Perspective Chapter: Impact of Tumor Metabolism on Immune Cells in the Tumor Microenvironment

Abstract

Metabolism is essential for a cell to obtain energy for its growth and development. In tumors, the rapid rate of cell proliferation leads to an increased demand for energy. Because nutrients in the tumor microenvironment are scarce, there is great competition between tumor cells and healthy cells to obtain them. Because of this, tumor cells undergo adaptations to outcompete healthy cells for nutrients. These adaptations cause characteristic changes to the tumor microenvironment, which in turn, causes changes to immune cells in the tumor tissue. These changes help the tumor evade immune detection and cause tumor growth and metastasis. This review will analyze the changes that take place in the tumor microenvironment, the impact they have on immune cells, and how this contributes to cancer progression.

1. Introduction

Metabolic reactions are chemical reactions that take place within cells or organisms and are essential for their survival. Metabolic processes include the breakdown of compounds for energy, the synthesis of necessary biomolecules, etc. Changes to the metabolic processes of cancer cells are a key characteristic of tumorigenesis. In order to supply their rapid rates of cell proliferation, tumor cells are in constant need of nutrients from the tumor microenvironment (TME), which are very scarce. This puts tumor cells in fierce competition with neighboring cells for these resources. Tumor cells undergo various adaptations, such as utilizing anaerobic glycolysis in favor of aerobic respiration, a process that allows them to synthesize ATP at higher rates. Such adaptations allow tumor cells to outcompete neighboring cells and allow the tumor to grow. The adaptations that the tumor cells undergo have an influence on the TME. For example, the aforementioned use of anaerobic respiration causes the TME to become more hypoxic and acidic.

These changes to the characteristics of the TME cause phenotypic alterations of immune cells within the TME. The TME includes cells of both the adaptive and innate immune systems, and they undergo notable changes to their metabolic pathways in response to the conditions of the TME or other signals within it. The former includes T cells and B cells, while the latter consists of tumor-associated macrophages (TAMs), natural killer (NK) cells, dendritic cells, and neutrophils.

These alterations of immune cells in the TME provide numerous benefits to the tumor. Namely, various altered pathways allow for the tumor to evade detection by the immune system, which contributes to the growth of tumors and the progression of cancer. This paper will discuss how the metabolic reprogramming of tumor cells contributes to changes in the conditions of the TME, the impact these changes have on the functionality of immune cells, and how they relate to the spread of cancer.

2. Changes to conditions of the TME

Tumor growth relies on the rapid proliferation of cells, which is an energetically demanding process. However, nutrients within the TME are often very scarce, and as a result, tumor cells are in fierce competition with healthy cells in the TME for these nutrients. Tumor cells adapt to these increased energy demands by shifting their metabolic pathways [1]. One such adaptation that tumor cells undergo is reprogramming of their glucose metabolism to utilize anaerobic glycolysis in preference to the tricarboxylic (TCA) and oxidative phosphorylation (OXPHOS) pathways ([2], Figure 1). This pathway, known as the Warburg effect, is active even in the presence of abundant oxygen, and it is key to a tumor cell’s ability to outcompete neighboring cells.

Figure 1.

(Warburg effect): The Warburg effect is a major metabolic reprogramming that cancer cells undergo. Normal cells exhibit a usage of both glycolytic and OXPHOS pathways, while cancer cells rely on glycolysis and produce excess lactate as a by-product. This reliance on glycolysis and production of molecules, such as lactate, cause major changes to the conditions of the TME [3].

Though the process of anaerobic glycolysis generates lower quantities of net ATP from glucose than the OXPHOS pathway, it allows for the metabolism of glucose to occur much more rapidly in tumor cells, thus leading to tumor cells outcompeting neighboring ones for nutrients. Additionally, other adaptive mechanisms of tumor cells allow them to overcome this inefficient method of obtaining energy. For example, many tumor cells can carry out autophagy, which allows them to recycle nutrients and prevents nutrient depletion [4]. Additionally, tumor cells can synthesize ATP using two ADP molecules, forming one ATP and one AMP [5, 6]. These adaptations make the Warburg effect a useful mechanism through which tumor cells can outcompete other cells within the TME for nutrients and proliferate. However, the process also causes drastic changes to the conditions of the TME.

