Metabolic Reprogramming of Immune Cells in Cancer Progression

Immune cells play a key role in host defense against infection and cancer. Upon encountering danger signals, these cells undergo activation leading to a modulation in their immune functions. However, recent studies reveal that immune cells upon activation also show distinct metabolic changes that impact their immune functions. Such metabolic reprogramming and its functional effects are well known for cancer cells. Given that immune cells have emerged as crucial players in cancer progression, it is important to understand whether immune cells also undergo metabolic reprogramming in tumors and how this might affect their contribution in cancer progression. This emerging aspect of tumor-associated immune cells is reviewed here, discussing metabolic reprogramming of different immune cell types, the key pathways involved, and its impact on tumor progression. Immune cells play a key role in host defense against infection and cancer. Upon encountering danger signals, these cells undergo activation leading to a modulation in their immune functions. However, recent studies reveal that immune cells upon activation also show distinct metabolic changes that impact their immune functions. Such metabolic reprogramming and its functional effects are well known for cancer cells. Given that immune cells have emerged as crucial players in cancer progression, it is important to understand whether immune cells also undergo metabolic reprogramming in tumors and how this might affect their contribution in cancer progression. This emerging aspect of tumor-associated immune cells is reviewed here, discussing metabolic reprogramming of different immune cell types, the key pathways involved, and its impact on tumor progression. The role of immune cells in cancer progression is well-recognized. Inflammation and immune evasion are considered as hallmarks of cancer progression, highlighting the direct involvement of immune cells (Hanahan and Weinberg, 2011Hanahan D. Weinberg R.A. Hallmarks of cancer: the next generation.Cell. 2011; 144: 646-674Abstract Full Text Full Text PDF PubMed Scopus (10320) Google Scholar). Supporting this fact, macrophages, which represent one of the major immune infiltrates in solid tumors, influence various aspect of cancer progression, e.g., survival and proliferation of cancer cells, angiogenesis, metastasis, cancer-related inflammation, and immunosuppression (Biswas and Mantovani, 2010Biswas S.K. Mantovani A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm.Nat. Immunol. 2010; 11: 889-896Crossref PubMed Scopus (738) Google Scholar, Qian and Pollard, 2010Qian B.Z. Pollard J.W. Macrophage diversity enhances tumor progression and metastasis.Cell. 2010; 141: 39-51Abstract Full Text Full Text PDF PubMed Scopus (995) Google Scholar). Similarly, other studies have indicated the involvement of almost every immune cell type including T cells, B cells, NK cells, NKT cells, basophils, neutrophils, dendritic cells (DCs), and myeloid-derived suppressor cells (MDSCs) in the regulation of cancer progression (Bindea et al., 2013Bindea G. Mlecnik B. Tosolini M. Kirilovsky A. Waldner M. Obenauf A.C. Angell H. Fredriksen T. Lafontaine L. Berger A. et al.Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer.Immunity. 2013; 39: 782-795Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar, Biswas and Mantovani, 2010Biswas S.K. Mantovani A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm.Nat. 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Med. 2013; 19: 1423-1437Crossref PubMed Scopus (309) Google Scholar). Recent studies have revealed that immune cells possess distinct metabolic characteristics that influence their immunological functions. For example, macrophage polarization is related to distinct metabolic characteristics pertaining to energy metabolism, iron metabolism, and lipid metabolism (Biswas and Mantovani, 2010Biswas S.K. Mantovani A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm.Nat. Immunol. 