Molecular cancer · 2025
Synergistic innate-adaptive immunity by NKG2D-specific CAR-macrophages drives durable remission in hepatocellular carcinoma.
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Zhao Zihao, Zheng Wenjing, He Yang, Zhang Han, Zhang Lingling, Huo Yi, Jiang Junwei, Zhang Chen, Lyu Haohan, Qin Weiwei, Liu Chen, Chang Feng, Shan Lequn, Wang Tao, Song Wenjie
Аннотация
BACKGROUND: Hepatocellular carcinoma (HCC) immunotherapy is limited by antigenic heterogeneity and an immunosuppressive microenvironment. This study engineered chimeric antigen receptor macrophages (CAR-Ms) targeting stress-inducible NKG2D ligands (NKG2DLs), broadly overexpressed in HCC, to enhance phagocytic clearance and remodel immunity.
METHODS: NKG2DL expression in HCC and association with survival were analyzed. CAR-Ms were constructed by fusing the NKG2D extracellular domain to FcγRI signaling. In vitro assays assessed phagocytosis, cytokine secretion, signaling, and T cell interactions. Therapeutic efficacy was evaluated in immunocompetent mice bearing subcutaneous, orthotopic, or metastatic HCC models, with or without anti-PD-L1. Tumor progression, immunity, and survival were analyzed via bioluminescence imaging, flow cytometry, histopathology, and serum biochemistry. Statistics analyses were performed using t-tests, ANOVA, and log-rank tests.
RESULTS: NKG2DLs were significantly upregulated in human HCC and correlated with poor prognosis. CAR-Ms selectively engulfed NKG2DL⁺ tumor cells, polarized to an M1 phenotype, and activated PI3K-AKT and cGAS-STING pathways, driving phagocytosis and pro-inflammatory cytokines secretion. They enhanced T cell chemokines (Cxcl10, Ccl5) and antigen presentation, boosting T cell recruitment and activation in vitro. In subcutaneous models, CAR-Ms suppressed tumor growth, reprogrammed tumor-associated myeloid cells toward M1, and induced durable immune memory (100% tumor rejection upon rechallenge), with T cell activation. In orthotopic models, CAR-M monotherapy induced complete regression by week 5 and 100% survival, with elevated CD8⁺ T cells and CAR-M specifically homing to liver tumors. CAR-Ms suppressed metastasis in peritoneal/pulmonary models. Combining CAR-Ms with PD-L1 blockade accelerated tumor clearance and survival versus monotherapies, enhancing T cell cytotoxicity. Safety assessments showed no significant organ toxicity based on histopathology and serum biochemistry.
CONCLUSIONS: NKG2D-directed CAR-Ms eliminate HCC through integrated innate phagocytosis, adaptive immune activation, and myeloid reprogramming, overcoming key therapeutic barriers. Combination with anti-PD-L1 enhances therapeutic efficacy by leveraging innate-adaptive crosstalk, providing a promising approach for HCC immunotherapy.
METHODS: NKG2DL expression in HCC and association with survival were analyzed. CAR-Ms were constructed by fusing the NKG2D extracellular domain to FcγRI signaling. In vitro assays assessed phagocytosis, cytokine secretion, signaling, and T cell interactions. Therapeutic efficacy was evaluated in immunocompetent mice bearing subcutaneous, orthotopic, or metastatic HCC models, with or without anti-PD-L1. Tumor progression, immunity, and survival were analyzed via bioluminescence imaging, flow cytometry, histopathology, and serum biochemistry. Statistics analyses were performed using t-tests, ANOVA, and log-rank tests.
RESULTS: NKG2DLs were significantly upregulated in human HCC and correlated with poor prognosis. CAR-Ms selectively engulfed NKG2DL⁺ tumor cells, polarized to an M1 phenotype, and activated PI3K-AKT and cGAS-STING pathways, driving phagocytosis and pro-inflammatory cytokines secretion. They enhanced T cell chemokines (Cxcl10, Ccl5) and antigen presentation, boosting T cell recruitment and activation in vitro. In subcutaneous models, CAR-Ms suppressed tumor growth, reprogrammed tumor-associated myeloid cells toward M1, and induced durable immune memory (100% tumor rejection upon rechallenge), with T cell activation. In orthotopic models, CAR-M monotherapy induced complete regression by week 5 and 100% survival, with elevated CD8⁺ T cells and CAR-M specifically homing to liver tumors. CAR-Ms suppressed metastasis in peritoneal/pulmonary models. Combining CAR-Ms with PD-L1 blockade accelerated tumor clearance and survival versus monotherapies, enhancing T cell cytotoxicity. Safety assessments showed no significant organ toxicity based on histopathology and serum biochemistry.
CONCLUSIONS: NKG2D-directed CAR-Ms eliminate HCC through integrated innate phagocytosis, adaptive immune activation, and myeloid reprogramming, overcoming key therapeutic barriers. Combination with anti-PD-L1 enhances therapeutic efficacy by leveraging innate-adaptive crosstalk, providing a promising approach for HCC immunotherapy.