Akter Zakia, Salamat Narges, Ali Md Yousuf, Zhang Li
Department of Biological Science, The University of Texas at Dallas, Richardson, TX, United States.
Front Oncol. 2023 Jan 4;12:1072739. doi: 10.3389/fonc.2022.1072739. eCollection 2022.
Cancer immunotherapy shows durable treatment responses and therapeutic benefits compared to other cancer treatment modalities, but many cancer patients display primary and acquired resistance to immunotherapeutics. Immunosuppressive tumor microenvironment (TME) is a major barrier to cancer immunotherapy. Notably, cancer cells depend on high mitochondrial bioenergetics accompanied with the supply of heme for their growth, proliferation, progression, and metastasis. This excessive mitochondrial respiration increases tumor cells oxygen consumption, which triggers hypoxia and irregular blood vessels formation in various regions of TME, resulting in an immunosuppressive TME, evasion of anti-tumor immunity, and resistance to immunotherapeutic agents. In this review, we discuss the role of heme, heme catabolism, and mitochondrial respiration on mediating immunosuppressive TME by promoting hypoxia, angiogenesis, and leaky tumor vasculature. Moreover, we discuss the therapeutic prospects of targeting heme and mitochondrial respiration in alleviating tumor hypoxia, normalizing tumor vasculature, and TME to restore anti-tumor immunity and resensitize cancer cells to immunotherapy.
与其他癌症治疗方式相比，癌症免疫疗法显示出持久的治疗反应和治疗益处，但许多癌症患者对免疫疗法表现出原发性和获得性耐药。免疫抑制性肿瘤微环境（TME）是癌症免疫疗法的主要障碍。值得注意的是，癌细胞依赖于高线粒体生物能量学以及血红素的供应来实现其生长、增殖、进展和转移。这种过度的线粒体呼吸增加了肿瘤细胞的耗氧量，从而在TME的各个区域引发缺氧和不规则血管形成，导致免疫抑制性TME、抗肿瘤免疫逃逸以及对免疫治疗药物的耐药性。在本综述中，我们讨论了血红素、血红素分解代谢和线粒体呼吸在通过促进缺氧、血管生成和肿瘤血管渗漏来介导免疫抑制性TME中的作用。此外，我们还讨论了靶向血红素和线粒体呼吸在缓解肿瘤缺氧、使肿瘤血管正常化以及TME以恢复抗肿瘤免疫并使癌细胞对免疫疗法重新敏感化方面的治疗前景。