2010; 11: 889-896Crossref PubMed Scopus (738) Google Scholar, Jha et al., 2015Jha A.K. Huang S.C. Sergushichev A. Lampropoulou V. Ivanova Y. Loginicheva E. Chmielewski K. Stewart K.M. Ashall J. Everts B. et al.Network Integration of Parallel Metabolic and Transcriptional Data Reveals Metabolic Modules that Regulate Macrophage Polarization.Immunity. 2015; 42: 419-430Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). Similarly, alterations in glucose and amino acid metabolism were reported for DCs and T cells upon activation (Pearce and Pearce, 2013Pearce E.L. Pearce E.J. Metabolic pathways in immune cell activation and quiescence.Immunity. 2013; 38: 633-643Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar). Taken together, these studies indicate that metabolic reprogramming is an important feature of immune cell activation. Metabolic reprogramming has been suggested as a key hallmark of cancer progression (Hanahan and Weinberg, 2011Hanahan D. Weinberg R.A. Hallmarks of cancer: the next generation.Cell. 2011; 144: 646-674Abstract Full Text Full Text PDF PubMed Scopus (10320) Google Scholar, Ward and Thompson, 2012Ward P.S. Thompson C.B. Metabolic reprogramming: a cancer hallmark even warburg did not anticipate.Cancer Cell. 2012; 21: 297-308Abstract Full Text Full Text PDF PubMed Scopus (587) Google Scholar). Cancer cells undergo an alteration in their mode of energy metabolism in order to fulfill the bioenergetic and biosynthetic needs for rapid cell proliferation, as well as to adapt to the tumor microenvironment. While such metabolic alterations in cancer cells has been long known, a key question that has not been investigated to depth is whether tumor-associated immune cells also undergo metabolic alterations during cancer progression. This is a pertinent question given the integral role of immune cells in cancer and their metabolic characteristics in other scenarios (e.g., infection, metabolic syndrome). This issue is reviewed here, highlighting the importance of metabolic reprogramming in the regulation of tumor-associated immune cell functions. In addition, some key molecular determinants that mediate the metabolic reprogramming in these cells and the therapeutic implications that might arise from these findings are also discussed. Cancer cells need to fulfill their bioenergetic and biosynthetic demands to support rapid proliferation. To do so, they alter their energy metabolism to a glycolytic mode, even under aerobic conditions, for rapid energy generation. This aerobic form of glycolysis is also known as Warburg effect (Ward and Thompson, 2012Ward P.S. Thompson C.B. Metabolic reprogramming: a cancer hallmark even warburg did not anticipate.Cancer Cell. 2012; 21: 297-308Abstract Full Text Full Text PDF PubMed Scopus (587) Google Scholar). Thus, tumor cells get most of their energy through high consumption of glucose and its conversion into lactic acid by glycolysis, as opposed to mitochondrial oxidative phosphorylation in normal cells (Figure 1). The glycolytic switch is also a useful adaptation to survive in the hypoxic tumor microenvironment. The shift to glycolysis is triggered by various mechanisms reviewed elsewhere (Cairns et al., 2011Cairns R.A. Harris I.S. Mak T.W. Regulation of cancer cell metabolism.Nat. Rev. Cancer. 