M1 polarization enhances the antitumor activity of chimeric antigen receptor macrophages in solid tumors

Background: Chimeric antigen receptor macrophage (CAR-M) therapy integrates CAR structure with macrophage function and shows promise for solid tumors. Because macrophage polarization affects antitumor activity, the authors hypothesized that inducing M1-type polarization would enhance CAR-M efficacy. Methods: A novel HER2-targeting CAR-M was generated using a humanized anti-HER2 scFv, a CD28 hinge, and the FcγRI transmembrane and intracellular domains. Phagocytosis, tumor-killing, and cytokine release were measured with or without M1-polarization (LPS + IFN-γ) pretreatment. Multiple syngeneic tumor models evaluated in vivo antitumor activity of M1-polarized CAR-Ms. Results: M1 polarization significantly enhanced CAR-M phagocytosis and cytotoxicity against target cells and increased costimulatory molecules and proinflammatory cytokines. In vivo, M1-polarized CAR-Ms suppressed tumor progression and prolonged survival in multiple murine models with enhanced cytotoxicity. Conclusions: The novel HER2-targeting CAR-M effectively eliminated HER2-positive tumor cells in vitro and in vivo; M1 polarization significantly improved antitumor activity, yielding stronger therapeutic effects in solid tumor immunotherapy.

Yi Huo, Han Zhang, Longqi Sa, Wenjing Zheng, Yang He, Haohan Lyu, Mengjie Sun, Lingling Zhang, Lequn Shan, Angang Yang, Tao Wang