The primary change caused by the Warburg effect is the acidification of the TME. These conditions are caused by the higher rates of anaerobic glycolysis and the production of lactic acid [7]. The acidic state of the TME confers numerous advantages for tumor growth, as it promotes the formation of new blood vessels, drug resistance, and suppression of the anticancer immune system [8]. The lactic acid that is produced can also act as a signaling molecule that regulates the migration of tumor cells: areas with a lower pH promote tumor cell invasion and metastasis [8].

Another important characteristic of the TME is its state of hypoxia. The delivery of oxygen and other nutrients to tissue occurs through blood vessels. Because tumors are undergoing constant growth, their receiving of blood flow is often irregular. In order to combat this, tumor tissues can form new blood vessels in a process referred to as angiogenesis [9]. This process allows tumors to continually receive the nutrients required to meet their metabolic demands. However, if angiogenesis fails, the aforementioned conditions of hypoxia and resource scarcity will arise in the TME. The tumor can still thrive under these conditions due to its reliance on anaerobic glycolysis [7]. Additionally, the hypoxic state acts as an additional stressor on the immune system and allows the tumor to evade immune attack.

The conditions in the TME also cause changes to the functionality of the immune system. For example, the hypoxic environment can negatively impact the immune detection of cancer cells and contributes to tumor immunity [10]. Signaling factors, called hypoxia-inducible factors (HIFs), are a key part of the regulation of tumor immunity genes. These factors can also inactivate lymphocytes in the TME, namely NK cells and CD8 T lymphocytes, thus preventing them from combating tumor growth. In this pathway, proinflammatory signals produced in hypoxic regions of the TME attract regulatory T cells (Tregs), which in turn suppress cytotoxic T cells from producing an immune response, thus promoting cancer growth [11]. The hypoxic conditions also act as a stressor on neutrophils and block them from attacking tumors. Finally, HIFs have negative impacts on the maturation of B cells, which they accomplish by increasing their rate of glycolysis. This metabolic change to B cells causes them to divide less rapidly (thus decreasing their immune response), prevents them from altering antibody production, and can even trigger cell death [10].

Additionally, the aerobic glycolysis pathway causes irregularities in the metabolite balance within tumor cells, a factor that causes changes to cell signaling and cell–cell interactions within the TME [12]. For example, the aforementioned acidic conditions of the TME created by the excessive lactate produced through glycolytic pathways interfere with the immune response of cytotoxic T cells. The lactic acid also interferes with the production of IFN-γ by NK cells, which inhibits phagocytic cells from attacking the tumor [13].

Amino acids, namely glutamine, arginine, and tryptophan, are also important metabolites that influence the function of immune cells within the TME. Glutamine is produced as a by-product of the catabolism of proteins in nutrient-scarce environments [13]. It is essential to the function of immune cells because it regulates immune cell activation and determination, namely that of T cells. When its availability is limited, T-cell functionality is suppressed [13]. Similar to glutamine, arginine plays a role in the activation of T cells and NK cells. Additionally, it regulates the secretion of cytokines [13]. Tumor cells consume a significant amount of the exogenous arginine in the TME, thus inhibiting the effect it has on immune cells [13]. Tryptophan also plays a role in the regulation of T cells, namely its cell cycle. When tryptophan is unavailable, the rate of T-cell apoptosis increases drastically [13].

Finally, lipids play an important role in the regulation of immune cell signaling within the TME. Fatty acids are needed for macrophage maturation and proliferation [13]. Additionally, they are necessary for the synthesis of membranes for effector immune cells. However, the accumulation of fatty acids within the TME can cause metabolic alterations to immune cells and make them anti-inflammatory. [13]. Similar effects can be induced by the accumulation of cholesterol within the TME, which causes T cells to lose their antitumor functionality. This occurs because high cholesterol levels can cause the disruption of T-cell membranes, thus impeding their ability to attack tumors [13].

3. Immune cell subtypes in TME

The tumor microenvironment is comprised of tumor cells, resident host cells, extracellular matrix, cancer-associated fibroblasts, vascular cells, and tumor-infiltrating immune cells [14]. Although tumor-infiltrating immune cells of both innate and adaptive arms of the immune system are often present in the TME, specific subtypes of immune cells, their number, and function can vary significantly depending on the tumor type and on the different stages of progression [14]. Functionally, tumor-infiltrating immune cells have been shown to be responsible for both tumor-inhibitory (antitumor) and tumor-promoting properties [15]. Recruitment of immune cells into the TME is tightly regulated by chemotactic factors and the expression of chemokine receptors on immune cells which together define the recruitment of activator or suppressor type of immune cells into the TME [16]. Based on the extent of immune cell infiltration into tumor tissue, the TME can be classified as immune-infiltrated, immune-excluded, and immune-silent.