2011; 11: 85-95Crossref PubMed Scopus (1018) Google Scholar, Ward and Thompson, 2012Ward P.S. Thompson C.B. Metabolic reprogramming: a cancer hallmark even warburg did not anticipate.Cancer Cell. 2012; 21: 297-308Abstract Full Text Full Text PDF PubMed Scopus (587) Google Scholar). For example, growth-factor signaling activates phosphoinositol 3-kinase (PI3K)-AKT, which induces the expression of glucose transporters (e.g., GLUT1) and the activation of glycolytic enzymes (e.g., HK2, PFKFB3). Mechanistically, PI3K-AKT signaling activates mammalian target of rapamycin (mTOR), which in turn activates the transcription factor, hypoxia-inducible factor 1 (HIF1). HIF1 cooperates with other transcription factors or oncogenes such as c-Myc, p53, or Oct1 to induce the expression of glycolytic genes including GLUT1, HK2, PFKFB3, LDHA, and suppressors of tricarboxylic acid (TCA) cycle such as PDK (Cairns et al., 2011Cairns R.A. Harris I.S. Mak T.W. Regulation of cancer cell metabolism.Nat. Rev. Cancer. 2011; 11: 85-95Crossref PubMed Scopus (1018) Google Scholar, Semenza, 2003Semenza G.L. Targeting HIF-1 for cancer therapy.Nat. Rev. Cancer. 2003; 3: 721-732Crossref PubMed Google Scholar, Ward and Thompson, 2012Ward P.S. Thompson C.B. Metabolic reprogramming: a cancer hallmark even warburg did not anticipate.Cancer Cell. 2012; 21: 297-308Abstract Full Text Full Text PDF PubMed Scopus (587) Google Scholar). Moreover, mutations in TCA cycle enzymes such as succinate dehydrogenase (SDH) or fumarate hydratase (FH) also contribute to the inhibition of this pathway while promoting glycolysis through HIF1 activation. Collectively, these events culminate in the metabolic reprogramming of cancer cells to a predominantly glycolytic mode of energy metabolism (Figure 1). Cancer cells require high concentrations of glutamine, which is necessary for supporting robust cell proliferation. Through the process of glutaminolysis, glutamine is converted to glutamate by glutaminase (GLS) and then to α-ketoglutarate (α-KG), which enters the TCA cycle to contribute to amino acid, nucleotide, and fatty-acid biosynthesis (Figure 1). Mechanistically, c-Myc plays an important role in promoting glutaminolysis in these cells (Gao et al., 2009Gao P. Tchernyshyov I. Chang T.C. Lee Y.S. Kita K. Ochi T. Zeller K.I. De Marzo A.M. Van Eyk J.E. Mendell J.T. Dang C.V. c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism.Nature. 2009; 458: 762-765Crossref PubMed Scopus (645) Google Scholar, Wise et al., 2008Wise D.R. DeBerardinis R.J. Mancuso A. Sayed N. Zhang X.Y. Pfeiffer H.K. Nissim I. Daikhin E. Yudkoff M. McMahon S.B. Thompson C.B. Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction.Proc. Natl. Acad. Sci. USA. 2008; 105: 18782-18787Crossref PubMed Scopus (540) Google Scholar). In addition, glutamine can also get converted to glutathione and thus contribute to the redox state. Cancer cells undergo changes in their lipid metabolism acquiring a lipogenic phenotype. The enzyme monoacylglycerol lipase (MAGL) is highly expressed in cancer cells, where it regulates a pro-tumorigenic lipid network that supports tumor growth (Nomura et al., 2010Nomura D.K. Long J.Z. Niessen S. Hoover H.S. Ng S.W. Cravatt B.F. Monoacylglycerol lipase regulates a fatty acid network that promotes cancer pathogenesis.Cell. 2010; 140: 49-61Abstract Full Text Full Text PDF PubMed Scopus (295) Google Scholar). On the basis of the various metabolic changes discussed above, metabolic reprogramming of cancer cells is indeed a hallmark of cancer progression (Hanahan and Weinberg, 2011Hanahan D. Weinberg R.A. Hallmarks of cancer: the next generation.Cell. 2011; 144: 646-674Abstract Full Text Full Text PDF PubMed Scopus (10320) Google Scholar, Ward and Thompson, 2012Ward P.S. Thompson C.B. Metabolic reprogramming: a cancer hallmark even warburg did not anticipate.Cancer Cell. 2012; 21: 297-308Abstract Full Text Full Text PDF PubMed Scopus (587) Google Scholar). Recent evidence indicates metabolism as an important regulator of immune cell phenotype and function (Biswas and Mantovani, 2012Biswas S.K. Mantovani A. Orchestration of metabolism by macrophages.Cell Metab. 2012; 15: 432-437Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar, Ghesquiere et al., 2014Ghesquiere B. Wong B.W. Kuchnio A. Carmeliet P. Metabolism of stromal and immune cells in health and disease.Nature. 