Tian Hui, Zhang Baofu, Li Liantao, Wang Gang, Li Huizhong, Zheng JunNian
Cancer Institute, Xuzhou Medical University, Xuzhou, China.
Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
Front Oncol. 2020 Aug 21;10:1692. doi: 10.3389/fonc.2020.01692. eCollection 2020.
Mitochondria as the cellular energy powerhouses provide a common site for multiple metabolic reactions in order to cover energy and biomolecule demands, thus integrating the diverse metabolic pathways to endow cells with metabolic adaptation. Mitochondrial plasticity is normally regulated by mitochondrial dynamics, mitochondrial metabolism and mitochondrial biogenesis. Given that tumor cells and T cells share the metabolic similarities of survival, proliferation, expansion as well as effector function, manipulation of mitochondrial plasticity would change the metabolic competition between "foe" and "friend" during tumor malignant progression. On the one hand, for "foe" tumor cells, mitochondrial plasticity provides the enhancement of tumor metastasis and the development of resistance to' diverse antitumor drugs. On the other hand, for "friend" T cells, mitochondrial plasticity promotes the generation of long-term memory T (T) cells and alleviates the exhaustion of tumor-infiltrating lymphocytes (TILs). Therefore, downregulation of mitochondrial plasticity of tumor cells through engineering tumor-targeting nanoparticles may effectively potentiate metabolic vulnerability and re-sensitize tumor to relevant therapeutic treatment. On the contrary, upregulation of mitochondrial plasticity of T cells through optimizing adoptive cellular immunotherapy (ACI) or chimeric antigen receptor (CAR)-T cell therapy would provide T cells with the robust metabolic fitness and the persistent immune function, thus blocking tumor metastasis and reoccurrence.
线粒体作为细胞的能量动力源，为多种代谢反应提供了一个共同的场所，以满足能量和生物分子的需求，从而整合各种代谢途径，赋予细胞代谢适应性。线粒体可塑性通常由线粒体动力学、线粒体代谢和线粒体生物发生来调节。鉴于肿瘤细胞和T细胞在生存、增殖、扩增以及效应功能方面具有代谢相似性，操纵线粒体可塑性会改变肿瘤恶性进展过程中“敌”与“友”之间的代谢竞争。一方面，对于“敌”肿瘤细胞而言，线粒体可塑性会增强肿瘤转移以及对多种抗肿瘤药物产生耐药性。另一方面，对于“友”T细胞来说，线粒体可塑性会促进长期记忆性T细胞的产生，并减轻肿瘤浸润淋巴细胞（TILs）的耗竭。因此，通过构建肿瘤靶向纳米颗粒来下调肿瘤细胞的线粒体可塑性，可能有效地增强代谢脆弱性，并使肿瘤对相关治疗重新敏感。相反，通过优化过继性细胞免疫疗法（ACI）或嵌合抗原受体（CAR）-T细胞疗法来上调T细胞的线粒体可塑性，将赋予T细胞强大的代谢适应性和持久的免疫功能，从而阻断肿瘤转移和复发。