Immune cells of the adaptive response in the TME include T- and B- subsets of lymphocytes. Both subtypes of CD3+ T lymphocytes (CD4+ helper T cells and CD8+ cytotoxic T cells) can be observed within the TME, where CD8+ T cells are predominantly responsible for cytotoxicity response against the tumor cells and CD4+ T cells either support CD8+ cell cytotoxic activity or act as regulatory T cells (Tregs) that suppress the antitumor immune responses. The types of chemotactic factors in the TME and expression cytokine receptors therefore collectively determine which subtype of T cells predominate in the TME. For example, chemokines CXCR3, and CXCR4 aid in directing the migration of cytotoxic T cells and NK cells into the tumor, whereas CCR4 expression is linked to the recruitment of suppressor Tregs into the TME [16]. B cells, which are primarily responsible for antibody-mediated immune response, are also observed in the TME but in relatively small numbers when compared with T cells. Tumor-infiltrating B cells appear to mediate the formation of lymphoid-like structures within the TME where their interaction with T cells regulates tumor progression [16].

Immune cells of innate response that are constituents of the TME include NK cells, macrophages, neutrophils, and dendritic cells [14, 16]. Natural killer (NK cells) mediate antitumor activity either via direct cell-mediated killing of tumor cells or by secretion of specific cytokines that indirectly contribute to the antitumor response. NK cells, although present in the TME, are less efficient at killing tumor cells within the tumor microenvironment, are highly effective against circulating tumor cells, and therefore more effective in preventing tumor metastasis [17]. Macrophages by far are the most common type of innate immune cells in TME and macrophage infiltration has been associated with poor prognosis of several solid tumors. Two distinct phenotypes of macrophages that mediate a pro-inflammatory response (M1 macrophages) and wound healing response (M2 macrophages) are commonly present in the tumor tissue [18]. However, the hypoxic state and presence of certain cytokines within the TME favor the M2 phenotype that supports tumor progression [18]. Neutrophils are the next variety of innate immune cells seen in the TME. Neutrophils are recruited into tumor tissue where they initially promote a local inflammatory response thereby promoting tumor cell apoptosis. As the tumor progresses, neutrophils can functionally support tumor growth through the modification of the extracellular matrix, and the release of growth factors that promote angiogenesis [19]. Dendritic cells (DCs), the most potent type of antigen-presenting cells; play an important role in cancer immunosurveillance and infiltration of DC into tumor tissue is associated with delayed tumor progression and metastasis [19].

4. Metabolism in lymphocytes: t cells

Metabolic pathways in T-lymphocyte vary depending on their differentiation status in their life cycle [20]. Naïve T lymphocytes mainly depend on TCA and OXPHOS to support basal metabolism. Continued signaling from cytokines, such as IL-7, is required to maintain glucose uptake by naïve T cells for sustaining the metabolism [20]. Following antigen recognition and activation, T cells undergo a metabolic change that is dependent on both glucose and amino acids as energy sources to support cell proliferation and to function as effector T cells [21]. Similar to the tumor cells, the effector T cells use Warburg metabolism to support energy demands associated with the secretion of cytotoxic cytokines and enzymes required for the removal of the tumor and virally infected cells. Therefore, within the TME, malignant cells compete with the effector T cells for energy sources and relatively nutrient deficiency in the TME can impair T-cell survival and proliferation [22]. The mechanisms underlying the regulation of T-cell effector functions by metabolic pathways also vary in different subsets of T cells. For example, in CD4 T cells, enzymes of the glycolytic pathway, such as GAPDH, can interact with mRNA of key cytokines, thereby preventing their translation [23]. Additionally, acetyl-CoA produced from citrate in cytosol due to the action of ATP citrate lyase (ACL) in both CD4 and CD8 T cells can directly modify histone acetylation status at the promoter regions of key cytokine genes involved in mediating effector functions [24]. Changes in mitochondrial structure and function are also implicated in the regulation of effector T-cell function as well as memory T-cell formation. Effector T cells, where mitochondria exhibit fragmentation, are poor in supporting electron transport machinery that leads to upregulation of anaerobic glycolysis, whereas in memory T cells, the mitochondrial fusion process allows proper function of ETC and facilitates lipid metabolism via fatty acid oxidation [25].