2014; 511: 167-176Crossref PubMed Scopus (34) Google Scholar, Pearce and Pearce, 2013Pearce E.L. Pearce E.J. Metabolic pathways in immune cell activation and quiescence.Immunity. 2013; 38: 633-643Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar). Because immune cells are crucial in tumor progression, it is important to understand how metabolic alterations in these cells regulate their pro- or anti-tumor properties. Macrophages are versatile innate immune cells that contribute to diverse situations including host defense, homeostasis, and pathology. Although they show phenotypic and functional diversity, initial studies with defined in vitro stimuli have indicated two main macrophage activation or polarization phenotypes. For example, inflammatory stimuli such as interferon-γ (IFN-γ)+LPS induce macrophages to an M1 phenotype characterized by production of inflammatory cytokines (e.g., interleukin-12 [IL-12], tumor necrosis factor [TNF], IL-6, IL-1), reactive nitrogen and oxygen intermediates (RNI, ROI), and microbicidal functions (Biswas and Mantovani, 2010Biswas S.K. Mantovani A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm.Nat. Immunol. 2010; 11: 889-896Crossref PubMed Scopus (738) Google Scholar). In contrast, anti-inflammatory stimuli such as IL-4, IL-13, IL-10, and glucocorticoid or immune complexes (IC)+LPS induce macrophages to an M2 phenotype characterized by decreased production of inflammatory cytokines, increased production of anti-inflammatory cytokines (e.g., IL-10), and factors that mediate immunosuppression and tissue remodeling. However, under in vivo situations such clearcut phenotypes are often blurred. Therefore, a multi-dimensional rather than a dichotomous (M1-M2) view of macrophage activation states was proposed recently wherein these cells integrate environmental signals in a stimulus-specific manner to induce specific functional outcomes (Xue et al., 2014Xue J. Schmidt S.V. Sander J. Draffehn A. Krebs W. Quester I. De Nardo D. Gohel T.D. Emde M. Schmidleithner L. et al.Transcriptome-based network analysis reveals a spectrum model of human macrophage activation.Immunity. 2014; 40: 274-288Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar). This necessitates a common framework to describe macrophage activation states (Murray et al., 2014Murray P.J. Allen J.E. Biswas S.K. Fisher E.A. Gilroy D.W. Goerdt S. Gordon S. Hamilton J.A. Ivashkiv L.B. Lawrence T. et al.Macrophage Activation and Polarization: Nomenclature and Experimental Guidelines.Immunity. 2014; 41: 14-20Abstract Full Text Full Text PDF PubMed Scopus (263) Google Scholar). Macrophages represent a major component of the lympho-reticular infiltrates in solid tumors and play a crucial role in cancer progression (Biswas et al., 2013Biswas S.K. Allavena P. Mantovani A. Tumor-associated macrophages: functional diversity, clinical significance, and open questions.Semin. Immunopathol. 2013; 35: 585-600Crossref PubMed Scopus (53) Google Scholar, Murdoch et al., 2008Murdoch C. Muthana M. Coffelt S.B. Lewis C.E. The role of myeloid cells in the promotion of tumour angiogenesis.Nat. Rev. Cancer. 2008; 8: 618-631Crossref PubMed Scopus (651) Google Scholar, Qian and Pollard, 2010Qian B.Z. Pollard J.W. Macrophage diversity enhances tumor progression and metastasis.Cell. 2010; 141: 39-51Abstract Full Text Full Text PDF PubMed Scopus (995) Google Scholar). On the one hand, macrophages by producing RNI, ROI, and inflammatory cytokines (e.g., TNF, IL-1, IL-6) contribute to genetic alterations and cancer-related inflammation that leads to tumorigenesis, as noted for many chronic-inflammation-induced cancers (Biswas et al., 2013Biswas S.K. Allavena P. Mantovani A. Tumor-associated macrophages: functional diversity, clinical significance, and open questions.Semin. 