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 r...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.展开更多
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)+1 种基金the Key R&D Plan of Shaanxi Province(grant number 2023-YBSF-667)the Xi’an Municipal Health Commission(grant number 2022 ms06).
文摘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.