Due to similarities in the metabolic pathways utilized, within the TME, competition for nutrients exists between tumor cells and the effector T cells [26]. Tumor cells with functional mutations that confer survival advantage can therefore outcompete effector T cells leading to the reduced number and/or function of cytotoxic CD8 cells. Furthermore, lactate produced by tumor cells in the hypoxic regions creates an acidic environment that can inhibit T-cell activation by preventing glycolysis [27]. In contrast with cytotoxic T cells, Tregs, upon activation, induce fatty acid biosynthesis and oxidative phosphorylation, conferring them with a metabolic advantage to thrive within the TME [28]. Tumor cells evade the immune response by upregulation of inhibitory receptors, such as programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte association protein 4 (CTLA4). These inhibitory receptors, known as immune checkpoints, are widely used as targets in cancer therapy as they also play a role in the metabolic regulation of T cells [29]. PD-1 expression downregulates glycolysis and increases fatty acid oxidation, which reduces their cytotoxic potential. PD-L1 expressed on tumor cells enhances glucose uptake and therefore blockade of PD-1/PD-L1 interaction can collectively potentiate antitumor activity of T cells [30]. CTLA-4 is a receptor expressed transiently on T cells following activation and plays an important role in regulating their activity. One of the mechanisms by which CTLA-4 suppresses T-cell activity is by down-regulating critical amino acid and nutrient transporters and inhibition of CTLA4 can restore the bioenergetic balance that favors the survival of T cells in the TME [29].

Another key area where understanding T-cell metabolism is critical is in cell-based therapies that utilize chimeric antigen receptor (CAR)-T and tumor-infiltrating lymphocytes (TIL). CAR-T treatment is an immunotherapeutic strategy in which samples of T cells taken from a patient’s blood are genetically modified to produce receptors that target tumor cells [31]. In TIL therapy, T lymphocytes are taken from the tumor microenvironment and cultured ex vivo. The amplified TILs are then infused with the tumor in order to promote the targeting of cancer cells. These cells undergo metabolic reprogramming to inhibit glycolysis in vivo, which increases the proliferation of T cells and thus increases antitumor efficacy [32]. These methods have proven beneficial as alternative therapies when conventional therapies fail due to the acquisition of tumor resistance or where checkpoint inhibitors therapies are not a viable option due to lack of expression of those receptors as targets [33]. Both CAR-T and TIL therapies require isolation and ex vivo expansion of tumor-specific lymphocytes prior to administering to the patients. Despite having tumor-specific activity, engineered CAR-T-cell therapies are prone to adverse events in the form of cytokine release syndrome ([32], Figure 2). It is beginning to be understood that some of the mechanisms underlying CAR-T-cell properties, therapeutic efficacy, and potential adverse events are linked to metabolic pathways in the engineered cells. Conditions used for ex vivo expansion of TIL and CAR-T cells also may alter the metabolic state of these cells, thus impacting therapeutic effectiveness [35]. It is possible that redirecting the metabolic pathways during their expansion may result in cells with beneficial properties targeting tumors [35].

Figure 2.

(cytokine release syndrome): CRS is an acute immune inflammatory response caused by the activation of the immune system, particularly T cells. This triggers the release of cytokines, which are molecules involved in directing immune function. These excess cytokines pose serious health risks, such as organ failure and potential death [34].

5. Metabolism in lymphocytes: nk cells

Resting NK cells predominately use glucose as fuel to carry out glycolysis and oxidative phosphorylation. Activation of NK cells via cytokine stimulation increases glucose uptake and the rate of glycolysis and oxidative phosphorylation, which support biosynthesis and secretion of IFN-Ƴ and other key enzymes, such as granzyme, that are required for NK cell effector function [35]. In contrast with other lymphocytes, pyruvate generated from glycolysis in NK cells is preferentially converted to citrate via citrate-malate shuttle (CMS) rather than metabolism via the TCA cycle [36]. Two subsets of NK cells are recognized based on the expression level of phenotypic marker CD56 (CD56 dim and CD56 bright) that appear to be metabolically distinct. For example, CD56 bright NK cells involved in cytokine production express higher levels of glucose transporter proteins, thus rapidly taking up glucose upon activation [37]. In addition to glucose, glutamine is also important as a fuel source for the metabolism of activated NK cells. Glutamine can regulate the uptake of critical amino acids and the breakdown products of glutamine enter the TCA cycle for generating ATP [37]. Metabolic pathways in NK cells are tightly regulated both during development and activation. Specific signal transduction pathways and transcription factors are involved in regulating the metabolic pathways in NK cells. Transcription factor steroid regulatory element binding protein (SREBP) regulates the expression of the components of the CMS pathway and the mammalian target of the rapamycin (mTOR) pathway regulates NK cell proliferation and metabolism [36]. Consequently, reduced mTOR activity of mature NK cells is associated with diminished metabolic activity that results in impaired effector functions of NK cells. The multifunctional transcription factor c-Myc plays an important role by upregulating glucose transporters and critical enzymes of glycolysis in NK cells [36].

