尽管免疫检查点阻断（ICB）疗法在癌症治疗中展现出显著的效益，但部分癌症患者表现出不敏感性或因存在大量免疫抑制细胞而产生获得性耐药。作为主要的免疫抑制细胞群体，肿瘤相关巨噬细胞（TAMs）阻碍了抗肿瘤免疫应答；然而，其潜在机制尚未完全阐明。我们通过单细胞RNA测序分析来描绘巨噬细胞景观，并揭示了成分1q（C1q）阳性TAMs的潜在机制。我们使用人类和小鼠的恶性胸腔积液（MPE）来探索C1q阳性TAMs的表型和功能。C1q阳性TAMs高度表达多种抑制性分子，其高浸润与不良预后显著相关。C1q阳性TAMs通过损害CD8阳性T细胞的抗肿瘤效应，促进MPE免疫抑制。从机理上讲，C1q阳性TAMs增强脂肪酸结合蛋白5（FABP5）介导的脂肪酸代谢，激活过氧化物酶体增殖物激活受体-γ转录因子，增加抑制性分子的基因表达。高脂饮食增加C1q阳性TAMs中抑制性分子的表达，加重MPE微环境的免疫抑制效应，而低脂饮食改善这些效应。此外，FABP5抑制剂抑制TAMs中抑制性分子的表达和肿瘤进展，同时增强ICB疗法在MPE和肺癌中的疗效。C1q阳性TAMs阻碍CD8阳性T细胞的抗肿瘤效应，促进MPE免疫抑制。针对C1q阳性TAMs可有效缓解免疫抑制，并增强ICB疗法的疗效。C1q阳性TAMs亚群有望成为癌症免疫治疗的治疗靶点。 © 作者（或其雇主）2023年。根据CC BY-NC授权，允许重新使用。无商业再利用。详见权限和条款。由BMJ出版。

Although immune checkpoint blockade (ICB) therapy has shown remarkable benefits in cancers, a subset of patients with cancer exhibits unresponsiveness or develop acquired resistance due to the existence of abundant immunosuppressive cells. Tumor-associated macrophages (TAMs), as the dominant immunosuppressive population, impede the antitumor immune response; however, the underlying mechanisms have not been fully elucidated yet.Single-cell RNA sequencing analysis was performed to portray macrophage landscape and revealed the underlying mechanism of component 1q (C1q)+ TAMs. Malignant pleural effusion (MPE) of human and mouse was used to explore the phenotypes and functions of C1q+ TAMs.C1q+ TAMs highly expressed multiple inhibitory molecules and their high infiltration was significantly correlated with poor prognosis. C1q+ TAMs promote MPE immunosuppression through impairing the antitumor effects of CD8+ T cells. Mechanistically, C1q+ TAMs enhance fatty acid binding protein 5 (FABP5)-mediated fatty acid metabolism, which activate transcription factor peroxisome proliferator-activated receptor-gamma, increasing the gene expression of inhibitory molecules. A high-fat diet increases the expression of inhibitory molecules in C1q+ TAMs and the immunosuppression of MPE microenvironment, whereas a low-fat diet ameliorates these effects. Moreover, FABP5 inhibition represses the expression of inhibitory molecules in TAMs and tumor progression, while enhancing the efficacy of ICB therapy in MPE and lung cancer.C1q+ TAMs impede antitumor effects of CD8+ T cells promoting MPE immunosuppression. Targeting C1q+ TAMs effectively alleviates the immunosuppression and enhances the efficacy of ICB therapy. C1q+ TAMs subset has great potential to be a therapeutic target for cancer immunotherapy.© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.