Translational research : the journal of laboratory and clinical medicine · 2026
SynNotch-iNOS CAR-macrophages remodel the tumor immune microenvironment and exhibit antitumor efficacy via a CD4+ T cell-dependent mechanism.
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Hong Yuling, Dang Buyun, Zhou Zhenqiong, Liang Cixin, Li Linying, Gao Qingxiang, Zhang Jia, Cheng Shih-Chin
Аннотация
BACKGROUND: Chimeric antigen receptor T-cell (CAR-T) therapy shows limited efficacy against solid tumors due to the immunosuppressive tumor microenvironment (TME). Macrophages possess superior infiltration capabilities, yet their therapeutic potential remains under-realized.
METHODS: We engineered a synNotch-iNOS CAR-macrophage (CAR iNOS-M) that releases nitric oxide (NO) upon CD19 recognition. Its efficacy was evaluated in syngeneic, immunocompetent murine models of metastatic melanoma.
RESULTS: CAR iNOS-M therapy effectively reprogrammed the pulmonary tumor immune microenvironment (TIME), inducing potent antitumor responses independent of CD8+ T cells but strictly dependent on CD4+ T cells. Mechanistically, CAR iNOS-M treatment led to a significant reduction in pro-tumorigenic lung interstitial macrophages (IMs), subsequently decreasing platelet factor 4 (PF4) levels. This disruption of the PF4 signaling axis inhibited the polarization of immunosuppressive Th1-Tregs, alleviating T-cell exhaustion.
CONCLUSIONS: This study delineates a novel indirect mechanism for CAR-M, shifting the focus from direct phagocytosis to strategic TIME remodeling, providing a foundation for treating solid tumors.
METHODS: We engineered a synNotch-iNOS CAR-macrophage (CAR iNOS-M) that releases nitric oxide (NO) upon CD19 recognition. Its efficacy was evaluated in syngeneic, immunocompetent murine models of metastatic melanoma.
RESULTS: CAR iNOS-M therapy effectively reprogrammed the pulmonary tumor immune microenvironment (TIME), inducing potent antitumor responses independent of CD8+ T cells but strictly dependent on CD4+ T cells. Mechanistically, CAR iNOS-M treatment led to a significant reduction in pro-tumorigenic lung interstitial macrophages (IMs), subsequently decreasing platelet factor 4 (PF4) levels. This disruption of the PF4 signaling axis inhibited the polarization of immunosuppressive Th1-Tregs, alleviating T-cell exhaustion.
CONCLUSIONS: This study delineates a novel indirect mechanism for CAR-M, shifting the focus from direct phagocytosis to strategic TIME remodeling, providing a foundation for treating solid tumors.