Although NK cells are highly effective in the targeted removal of tumor cells, the tumor microenvironment poses a challenge to the appropriate function of the NK cells. Firstly, changes in the metabolic properties of tumor cells create an environment that is low in critical nutrients (glucose and glutamine) and oxygen (hypoxic state) that are essential for the normal metabolism of NK cells [38]. Secondly, anaerobic glycolysis of tumor cells produces lactic acid that creates an unfavorable acidic environment, leading to reactive oxygen species (ROS) production in NK cells and induction of apoptosis [38]. Furthermore, transforming growth factor β (TGF-β), a cytokine that is commonly upregulated in several cancers can inhibit NK cell metabolism, presumably via the inhibition of mTor activity [39]. Metabolic adaptation of NK cells within the TME involves the activation of enzymes in the gluconeogenetic pathways, such as FBP-1, to generate glucose needed for NK cell metabolism. Therefore, dysregulated FBP-1 expression in NK cells further reduces their ability to survive in the TME and thus reduces immune function [40]. The hypoxic state of TME is associated with mitochondrial fragmentation in certain tumors, which perturb the survival and cytotoxic properties of NK cells [41]. In addition to the aforementioned factors, certain other metabolites that are elevated in the TME (adenosine, prostaglandin E2 (PGE2), and kynurenine) may also be responsible for reduced NK cell function via mechanisms that are yet to be understood [36]. Restoring normal metabolic function and survival of NK cells in the TME is one of the bases for pharmacological approaches to treat cancer where infiltrated NK cells have potent antitumor activity. Targeting TGF-β or its downstream signaling pathways and/or restoration of c-Myc protein levels via inhibition of enzymes (GSK3) are potential therapeutic approaches [39]. Additionally, culturing autologous NK cells ex vivo and inhibiting FBP-1 has proven to restore immune function, namely cytotoxicity ([40], Figure 3). Other cells in the TME (cytotoxic and Tregs, stromal fibroblasts, etc.) have also been shown to modulate the expression of various activating and inhibitory receptors on NK cells that in turn regulate the metabolic and antitumor properties of NK cells [38]. Therefore, targeting inhibitory NK cell receptors, such as NKG2A, is one of the strategies being evaluated as NK cell-mediated antitumor immunotherapy ([38], Figure 3).

Figure 3.

(targeting of NK-cell metabolic pathways): The targeting of major receptors and metabolites, namely FBP-1 in NK cells, holds great promise in restoring the antitumor efficacy of NK cells in the TME [40].

6. Metabolism in the innate immune system: tumor-associated macrophages

Macrophages are specialized immune cells that develop from myeloid progenitor cells and are highly efficient in phagocytosis and the removal of pathogens [42]. Tumor-associated macrophages (TAMs) are macrophages that are specifically recruited into tumor tissue due to cytokines and growth factors secreted by cells within the tumor microenvironment [43]. TAMs are one of the most abundant leukocytes within the TME and have been implicated in tumor progression and metastasis [44]. Macrophages were further classified as inactive (M0), pro-inflammatory (M1), and anti-inflammatory (M2) subtypes based on specific immune responses elicited by these cells. Inactive macrophages (M0) are undifferentiated cells and can reprogram themselves into polarized M1 and M2 cells after exposure to stimuli [45]. These distinct subtypes of macrophages utilize different metabolic pathways to exert their functional effects and TAMs are further induced to undergo a metabolic switch to survive in the tumor microenvironment. The key features of M1 and M2 macrophages in the utilization of various metabolic pathways are as follows. Although both M1 and M2 macrophages metabolize glucose via glycolytic pathways, in M1 macrophages it is essential for pro-inflammatory properties, such as cytokine production, and in mediating phagocytosis [46]. Similarly, the pentose phosphate pathway, which produces NADPH, is also critical in M1 macrophages, where NADPH-oxidase-dependent generation of reactive oxygen species (ROS) and regeneration of glutathione [47]. Arginine is also metabolized differently in M1 and M2 macrophages by virtue of the expression of distinct enzymes that break down arginine. Notably, M1 cells express inducible nitric oxide Synthase or iNOs that produces NO from arginine [46] and M2 macrophages express the enzyme arginase that metabolizes arginine to produce ornithine. NO has an important function in mediating pro-inflammatory response and ornithine serves as a precursor for polyamine synthesis that is critical in wound healing and repair processes that are mediated by M2 macrophages [48]. The TCA cycle in M2 macrophages is coupled to mitochondrial oxidative phosphorylation, whereas in M1 macrophages, intermediate metabolites of the TCA cycle, citrate and succinate, accumulate and are redirected toward the processes that lead to the production of inflammatory mediators, such as prostaglandin E2 (PGE2) [49].

