摘要
The potential of macrophage-mediated phagocytosis as a cancer treatment is promising.Blocking the CD47–SIRPαinteraction with a CD47-specific antibody significantly enhances macrophage phagocytosis.However,concerns regarding their toxicity to nontumor cells remain substantial.Here,we engineered chimeric antigen receptor macrophages(CAR-Ms)by fusing a humanized single-chain variable fragment with FcγRIIa and integrating short hairpin RNA to silence SIRPα,thereby disrupting the CD47–SIRPαsignaling pathway.These modified CAR-shSIRPα-M cells exhibited an M1-like phenotype,superior phagocytic function,substantial cytotoxic effects on HER2-positive tumor cells,and the ability to eliminate patient-derived organoids.In vivo,CAR-M cells significantly inhibited tumor growth and prolonged survival in tumor-bearing mice.Notably,CAR-shSIRPα-M cells enhanced cytotoxic T-cell infiltration into tumors,thereby enhancing the antitumor response in both the humanized immune system mouse model and immunocompetent mice.Mechanistically,SIRPαinhibition activated inflammatory pathways and the cGAS-STING signaling cascade in CAR-M cells,leading to increased production of proinflammatory cytokines,reactive oxygen species,and nitric oxide,thereby enhancing their antitumor effects.These findings underscore the potential of SIRPαinhibition as a novel strategy to increase the antitumor efficacy of CAR-M cells in cancer immunotherapy,particularly against solid tumors.
基金
funded by grants from the National Natural Science Foundation of China(grant number 82073361)
the State Key Laboratory of Cancer Biology Project(grant number CBSKL2022ZZ21)
the Key R&D Plan of Shaanxi Province(grant number 2023-YBSF-667)
the Xi’an Municipal Health Commission(grant number 2022 ms06).
