检查点抑制剂，特别是抗 PD-1，已在治疗转移性黑色素瘤方面取得了成功；然而，一些患者会产生耐药性。树突状细胞（DC）在启动免疫反应中发挥着关键作用，但在某些情况下它们会变得无效。我们研究了 MerTK（一种负责骨髓细胞清除死细胞的受体酪氨酸激酶）在肿瘤微环境中 DC 功能和代谢调节中的作用。对 PD-1 耐药的肿瘤表现出 MerTK DC 水平升高。在体外用凋亡的死亡黑色素瘤细胞处理野生型 DC 会导致 MerTK 表达增加、线粒体呼吸和脂肪酸氧化升高以及 T 细胞刺激能力降低，这些都是功能失调的 DC 的特征。相比之下，死亡细胞对 MerTK 缺陷的 DC 的代谢影响有限，相反， DC 维持了抗原呈递、刺激表型。在 DC 室中选择性消融 MerTK 的小鼠中，抗 PD-1 减缓肿瘤进展和诱导特异性 T 细胞浸润的功效显着增加，这表明治疗靶向 MerTK 来调节 DC 代谢和功能并增强抗 PD-1 的可能性。 -PD-1疗法。

Checkpoint inhibitors, specifically anti-PD-1, have shown success in treating metastatic melanoma; however, some patients develop resistance. Dendritic cells (DCs) play a key role in initiating an immune response but in certain circumstances they become ineffective. We investigated the role of MerTK, a receptor tyrosine kinase responsible for myeloid cell clearance of dead cells, in the regulation of DC function and metabolism in the tumor microenvironment. Tumors resistant to anti-PD-1 exhibited increased levels of MerTK+ DCs. Treating wild-type DCs with apoptotic dead melanoma cells in vitro resulted in increased MerTK expression, elevated mitochondrial respiration and fatty acid oxidation, and reduced T-cell stimulatory capacity, all characteristics of dysfunctional DCs. In contrast, dead cells had only limited effect on the metabolism of MerTK-deficient DCs, which instead maintained an antigen presenting, stimulatory phenotype. The efficacy of anti-PD-1 to slow tumor progression and induce specific T-cell infiltration was markedly increased in mice with selective ablation of MerTK in the DC compartment, suggesting the possibility of therapeutically targeting MerTK to modulate DC metabolism and function and enhance anti-PD-1 therapy.