The subtypes of macrophages within the TME vary with the progression of tumors. During the early stages of tumors, M1 macrophage polarization is favored, thus leading to the recruitment of cytotoxic CD8 cells and NK cells ([50], Figure 4) and the antitumor property of TAMs. However, as tumors progress, polarization to M2 macrophages is favored due to progressive changes in the TME ([50], Figure 4). Due to aerobic glycolysis of tumor cells, lactic acid in the TME induces M2-like TAM polarization of TAMs [46]. Additionally, TAMs have also been implicated in regulating tumor metastasis and angiogenesis further supporting the survival and spread of tumors. Metabolically, TAMs utilize glucose as the primary energy source with oxidative phosphorylation favoring their differentiation into pro-tumorogenic M2 macrophages [46]. As TAMs constitute the predominant cell population in the TME, potential therapies for cancer are based on metabolic targeting either to inhibit TAM polarization to an M2 phenotype or to selectively deplete M2 cells within the TME [52]. However, considering the complexity of concurrent metabolic processes occurring in other cells in the TME, these approaches have some limitations. Nevertheless, inhibition of OXPHOS pathways in TAMs has been shown to decrease tumor progression [53]. Future therapies directing metabolic processes via targeted drug delivery to TAMs may prove useful to overcome limitations associated with current strategies [52].

Figure 4.

(TAM polarization): TAMs undergo metabolic changes that trigger polarization to the M2 phenotype, which has pro-tumorigenic properties and contributes to cancer progression [51].

7. Conclusion

Cancer cells undergo key changes to their metabolic processes as an adaptation to outcompete other cells in the TME. This metabolic reprogramming causes the chemical conditions of the TME to change. The most notable of these changes is the development of hypoxic and acidic conditions due to a reliance on anaerobic glycolysis rather than OXPHOS pathways to produce ATP (Warburg effect), as well as the limited availability of nutrients. Additionally, the unique metabolism of cancer cells causes irregularities in the metabolite balance within the TME. Such changes have significant impacts on immune cells within the TME and their antitumor efficacy. All immune cell types in the TME of both the adaptive and innate immune systems undergo metabolic alterations in response to changes in the TME. These alterations greatly reduce immune function and contribute to tumor progression. The limited availability of nutrients in the TME downregulates the function of effector T cells and cytotoxic T cells and prevent their proliferation, and also prevents the formation of memory T cells. The antitumor efficacy of NK cells is reduced by the acidic and nutrient-scarce TME, which both triggers apoptosis, as well as the hypoxic state, which triggers mitochondrial fragmentation and reduces cytotoxic capabilities. The conditions of the TME cause TAMs to undergo polarization to the M2 subtype, which has pro-tumorigenic properties and can contribute to angiogenesis. Metabolism in the TME has become a focus of cancer treatment. Common treatments are based on culturing autologous immune cell types ex vivo and modifying their metabolic properties. These immune cells are amplified in order to improve immune function and are then infused with the tumor. These treatments must be further explored, but the targeting of immune cell metabolism in the TME proves to be a promising strategy in the treatment of cancer.

Acknowledgments

Funding for the publication of this paper was made possible by a grant from the Assisi Foundation of Memphis. Brown, Chester, PhD (PI). We also thank Yirui Tang for drawing the figures used in this paper.

Conflict of interest

The authors have declared that no conflict of interest exists.