Immune Cells vs. Cancer Cells: A Microscopic Energy Battle 2

45 Like living organisms, cancer cells require energy to survive and interact with their environment. 46 Recently, investigators demonstrated that cancer cells can hijack mitochondria from immune cells. 47 This behavior sheds light on a pivotal piece in the puzzle of cancer, the ‘ dependence ’ . This article 48 illustrates how new, functional mitochondria help cancer cells to survive in the harsh tumor 49 microenvironment, evade immune cells, and improve their malignancy. Finally, we will discuss how 50 blocking the routes supplying energy for cancer cells can improve the treatment outcomes of 51 radiotherapy, chemotherapy, and immunotherapy. This article provides a new theory in oncology, 52 the ‘ energy battle ’ between cancer and immune cells. It alludes each party with a higher energy level 53 can be the winner. This theory explains cancer biogenesis and provides novel insights to improve 54 treatment outcomes. 55


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All living organisms require energy for their maintenance, growth, repopulation, and 59 appropriate response to external stimuli. Some organisms are self-sufficient ('autotrophs') and 60 acquire energy from sunlight or chemicals. The remaining organisms ('heterotrophs') rely on 61 autotrophs to secure energy [1] . A recent in vitro experiment from the United States demonstrated 62 that cancer cells are dependent on normal cells for their living and function. In Nov 2021, Saha et 63 al. demonstrated that cancer cells can hijack mitochondria (the cell's energy factories) from immune 64 cells via nanoscale tube-like structures [2] . Besides providing energy, mitochondria are essential 65 mediators for cancer cells' survival and evolution. In the following section, we describe how new, 66 functional mitochondria are vital for evolving cancer. Cancer cells can survive in the harsh tumor microenvironment (TME) by (1) metabolic 73 switch to aerobic glycolysis (Warburg effect), (2) enhanced antioxidant capacity, (3) protective cell 74 cycle arrest ('quiescence' or 'dormancy'), and (4) autophagy [3] . Mitochondria are involved in the 75 aforementioned four strategies. Hexokinase (HK) is the rate-limiting enzyme of glycolysis, which 76 catalyzes the phosphorylation of glucose to glucose-6P. Functional mitochondria enable cancer cells 77 to drive sustained aerobic glycolysis by protecting HK from ubiquitination and by saving HK from 78 the negative-feedback effect of downstream glucose-6P [4] . The sustained glycolytic pathway provides 79 three benefits for cancer cells: (1) aerobic glycolysis can satisfy the anabolic demands of cancer cells 80 by providing lipids, proteins, and nucleotides [5] ; (2) the pyruvates (interim products of aerobic 81 glycolysis) can serve as an antioxidant and neutralizes the intracellular reactive oxygen species 82 (ROS)-as a byproduct of cellular metabolism [6] ; and (3) normoxic cancer cells can utilize lactate 83 (final products of glycolysis) as an energy source ('metabolic symbiosis') [5] . Emerging evidence has 84 put forward the mitochondria reaction to hypoxia in dormant cancer cells. In an in vitro model of 85 dormant breast cancer, chronic hypoxia led to a marked increase in mitochondria number and 86 mitochondrial ROS (mtROS)-denoting mitochondria metabolism [7] . In addition, mitochondria 87 hijacking enables cancer cells to replace the old, defective mitochondria (degraded by mitophagy) 88 with the new, functional mitochondria from immune cells to reply to the mitochondria demands [2] . into TME, defective antigen presentation, and releasing immune-suppressive mediators [9] . In 97 addition, the new functional mitochondria enable cancer cells to run more aerobic glycolysis. The 98 glycolysis upregulation leads to TME acidosis by disposing of lactate-as the end product of aerobic 99 glycolysis-in the extracellular milieu. In low-pH TME, T cells lose their function and enter a state 100 of anergy followed by apoptosis. Moreover, the activated glycolysis leads to enhanced expression of 101 glucose transporters (such as GLUT-1) and glycolytic enzymes in cancer cells. This process is 102 mediated by lactate-induced hypoxia-inducible factor-1α (HIF-1α) overexpression, which in turn 103 upregulates the GLUT-1 [10][11][12] . This process makes the glucose out of the reach of T cells and further 104 impedes the appropriate function of immune cells.

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Mitochondria generate 90% of the total cellular ROS volume [13] . Cancer cells with more 108 functional mitochondria have an elevated 'ROS balance'. In other words, they can generate more 109 mtROS on one hand, and better remove the generated ROS on the other hand. The former gives 110 rise to genomic instability, cell cycle checkpoint evasion, and enhances the ability to metastasize (by 111 driving epithelial-mesenchymal transition), and the latter impedes self-damage of oxidative stress to 112 mitochondrial and cellular nucleic acid, proteins, and lipids [14] .

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Most chemotherapeutics trigger cell death through oxidative stress. This is mediated by 116 damage to cancer cell components and promoting apoptosis [15] . Ionizing radiation can damage cancer cells by direct damage to DNA or dominantly through ROS generation and indirect damages to 118 cellular or mitochondrial components [16] . Mitochondria protect cancer cells from chemotherapy and 119 radiotherapy by scavenging the generated ROS. Besides, mitochondria can give rise to multidrug 120 resistance by providing enough ATP molecules for the ATP-dependent multidrug efflux pumps [17] .

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In addition to radiotherapy and chemotherapy, mitochondria can enhance the resistance to proliferation, migration, and cancer cell killing [18][19][20] . All these phases are ATP-dependent [8,18] . On 145 the other hand, cancer cells with weaker mitochondria cannot tolerate the bulk of ROSs generated 146 during radiotherapy and chemotherapy. Shifting the energy balance toward the immune cells can be 147 achieved by improving T cells' mitochondria in quantity and quality. For the primer, the T cells' 148 mitochondria numbers can be saved by blocking mitochondria hijacking [2] . The mitochondria 149 quality can increase by two strategies; (1) improving the lifestyle by regular exercise [21] , low-SDA 150 (specific dynamic action) diet [22] , good sleep [23] , healthy weight [24] , and smoking cessation [25] ; and

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Hitherto, scientists believed that cancer is an autonomous organism that does not obey the general 158 body regulations [27] . This notion seems to be true; however, it is not the whole story. The recent 159 finding of mitochondria hijacking from immune cells revealed another behavior of cancer cells, the 160 reliance on normal cells for survival and function. This feature seems to be cancer's Achilles' heel, 161 and the human being can overcome cancer by targeting this-and the possible other-route for 162 energy supply. Further studies are warranted to examine this theory. Abbreviations: EMT, epithelial-mesenchymal transition; GLUT-1, Glucose transporter-1; HIF, hypoxia-inducible 243 factor; HK, hexokinase; PD-1, programmed cell death protein-1; ROS, reactive oxygen species; TME, tumor 244 microenvironment. (Created with BioRender.com) 245