhaustion. It also blocked IL-10-driven STAT3 phosphorylation while activating TLR9 downstream signaling, taking on an M1-like phenotype characterized by enhanced phagocytic capacity and cytotoxicity. In a model of breast cancer, infused macrophages selectively accumulated in tumors, depleted local IL-10 while inducing inflammatory cytokine production, suppressed tumor growth, and improved survival without toxic effects.