Hou Wanting, Xiao Chaoxin, Zhou Ruihan, Yao Xiaohong, Chen Qin, Xu Tongtong, Cao Fujun, Wang Yulin, Li Xiaoying, Yan Ouying, Ai Xiaolin, Yi Cheng, Cao Dan, Zhao Chengjian
Department of Abdominal Oncology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, People's Republic of China.
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan Province, People's Republic of China.
Theranostics. 2025 Jan 1;15(1):258-276. doi: 10.7150/thno.98285. eCollection 2025.
Dysfunctional tumor vasculature, hypoxia, and an immunosuppressive microenvironment are significant barriers to effective cancer therapy. Autophagy, which is critical for maintaining cellular homeostasis and apoptosis resistance, is primarily triggered by hypoxia and nutrient deprivation, conditions prevalent in dysfunctional tumor vessels due to poor circulation. However, the role of autophagy in dysfunctional tumor endothelial cells and its impact on treatment and the tumor microenvironment (TME) remain poorly understood. We used multiplex immunofluorescence and transgene-based imaging to characterize autophagy in endothelial cells from clinical tumor samples, zebrafish xenograft tumors, and murine models. Using a zebrafish xenograft vasculature platform, we analyzed the effects of autophagy inhibitors on the structure and function of the tumor vasculature. In mice, we investigated autophagy inhibition via endothelial-specific autophagy gene knockout ( ) and the autophagy inhibitor SBI-0206965 and evaluated the synergistic effects of combining SBI-0206965 with low-dose chemotherapy (5-fluorouracil, 5-FU) or PD-1 antibody. Human umbilical vein endothelial cells (HUVECs) were cultured under hypoxic, glucose-deprived, and serum-free conditions to simulate dysfunctional tumor endothelial cells and to explore the mechanisms by which autophagy inhibition optimizes tumor vasculature. Elevated autophagy was observed in tumor endothelial cells within the dysfunctional vasculature. Autophagy inhibition, through either genetic knockout or pharmacological inhibition, selectively prunes dysfunctional vessels and improves vascular function. It also stimulates the formation of a perivascular immune niche, thereby optimizing the tumor immune microenvironment (TiME). Furthermore, combining the autophagy inhibitor SBI-0206965 with low-dose 5-FU or PD-1 antibody potentiated the anti-tumor effects. Mechanistic studies have indicated that autophagy acts as a protective response to the hypoxic and nutrient-deprived TME, while its inhibition, mediated by p53 activation, promotes tumor endothelial cell apoptosis in dysfunctional tumor vessels, further optimizing the structure and function of the tumor vasculature. Targeting endothelial cell autophagy is a promising strategy for remodeling the dysfunctional tumor vasculature, optimizing the TiME, and boosting the efficacy of chemotherapy and immunotherapy.
功能失调的肿瘤血管系统、缺氧以及免疫抑制微环境是有效癌症治疗的重大障碍。自噬对于维持细胞内稳态和抗凋亡至关重要，主要由缺氧和营养剥夺引发，而在因循环不良导致功能失调的肿瘤血管中，这些情况普遍存在。然而，自噬在功能失调的肿瘤内皮细胞中的作用及其对治疗和肿瘤微环境（TME）的影响仍知之甚少。我们使用多重免疫荧光和基于转基因的成像技术来表征临床肿瘤样本、斑马鱼异种移植肿瘤和小鼠模型中内皮细胞的自噬情况。利用斑马鱼异种移植血管平台，我们分析了自噬抑制剂对肿瘤血管结构和功能的影响。在小鼠中，我们通过内皮特异性自噬基因敲除（ ）和自噬抑制剂SBI - 0206965研究了自噬抑制作用，并评估了将SBI - 0206965与低剂量化疗药物（5 - 氟尿嘧啶，5 - FU）或PD - 1抗体联合使用的协同效应。将人脐静脉内皮细胞（HUVECs）置于缺氧、无糖和无血清条件下培养，以模拟功能失调的肿瘤内皮细胞，并探索自噬抑制优化肿瘤血管系统的机制。在功能失调的血管系统内的肿瘤内皮细胞中观察到自噬增加。通过基因敲除或药物抑制进行自噬抑制，可选择性地修剪功能失调的血管并改善血管功能。它还能刺激血管周围免疫龛的形成，从而优化肿瘤免疫微环境（TiME）。此外，将自噬抑制剂SBI - 0206965与低剂量5 - FU或PD - 1抗体联合使用可增强抗肿瘤效果。机制研究表明，自噬是对缺氧和营养缺乏的TME的一种保护反应，而由p53激活介导的自噬抑制可促进功能失调的肿瘤血管中肿瘤内皮细胞凋亡，进一步优化肿瘤血管系统的结构和功能。靶向内皮细胞自噬是重塑功能失调的肿瘤血管系统、优化TiME以及提高化疗和免疫治疗疗效的一种有前景的策略。