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Macrophages by producing various pro-angiogenic molecules (e.g., EGF, VEGFA) also serve as important regulators of tumor angiogenesis (Murdoch et al., 2008Murdoch C. Muthana M. Coffelt S.B. Lewis C.E. The role of myeloid cells in the promotion of tumour angiogenesis.Nat. Rev. Cancer. 2008; 8: 618-631Crossref PubMed Scopus (651) Google Scholar). Although tumor-associated macrophages (TAMs) are generally described as an M2-like population, evidence suggesting an inflammatory (M1-like) phenotype or a phenotype with overlapping inflammatory and immunosuppressive features have also been reported (Franklin et al., 2014Franklin R.A. Liao W. Sarkar A. Kim M.V. Bivona M.R. Liu K. Pamer E.G. Li M.O. The cellular and molecular origin of tumor-associated macrophages.Science. 2014; 344: 921-925Crossref PubMed Scopus (84) Google Scholar, Mantovani et al., 2002Mantovani A. Sozzani S. Locati M. Allavena P. Sica A. 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This is consistent with the functional diversity of these cells, the complex and dynamic nature of tumor microenvironmental signals in vivo, and the stage and type of cancer involved. Polarized macrophages show distinct modes of glucose metabolism. For example, murine macrophages treated with the M1 stimuli IFNγ+LPS or LPS alone induced increased glycolysis, whereas exposure to M2 stimuli IL-4 induced increased oxidative phosphorylation (Rodriguez-Prados et al., 2010Rodriguez-Prados J.C. Traves P.G. Cuenca J. Rico D. Aragones J. Martin-Sanz P. Cascante M. Bosca L. Substrate fate in activated macrophages: a comparison between innate, classic, and alternative activation.J. Immunol. 2010; 185: 605-614Crossref PubMed Scopus (132) Google Scholar, Tannahill et al., 2013Tannahill G.M. Curtis A.M. Adamik J. Palsson-McDermott E.M. McGettrick A.F. Goel G. Frezza C. Bernard N.J. Kelly B. Foley N.H. et al.Succinate is an inflammatory signal that induces IL-1beta through HIF-1alpha.Nature. 2013; 496: 238-242Crossref PubMed Scopus (204) Google Scholar, Vats et al., 2006Vats D. Mukundan L. Odegaard J.I. Zhang L. Smith K.L. Morel C.R. Wagner R.A. Greaves D.R. Murray P.J. Chawla A. Oxidative metabolism and PGC-1beta attenuate macrophage-mediated inflammation.Cell Metab. 2006; 4: 13-24Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar). Similarly, human monocytes upon β-glucan stimulation switched to a glycolytic mode, with concomitant reduction of oxidative phosphorylation (Cheng et al., 2014Cheng S.C. Quintin J. Cramer R.A. Shepardson K.M. Saeed S. Kumar V. Giamarellos-Bourboulis E.J. Martens J.H. Rao N.A. Aghajanirefah A. et al.mTOR- and HIF-1alpha-mediated aerobic glycolysis as metabolic basis for trained immunity.Science. 2014; 345: 1250684Crossref PubMed Scopus (2) Google Scholar). The shift to glycolysis is mediated through the AKT-mTOR-HIF1α pathway. In murine macrophages, LPS-induced shift to glycolysis results in the accumulation of the TCA cycle intermediate, succinate, which via the transcription factor HIF1α induces the expression of the inflammatory cytokine IL-1β (Tannahill et al., 2013Tannahill G.M. Curtis A.M. Adamik J. Palsson-McDermott E.M. McGettrick A.F. Goel G. Frezza C. Bernard N.J. Kelly B. Foley N.H. et al.Succinate is an inflammatory signal that induces IL-1beta through HIF-1alpha.Nature. 2013; 496: 238-242Crossref PubMed Scopus (204) Google Scholar). Glycolysis also induces TNF expression in macrophages (Dietl et al., 2010Dietl K. Renner K. Dettmer K. Timischl B. Eberhart K. Dorn C. Hellerbrand C. Kastenberger M. Kunz-Schughart L.A. Oefner P.J. et al.Lactic acid and acidification inhibit TNF secretion and glycolysis of human monocytes.J. Immunol. 