肿瘤微环境中T细胞的位置决定了其与靶点相遇和肿瘤杀伤的可能性。CD8+ T细胞在肿瘤实质中的排除与免疫疗法的反应差相关，但这种明显模式的生物学机制尚不清楚。本研究表明，血管不稳定因子血管生成素2（ANGPT2）会导致肿瘤周围血管完整性受损，导致T细胞无法渗透到肿瘤核心。与T细胞分布、血管完整性和免疫疗法反应相结合，对整个肿瘤横截面中ANGPT2的空间调节进行了分析，使用同种异体小鼠黑色素瘤模型。发现T细胞排除与ANGPT2上调和小鼠和人类黑色素瘤周围血管渗漏率升高有关。药物和基因阻断ANGPT2均促进CD8+ T细胞渗透到肿瘤核心，产生抗肿瘤效应。重要的是，阻断ANGPT2后的T细胞排除翻转不仅增强了免疫原性、对疗法有反应的小鼠黑色素瘤对抗PD-1免疫检查点阻滞疗法的反应，而且还使不反应的肿瘤对免疫疗法产生了敏感性。ANGPT2阻断后的治疗反应，由于CD8+ T细胞渗透到肿瘤核心的改善，与空间TIE2信号激活和在肿瘤周围增加血管完整性的情况相吻合，其中内皮细胞的粘附分子表达降低。这些数据凸显了ANGPT2 / TIE2信号作为T细胞排除的关键介质， 并且这是提高黑色素瘤免疫检查点阻滞疗法治疗效果的一个有前途的靶点。

T cell position in the tumor microenvironment determines the probability of target encounter and tumor killing. CD8+ T cell exclusion from the tumor parenchyma is associated with poor response to immunotherapy, and yet the biology that underpins this distinct pattern remains unclear. Here we show that the vascular destabilizing factor angiopoietin-2 (ANGPT2) causes compromised vascular integrity in the tumor periphery, leading to impaired T cell infiltration to the tumor core. The spatial regulation of ANGPT2 in whole tumor cross-sections was analyzed in conjunction with T cell distribution, vascular integrity, and response to immunotherapy in syngeneic murine melanoma models. T cell exclusion was associated with ANGPT2 upregulation and elevated vascular leakage at the periphery of human and murine melanomas. Both pharmacological and genetic blockade of ANGPT2 promoted CD8+ T cell infiltration into the tumor core, exerting antitumor effects. Importantly, the reversal of T cell exclusion following ANGPT2 blockade not only enhanced response to anti-PD-1 immune checkpoint blockade therapy in immunogenic, therapy responsive mouse melanomas, but it also rendered non-responsive tumors susceptible to immunotherapy. Therapeutic response after ANGPT2 blockade, driven by improved CD8+ T cell infiltration to the tumor core, coincided with spatial TIE2 signaling activation and increased vascular integrity at the tumor periphery where endothelial expression of adhesion molecules was reduced. These data highlight ANGPT2/TIE2 signaling as a key mediator of T cell exclusion and a promising target to potentiate immune checkpoint blockade efficacy in melanoma.