Jayaprakash Priyamvada, Vignali Paolo Dario Angelo, Delgoffe Greg M, Curran Michael A
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA; email:
Tumor Microenvironment Center, Department of Immunology, UPMC Hillman Cancer Center and University of Pittsburgh, Pittsburgh, Pennsylvania 15232, USA.
Annu Rev Med. 2022 Jan 27;73:251-265. doi: 10.1146/annurev-med-060619-022830. Epub 2021 Oct 26.
In order to fuel their relentless expansion, cancers must expand their vasculature to augment delivery of oxygen and essential nutrients. The disordered web of irregular vessels that results, however, leaves gaps in oxygen delivery that foster tumor hypoxia. At the same time, tumor cells increase their oxidative metabolism to cope with the energetic demands of proliferation, which further worsens hypoxia due to heightened oxygen consumption. In these hypoxic, nutrient-deprived environments, tumors and suppressive stroma evolve to flourish while antitumor immunity collapses due to a combination of energetic deprivation, toxic metabolites, acidification, and other suppressive signals. Reversal of cancer hypoxia thus has the potential to increase the survival and effector function of tumor-infiltrating T cells, as well as to resensitize tumors to immunotherapy. Early clinical trials combining hypoxia reduction with immune checkpoint blockade have shown promising results in treating patients with advanced, metastatic, and therapeutically refractory cancers.
为了推动其不断的扩张，癌症必须扩展其脉管系统以增加氧气和必需营养物质的输送。然而，由此产生的紊乱的不规则血管网络会导致氧气输送出现缺口，进而引发肿瘤缺氧。与此同时，肿瘤细胞会增加其氧化代谢以应对增殖所需的能量需求，由于耗氧量增加，这会进一步加剧缺氧。在这些缺氧、营养匮乏的环境中，肿瘤和抑制性基质不断演变并蓬勃发展，而抗肿瘤免疫则因能量剥夺、有毒代谢产物、酸化及其他抑制性信号的综合作用而崩溃。因此，逆转癌症缺氧有可能提高肿瘤浸润性T细胞的存活率和效应功能，同时使肿瘤对免疫疗法重新敏感。将降低缺氧与免疫检查点阻断相结合的早期临床试验在治疗晚期、转移性和难治性癌症患者方面已显示出有前景的结果。
