Abstract
Macrophage-mediated phagocytosis of tumor cells elicits potent antitumor immunity. Nonetheless, sole-blockade of the anti-phagocytosis molecule CD47 has yielded insufficient therapeutic outcomes. Here, we report that glioblastoma (GBM) cells expressed abundant levels of phagocytosis checkpoint CD24. We further show that dual blockade of CD24 and CD47 synergistically enhances the pro-phagocytic activity of macrophages, thereby improving tumor antigen cross-presentation and activating the cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS-STING) pathway. This innate immune activation facilitates T cell infiltration into tumors and sensitizes tumors to anti-PD1 therapy, improving survival outcomes in murine GBM models, including immunosuppressive tumors reflecting human GBM-like features. Thus, our results indicate that dual-phagocytosis checkpoint blockade offers a promising therapeutic avenue to potentiate cancer immunotherapy.
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Publicly available single-cell RNA sequencing data were obtained from GEO under accession code GSE182109. All data are included in the Supplementary Information or available from the authors, as are unique reagents used in this Article. The raw numbers for charts and graphs are available in the Source Data file whenever possible. Source data are provided with this paper.
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Acknowledgements
This research was supported in part by Break Through Cancer Foundation, the National Institutes of Health/ National Institute of Neurological Disorders and Stroke Grant R01NS117828 (W.J.), the American Cancer Society Research Scholar Grant (RSG-22052-01-IBCD, W.J.), CPRIT Scholar in Cancer (RR250092, B.R.S.), The National Cancer Institute of the National Institutes of Health (1K08CA296776, B.R.S.), the James P. Allison Institute (P.S.), and the James P. Allison Institute’s Andrew Sabin Family Recruitment and Retention Fund (B.Y.S.K.).
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J.Ha., B.Y.S.K., and W.J. conceived the project and were responsible for all phases of the research. J.Ha. conducted the majority of the experiments and data analyses. Y.W., Y.M., A.W., S.D., S.D.J., J.L.E., M.C., Y-T.C., X.W., M.D., M.N.T., S.M., W.D., A.G., S.B., S.J., and B.S. assisted with data collection. J.S.W., S.M.R., F.D., I.E.M., S.P., S.D.F., C.I.E., K.A., J.Hu, S.G., V.K.P., F.F.L., K.H., and P.S. assisted with data analysis and interpretation. The manuscript was drafted by J.Ha., Y.W., B.Y.S.K., and W.J. and was revised and approved by all authors.
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Ha, J., Wang, Y., Ma, Y. et al. Dual phagocytosis-checkpoint blockade revitalizes immune surveillance in mouse models of glioblastoma. Nat Commun (2026). https://doi.org/10.1038/s41467-026-70221-9
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DOI: https://doi.org/10.1038/s41467-026-70221-9
