Hypoxia, a hallmark of solid tumors, determines the selection of invasive and aggressive malignant clones displaying resistance to radiotherapy, conventional chemotherapy or targeted therapy. The recent introduction of immunotherapy, based on immune checkpoint inhibitors (ICPIs) and chimeric antigen receptor (CAR) T-cells, has markedly transformed the prognosis in some tumors but also revealed the existence of intrinsic or acquired drug resistance. In the current review we highlight hypoxia as a culprit of immunotherapy failure. Indeed, multiple metabolic cross talks between tumor and stromal cells determine the prevalence of immunosuppressive populations within the hypoxic tumor microenvironment and confer upon tumor cells resistance to ICPIs and CAR T-cells. Notably, hypoxia-triggered angiogenesis causes immunosuppression, adding another piece to the puzzle of hypoxia-induced immunoresistance. If these factors concurrently contribute to the resistance to immunotherapy, they also unveil an unexpected Achille’s heel of hypoxic tumors, providing the basis for innovative combination therapies that may rescue the efficacy of ICPIs and CAR T-cells. Although these treatments reveal both a bright side and a dark side in terms of efficacy and safety in clinical trials, they represent the future solution to enhance the efficacy of immunotherapy against hypoxic and therapy-resistant solid tumors.

缺氧是实体瘤的标志，它决定了对放射治疗、常规化疗或靶向治疗表现出抗性的侵袭性和侵袭性恶性克隆的选择。最近引入的基于免疫检查点抑制剂 (ICPI) 和嵌合抗原受体 (CAR) T 细胞的免疫疗法显着改变了一些肿瘤的预后，但也揭示了存在内在或获得性耐药性。在当前的综述中，我们强调缺氧是免疫治疗失败的罪魁祸首。事实上，肿瘤和基质细胞之间的多重代谢交叉对话决定了缺氧肿瘤微环境中免疫抑制群体的普遍性，并赋予肿瘤细胞对 ICPI 和 CAR T 细胞的抗性。值得注意的是，缺氧触发的血管生成会导致免疫抑制，为缺氧诱导的免疫抗性之谜增添了另一块。如果这些因素同时导致对免疫治疗的抵抗，它们也揭示了一个意想不到的缺氧肿瘤的致命弱点，为可能挽救 ICPI 和 CAR T 细胞功效的创新联合疗法提供基础。尽管这些治疗在临床试验中的疗效和安全性方面既有光明的一面，也有黑暗的一面，但它们代表了未来提高免疫疗法对缺氧和耐药实体瘤疗效的解决方案。为可能挽救 ICPI 和 CAR T 细胞功效的创新联合疗法提供基础。尽管这些治疗在临床试验中的疗效和安全性方面既有光明的一面，也有黑暗的一面，但它们代表了未来提高免疫疗法对缺氧和耐药实体瘤疗效的解决方案。为可能挽救 ICPI 和 CAR T 细胞功效的创新联合疗法提供基础。尽管这些治疗在临床试验中的疗效和安全性方面既有光明的一面，也有黑暗的一面，但它们代表了未来提高免疫疗法对缺氧和耐药实体瘤疗效的解决方案。