Targeted Anti-Mitochondrial Therapy: The Future of Oncology

Abstract

Like living organisms, cancer cells require energy to survive and interact with their environment. Mitochondria are the main organelles for energy production and cellular metabolism. Recently, investigators demonstrated that cancer cells can hijack mitochondria from immune cells. This behavior sheds light on a pivotal piece in the cancer puzzle, the dependence on the normal cells. This article illustrates the benefits of new functional mitochondria for cancer cells that urge them to hijack mitochondria. It describes how functional mitochondria help cancer cells' survival in the harsh tumor microenvironment, immune evasion, progression, and treatment resistance. Recent evidence has put forward the pivotal role of mitochondria in the metabolism of cancer stem cells (CSCs), the tumor components responsible for cancer recurrence and metastasis. This theory highlights the mitochondria in cancer biology and explains how targeting mitochondria may improve oncological outcomes.

Keywords: ATP; T cell; cancer cell; cancer stem cell; cancer treatment; mitochondria.

Figure 1

Schematic model of mitochondria’s role in cancer survival, immune evasion, progression, and treatment resistance. The white boxes depict the mitochondria regulation outcomes. (A) Survival in the tumor microenvironment (TME) (orange area): Functional mitochondria are requisite for cancer cells to survive in the harsh TME by facilitating/mediating (A1) glycolysis, (A2) ROS clearing, (A3) cell cycle arrest, (A4) enhanced pH homeostasis, (A5) autophagy, (A6) mitochondrial hijacking, and (A7) angiogenesis. (B) Immune evasion (purple area): Mitochondria assist cancer cells in evading the immune cells by mediating (B1) TME acidification, (B2) glucose influx, (B3) PD-1 upregulation on T cells (by mitochondrial hijacking), (B4) recruiting myeloid-derived suppressor cells (MDSCs), (B5) PD-L1 overexpression on cancer cells, (B6) MHC-1 downregulation, and (B7) immunosuppressants secretion. Moreover, mitochondrial hijacking from T cells depletes T cells’ energy and impedes long-term activity against cancer. (3) Malignancy upgrading (light blue area): Mitochondria are essential for cancer progression by mediating (C1) genomic instability, (C2) quiescence evasion, and (C3) epithelial-to-mesenchymal transition. These actions are mediated by reactive oxygen species (ROS) production. (D) Resistance to treatment (dark blue area): (D1) Mitochondria can serve as a defense shield for cancer cells against radiotherapy and chemotherapy by clearing ROSs. (D2–4) Moreover, they improve chemotherapy resistance by mediating efflux pump expression, providing ATP for efflux pumps, and inducing cell cycle arrest. (D5) In addition, mitochondria hijacking from T cells impairs the long-term effect of anti-PD-1 immunotherapy. Note: The HIF- and GTP-mediated extracellular outcomes are shown in their corresponding white boxes. ATP indicates adenosine triphosphate; CA IX, carbonic anhydrase IX; EMT, epithelial–mesenchymal transition; FAK/Src/MAPK, focal adhesion kinase/Src/mitogen-activated protein kinase; GLUT-1, Glucose transporter-1; GTP, guanosine triphosphate; G6PD, glucose 6-phosphate dehydrogenase; HIF, hypoxia-inducible factor; HK2, hexokinase 2; IFN, interferon; IL-10, interleukin-10; LDH, lactate dehydrogenase; MDSC, myeloid-derived suppressor cell; MHC-1, major histocompatibility complex class I; mTORC1, mechanistic target of rapamycin complex 1; mtDNA, mitochondrial DNA; NADPH, nicotinamide adenine dinucleotide phosphate; NRF2, nuclear factor-erythroid 2 related factor 2; PI3K/Akt/mTOR, phosphatidylinositol-3- kinase/protein kinase B/mammalian target of rapamycin; PD-1, programmed cell death protein-1; PD-L1, programmed cell death protein-ligand 1; PKM2, pyruvate kinase M2; ROS, reactive oxygen species; STING, stimulator of interferon genes; TGF-β,transforming growth factor-beta; TME, tumor microenvironment; VEGF, vascular endothelial growth factor; VEGFA/SOX2/SNAI2, vascular endothelial growth factor A-SRY-Box Transcription Factor 2.