The immune system is a potent defense mechanism regulating tumor development and progression. However, immune cells are often functionally compromised in cancer patients, and tumor rejection does not follow successful induction of a CTL response. This is, in part, due to the existing conflict between the tumor system and an unfavorable tumor microenvironment (TME) that is able to neutralize or paralyze the immune system of the host. The recent advances in the field of immune checkpoint inhibitors have changed the focus from targeting the tumor to targeting T lymphocytes. It has been well established that the TME and associated multiple factors contribute to the failures in cancer therapies, including immunotherapy. In this regard, hypoxia, which is a hallmark of solid tumors, is strongly associated with advanced disease stages and poor clinical outcomes. Hypoxia plays a crucial role in tumor promotion and immune escape by conferring tumor resistance, immunosuppression, and tumor heterogeneity, which contribute to the generation of diverse cancer invasion programs and enhanced stroma plasticity. Tumor hypoxic stress interferes with the mesenchymal transition EMT, conferring to cancer cells a high degree of plasticity and the capacity to escape from immune surveillance. Tumors have been also shown to take advantage of hypoxic conditions that impede normal cells. Thus, tumor progression may be mediated by hypoxia-induced phenotypic changes and subsequent clonal selection of malignant cells that overexpress hypoxia-responsive molecules, such as HIF-1α. Currently, the resistance of tumor cells to cell-mediated cytotoxicity remains a drawback in the immunotherapy of cancer, and its molecular basis is poorly understood. In this review, I focus on hypoxia as a key process that evolved in the TME, and I discuss how solid tumors use hypoxic stress as a potent saboteur of the antitumor immune reaction by shaping a compromised cytotoxic cell function through the alteration of tumor target susceptibility to cell-mediated cytotoxicity. Exploiting hypoxia-associated tumor escape capacities may hold promise for attenuating tumor heterogeneity and plasticity, overcoming alteration of antitumor cytotoxic response and improving its effectiveness in cancer patients.

中文翻译：

---

抗肿瘤细胞毒性反应：如果杀伤细胞播放音乐，则微环境缺氧播放音乐。

免疫系统是调节肿瘤发展和进程的有效防御机制。但是，免疫细胞通常在癌症患者中功能受损，并且肿瘤排斥反应不会成功诱导CTL反应。部分原因是由于肿瘤系统与不利的肿瘤微环境（TME）之间存在冲突，该环境能够中和或瘫痪宿主的免疫系统。免疫检查点抑制剂领域的最新进展已将重点从靶向肿瘤变为靶向T淋巴细胞。众所周知，TME和相关的多种因素会导致包括免疫治疗在内的癌症治疗失败。在这方面，缺氧是实体瘤的标志，与晚期疾病和不良的临床结局密切相关。缺氧通过赋予肿瘤抗性，免疫抑制和肿瘤异质性，在肿瘤的促进和免疫逃逸中起关键作用，这有助于产生多种癌症侵袭程序并增强基质可塑性。肿瘤的低氧应激会干扰间充质转化EMT，从而赋予癌细胞高度的可塑性和逃避免疫监视的能力。还显示出肿瘤利用了阻碍正常细胞的低氧条件。因此，肿瘤的进展可能是由低氧诱导的表型变化和随后过度表达低氧反应性分子（例如HIF-1α）的恶性细胞的克隆选择介导的。目前，肿瘤细胞对细胞介导的细胞毒性的抗性仍然是癌症免疫治疗中的一个缺点，其分子基础尚不为人所知。在这篇综述中，我将缺氧作为TME中发展的关键过程，并讨论实体瘤如何通过改变肿瘤靶标易感性来塑造受损的细胞毒性细胞功能，从而利用低氧应激作为抗肿瘤免疫反应的有效破坏者。对细胞介导的细胞毒性。利用与缺氧相关的肿瘤逃逸能力可能有望减弱肿瘤的异质性和可塑性，克服抗肿瘤细胞毒性反应的改变并提高其在癌症患者中的有效性。我将缺氧作为TME中发展的关键过程，并讨论实体肿瘤如何通过改变肿瘤靶标对细胞介导的易感性而形成受损的细胞毒性细胞功能，从而利用低氧应激作为抗肿瘤免疫反应的有效破坏者。细胞毒性。利用与缺氧相关的肿瘤逃逸能力可能有望减弱肿瘤的异质性和可塑性，克服抗肿瘤细胞毒性反应的改变并提高其在癌症患者中的有效性。我将缺氧作为TME中发展的关键过程，并讨论实体肿瘤如何通过改变肿瘤靶标对细胞介导的易感性而形成受损的细胞毒性细胞功能，从而利用低氧应激作为抗肿瘤免疫反应的有效破坏者。细胞毒性。利用与缺氧相关的肿瘤逃逸能力可能有望减弱肿瘤的异质性和可塑性，克服抗肿瘤细胞毒性反应的改变并提高其在癌症患者中的有效性。