在胃癌（GC）中，免疫检查点阻断（ICB）的治疗反应仍然不尽如人意。针对骨髓细胞检查点可能作为目前ICB方案的辅助治疗。我们试图评估C5aR1+TAMs在调节抗肿瘤免疫和与抗编程性细胞死亡蛋白-1（PD-1）和C5aR1阻断的联合治疗疗效中的关键作用。我们发现C5aR1主要表达于巨噬细胞上，高水平的C5aR1+TAMs浸润可以预测较差的预后和较差的化疗反应。流式细胞术（FCM）和单细胞RNA测序（scRNA-seq）数据显示，C5aR1+TAMs表现出免疫抑制性质，可能有助于CD8+T细胞功能失调。C5aR1的阻断可以减弱TAMs的免疫抑制功能，并导致CD8+T细胞介导的抗肿瘤免疫重新激活。此外，基于新鲜GC手术标本的体外干预实验表明，C5aR1阻断与PD-1抑制剂联合使用可以对肿瘤清除产生协同效应。我们的研究证实了C5aR1是一个关键的骨髓检查点，发挥着调节TAMs和CD8+T细胞免疫耐受性的重要作用。C5aR1的阻断可以重新调节TAMs，并重新激活CD8+T细胞的细胞毒性，从而提高GC抗-PD-1治疗的疗效。©2023年作者。国际癌症杂志由约翰威利和儿子有限公司代表UICC出版。

In gastric cancer (GC), the therapeutic response of immune checkpoint blockade (ICB) remains suboptimal. Targeting myeloid cell checkpoints might be feasible as adjuvant to current ICB regimens. We sought to evaluate the crucial role of C5aR1+ TAMs in regulating antitumor immunity and the efficacy of combinatorial treatment with antiprogrammed cell death protein-1 (PD-1) and C5aR1 blockade. Here, we found that C5aR1 was predominantly expressed on macrophages and high level of C5aR1+ TAMs infiltration could predict poor prognosis and inferior chemotherapeutic response. The flow cytometry (FCM) and single-cell RNA-seq (scRNA-seq) data revealed that C5aR1+ TAMs exhibited immunosuppressive property which might contribute to CD8+ T cell dysfunction. Blockade of C5aR1 could diminish the immunosuppressive function of TAMs and led to reinvigorated CD8+ T cells mediated antitumor immunity. Moreover, using in vitro intervention experiment based on fresh GC surgical specimens, we discovered that C5aR1 blockade exert a synergistic effect when combined with PD-1 inhibitor for tumor clearance. Our study demonstrated that C5aR1 is a critical myeloid checkpoint and plays a crucial role in regulating the immunosuppressive property of TAMs and CD8+ T cell immune tolerance. C5aR1 blockade reprograms TAMs and reinvigorated the cytotoxicity of CD8+ T cells, thus improving the efficacy of anti-PD-1 therapy for tumor eradication in GC.© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.