Dual phagocytosis-checkpoint blockade revitalizes immune surveillance in mouse models of glioblastoma

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. Macrophage-dependent phagocytosis elicits robust antitumor immunity. Nevertheless, therapeutic strategies harnessing phagocytosis have been met with limited success. Here the authors demonstrate that dual-phagocytosis checkpoint blockade, achieved by simultaneously targeting CD47 and CD24, greatly enhances tumor cell phagocytosis thus increasing antigen-presentation capacity, cGAS-STING activation and T cell infiltration into the tumor microenvironment, ultimately fostering robust antitumor immunity in preclinical mouse models of glioblastoma.