Paradoxically, obesity is a risk factor for cancer but is also associated with a survival advantage in patients treated with immune-checkpoint inhibitors. Macrophage expression of programmed cell death protein 1 (PD1) might link these two findings, according to a new study by Jeffrey Rathmell and colleagues.

In vitro, upregulation of PD1 expression on macrophages depended on inflammation-induced glycolysis; enhanced PD1 had direct effects on the macrophage phenotype as it promoted lipid uptake and metabolism, while inhibiting glycolysis and phagocytosis. Accordingly, in vivo anti-PD1 treatment increased TAM phagocytosis and lowered lipid uptake, with reduced tumour weight even in T cell-depleted mice. Moreover, selective loss of PD1 on macrophages improved T cell activation and proliferation. Overall, despite its protumour effects, obesity-induced PD1 on TAMs might enhance the benefits of targeting PD1 beyond its direct effects on T cells by rewiring macrophages.

矛盾的是，肥胖是癌症的危险因素，但也与接受免疫检查点抑制剂治疗的患者的生存优势相关。 Jeffrey Rathmell 及其同事的一项新研究表明，程序性细胞死亡蛋白 1 (PD1) 的巨噬细胞表达可能将这两个发现联系起来。

在体外，巨噬细胞上 PD1 表达的上调取决于炎症诱导的糖酵解；增强的PD1对巨噬细胞表型有直接影响，因为它促进脂质摄取和代谢，同时抑制糖酵解和吞噬作用。因此，体内抗PD1治疗增加了TAM吞噬作用并降低了脂质摄取，甚至在T细胞耗尽的小鼠中也减少了肿瘤重量。此外，巨噬细胞上PD1的选择性缺失改善了T细胞的活化和增殖。总体而言，尽管具有促肿瘤作用，但肥胖诱导的 TAM 上的 PD1 可能会增强靶向 PD1 的益处，超越其通过重新连接巨噬细胞对 T 细胞的直接影响。