Chen Siqi, Wang Yingyu, Dang Jessica, Song Nuozi, Chen Xiaoxin, Wang Jinhui, Huang Guo N, Brown Christine E, Yu Jianhua, Weissman Irving L, Rosen Steven T, Feng Mingye
Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA, USA.
City of Hope National Medical Center, Duarte, CA, USA.
Nat Commun. 2025 Apr 30;16(1):4069. doi: 10.1038/s41467-025-59326-9.
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.
基于巨噬细胞的癌症细胞疗法已引起广泛关注。然而，工程化巨噬细胞靶向癌症异质性和调节适应性免疫的能力仍不清楚。在此，利用髓系抗体依赖性细胞吞噬生物学和吞噬检查点阻断，我们报道了增强型合成吞噬受体（eSPR），它将FcRγ驱动的吞噬嵌合抗原受体（CAR）与内置分泌型CD47阻滞剂整合在一起。eSPR工程使巨噬细胞能够对抗肿瘤抗原异质性。通过腺病毒载体转导后，eSPR巨噬细胞具有内在的促炎印记并抵抗肿瘤极化。在转录组学和表型上，eSPR巨噬细胞引发更有利的肿瘤免疫格局。从机制上讲，eSPR巨噬细胞通过吞噬依赖性抗原交叉呈递原位刺激CD8 T细胞。我们还在人原代巨噬细胞中验证了eSPR系统的功能。
