CAR macrophages with built-In CD47 blocker combat tumor antigen heterogeneity and activate T cells via cross-presentation

作者：Siqi Chen, Yingyu Wang, Jessica Dang, Nuozi Song, X Chen, Jinhui Wang, Guo N. Huang, Christine E. Brown, Jianhua Yu, Irving L. Weissman, Steven T. Rosen, Mingye Feng · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-59326-9 · 被引用次数：42 · 研究领域：Phagocytosis and Immune Regulation、Immune cells in cancer、CAR-T cell therapy research

Macrophage-based cancer cellular therapy has gained substantial interest. However, the capability of engineered macrophages to target cancer heterogeneity and modulate adaptive immunity remains unclear. Here, exploiting the myeloid antibody-dependent cellular phagocytosis biology and phagocytosis checkpoint blockade, we report the enhanced synthetic phagocytosis receptor (eSPR) that integrate FcRγ-driven phagocytic chimeric antigen receptors (CAR) with built-in secreted CD47 blockers. The eSPR engineering empowers macrophages to combat tumor antigen heterogeneity. Transduced by adenoviral vectors, eSPR macrophages are intrinsically pro-inflammatory imprinted and resist tumoral polarization. Transcriptomically and phenotypically, eSPR macrophages elicit a more favorable tumor immune landscape. Mechanistically, eSPR macrophages in situ stimulate CD8 T cells via phagocytosis-dependent antigen cross-presentation. We also validate the functionality of the eSPR system in human primary macrophages. Engineering macrophages to express chimeric antigen receptors (CARs) for targeted tumor cell phagocytosis has shown encouraging results. Here the authors engineer macrophages with enhanced synthetic phagocytosis receptors which incorporate a FcRɣ-driven phagocytosis CAR and an auto-secreted CD47 blocker, showing improved anti-tumor efficacy