Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan 430022, China.
Hubei Engineering Research Center for Skin Repair and Theranostics, Wuhan 430022, China.
Sci Adv. 2024 Oct 4;10(40):eado8366. doi: 10.1126/sciadv.ado8366.
Despite our increasing understanding of macrophage heterogeneity, drivers of macrophage phenotypic and functional polarization in the microenvironment are not fully elucidated. Here, our single-cell RNA sequencing data identify a subpopulation of macrophages expressing high levels of the phagocytic receptor MER proto-oncogene tyrosine kinase (MerTK macrophages), which is closely associated with melanoma progression and immunotherapy resistance. Adoptive transfer of the MerTK macrophages into recipient mice notably accelerated tumor growth regardless of macrophage depletion. Mechanistic studies further revealed that ALK And LTK Ligand 1 (ALKAL1), a target gene of aryl hydrocarbon receptor (AhR), facilitated MerTK phosphorylation, resulting in heightened phagocytic activity of MerTK macrophages and their subsequent polarization toward an immunosuppressive phenotype. Specifically targeted delivery of AhR antagonist to tumor-associated macrophages with mannosylated micelles could suppress MerTK expression and improved the therapeutic efficacy of anti-programmed cell death ligand 1 therapy. Our findings shed light on the regulatory mechanism of MerTK macrophages and provide strategies for improving the efficacy of melanoma immunotherapy.
尽管我们对巨噬细胞异质性的认识不断增加，但微环境中巨噬细胞表型和功能极化的驱动因素仍未完全阐明。在这里，我们的单细胞 RNA 测序数据确定了一个表达高水平吞噬受体 MER 原癌基因酪氨酸激酶（MerTK 巨噬细胞）的巨噬细胞亚群，该亚群与黑色素瘤的进展和免疫治疗耐药密切相关。将 MerTK 巨噬细胞过继转移到受体小鼠中，无论是否耗尽巨噬细胞，都明显加速了肿瘤的生长。机制研究进一步表明，芳香烃受体 (AhR) 的靶基因 ALK And LTK Ligand 1 (ALKAL1) 促进了 MerTK 的磷酸化，导致 MerTK 巨噬细胞的吞噬活性增强，并随后向免疫抑制表型极化。用甘露糖化胶束将 AhR 拮抗剂特异性递送至肿瘤相关巨噬细胞，可以抑制 MerTK 的表达，并提高抗程序性细胞死亡配体 1 治疗的疗效。我们的研究结果揭示了 MerTK 巨噬细胞的调控机制，并为提高黑色素瘤免疫治疗的疗效提供了策略。
