Abstract
Macrophage-mediated phagocytosis of tumor cells is essential for eliciting potent antitumor immunity. Nonetheless, previous efforts focusing solely on blockade of the anti-phagocytosis molecule CD47 have yielded insufficient therapeutic outcomes. Here, we identified that glioblastoma (GBM) cells expressed abundant levels of CD24, a recently described phagocytosis checkpoint. We further found that combining CD24 blockade with CD47 inhibition synergistically enhanced 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 facilitated T cell infiltration into tumors and sensitizes tumors to anti-PD1 therapy. Consequently, dual phagocytosis checkpoint blockade combined with PD1 inhibition substantially improved survival outcomes in murine GBM models, including immunosuppressive tumors reflecting human GBM-like features. Together, these findings highlight that modulating phagocytosis via dual checkpoint blockade offers a promising therapeutic avenue to potentiate cancer immunotherapy.