2010; 184: 1200-1209Crossref PubMed Scopus (44) Google Scholar). Together, these observations suggest glycolysis to regulate the inflammatory phenotype of macrophages. TAMs show a “smoldered” inflammatory phenotype that promotes cancer-related inflammation (Mantovani et al., 2008Mantovani A. Allavena P. Sica A. Balkwill F. Cancer-related inflammation.Nature. 2008; 454: 436-444Crossref PubMed Scopus (2933) Google Scholar). Importantly, TAMs accumulate in hypoxic areas of tumors where they express HIF1α (Burke et al., 2003Burke B. Giannoudis A. Corke K.P. Gill D. Wells M. Ziegler-Heitbrock L. Lewis C.E. Hypoxia-induced gene expression in human macrophages: implications for ischemic tissues and hypoxia-regulated gene therapy.Am. J. Pathol. 2003; 163: 1233-1243Abstract Full Text Full Text PDF PubMed Google Scholar). Because many glycolytic genes such as GLUT1, HK2, PFKFB3, and PGK1 are regulated by HIF1α (Semenza et al., 1994Semenza G.L. Roth P.H. Fang H.M. Wang G.L. Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1.J. Biol. 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On the basis of this, one might speculate that macrophages at the early stages of tumor onset preferentially utilize a glycolytic mode of energy metabolism to induce cancer-related inflammation and tumorigenesis (Figure 2A). A shift to glycolysis also serves as an adaptation for survival in the hypoxic tumor microenvironment. Lactic acid is an important end-product of glycolysis. Increased glycolysis in TAMs, tumor cells, and other stromal cells (e.g., cancer-associated fibroblast, CAFs) would result in lactic acid accumulation in the tumor microenvironment (Ghesquiere et al., 2014Ghesquiere B. Wong B.W. Kuchnio A. Carmeliet P. Metabolism of stromal and immune cells in health and disease.Nature. 2014; 511: 167-176Crossref PubMed Scopus (34) Google Scholar). Lactic acid polarizes TAMs to a tumor-promoting phenotype characterized by the expression of arginase 1 (ARG1), VEGFA, and several M2 markers via HIF1α activation (Colegio et al., 2014Colegio O.R. Chu N.Q. Szabo A.L. Chu T. 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Biol. Chem. 2013; 288: 21161-21172Crossref PubMed Scopus (19) Google Scholar). In contrast, tumor-derived lactic acid was reported to upregulate the pro-inflammatory cytokine IL-23 in human macrophages and murine TAMs from B16 melanoma, upon BCG treatment (Shime et al., 2008Shime H. Yabu M. Akazawa T. Kodama K. Matsumoto M. Seya T. Inoue N. Tumor-secreted lactic acid promotes IL-23/IL-17 proinflammatory pathway.J. Immunol. 2008; 180: 7175-7183Crossref PubMed Google Scholar). Such opposite effects might be explained by the dynamic changes in lactic acid levels in growing tumors, which could induce differential macrophage responses in line with their functional plasticity in tumors (Biswas and Mantovani, 2010Biswas S.K. Mantovani A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm.Nat. Immunol. 2010; 11: 889-896Crossref PubMed Scopus (738) Google Scholar). IL-4 is a well-known M2-polarizing macrophage stimulus. In PyMT-MMTV-driven spontaneous mammary carcinoma, Th2 cell-derived IL-4 polarized TAMs to an immunosuppressive (M2) phenotype (DeNardo et al., 2009DeNardo D.G. Barreto J.B. Andreu P. Vasquez L. Tawfik D. Kolhatkar N. Coussens L.M. CD4(+) T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages.Cancer Cell. 2009; 16: 91-102Abstract Full Text Full Text PDF PubMed Scopus (465) Google Scholar). Because IL-4 promotes oxidative phosphorylation in macrophages (Vats et al., 2006Vats D. Mukundan L. Odegaard J.I. Zhang L. Smith K.L. Morel C.R. Wagner R.A. Greaves D.R. Murray P.J. Chawla A. Oxidative metabolism and PGC-1beta attenuate macrophage-mediated inflammation.Cell Metab. 2006; 4: 13-24Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar), it might be speculated that TAMs in such tumors preferentially utilize oxidative phosphorylation instead of glycolysis. Given the heterogeneity and dynamic nature of tumor microenvironment across different cancers, as well as different stage