Tumor endothelial cell autophagy is a key vascular-immune checkpoint in melanoma

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 InflammatoryHigh/AutophagyLow 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. imageTumor endothelial cell (EC)-autophagy was identified as a major barrier to anti-tumor immune responses against melanoma.Endothelial cell-specific knockout of autophagy promoted the concomitant activation of the STING-Type I Interferon and NF-kappa B signaling.An "inflamed TEC" signature, identified in EC-specific autophagy-deficient mice, correlated with low vascular autophagy levels across several human cancer types.An InflamedHigh/AutophagyLow status in TECs of melanoma patients was associated with better response to anti-PD1 therapy. Tumor endothelial cell (EC)-autophagy was identified as a major barrier to anti-tumor immune responses against melanoma.image