Tumor endothelial cells (TECs) actively repress inflammatory responses and maintain an immune-excluded tumor phenotype. However, the molecular mechanisms that sustain TEC-mediated immunosuppression remain largely elusive. Here, we show that autophagy ablation in TECs boosts antitumor immunity by supporting infiltration and effector function of T-cells, thereby restricting melanoma growth. In melanoma-bearing mice, loss of TEC autophagy leads to the transcriptional expression of an immunostimulatory/inflammatory TEC phenotype driven by heightened NF-kB and STING signaling. In line, single-cell transcriptomic datasets from melanoma patients disclose an enriched Inflammatory^High/Autophagy^Low TEC phenotype in correlation with clinical responses to immunotherapy, and responders exhibit an increased presence of inflamed vessels interfacing with infiltrating CD8⁺ T-cells. Mechanistically, STING-dependent immunity in TECs is not critical for the immunomodulatory effects of autophagy ablation, since NF-kB-driven inflammation remains functional in STING/ATG5 double knockout TECs. Hence, our study identifies autophagy as a principal tumor vascular anti-inflammatory mechanism dampening melanoma antitumor immunity.

中文翻译：

---

肿瘤内皮细胞自噬是黑色素瘤中关键的血管免疫检查点

肿瘤内皮细胞（TEC）主动抑制炎症反应并维持免疫排斥的肿瘤表型。然而，维持 TEC 介导的免疫抑制的分子机制在很大程度上仍然难以捉摸。在这里，我们发现 TEC 中的自噬消融通过支持 T 细胞的浸润和效应功能来增强抗肿瘤免疫力，从而限制黑色素瘤的生长。在患有黑色素瘤的小鼠中，TEC 自噬的丧失导致由 NF-kB 和 STING 信号传导增强驱动的免疫刺激/炎症 TEC 表型的转录表达。来自黑色素瘤患者的单细胞转录组数据集揭示了与免疫治疗的临床反应相关的丰富的炎症性^高/自噬^低TEC 表型，并且反应者表现出与浸润性 CD8 ⁺ T 细胞连接的炎症血管的存在增加。从机制上讲，TEC 中的 STING 依赖性免疫对于自噬消融的免疫调节作用并不重要，因为 NF-kB 驱动的炎症在 STING/ATG5 双敲除 TEC 中仍然发挥作用。因此，我们的研究确定自噬是抑制黑色素瘤抗肿瘤免疫的主要肿瘤血管抗炎机制。