The immune system maintains its defense against infected antigens and self-antigens through an appropriate balance between activation and inhibition of immune response. At its core, this process involves receptor-ligand binding between T cells activated by antigens and various cells within the immune system, and the immune response is known to play an important role in carcinogenesis and anti-tumor immunity (Naidoo et al., 2014).

The immune response is the intraorganism defense mechanism that responds to threats to self. This defensive reaction takes place in three stages: recognition, processing, and reaction. Non-self elements are recognized as foreign substances by cells or active molecules involved in the immune response. Cells or active molecules involved in innate immunity recognize molecular patterns of non-self antigens. Innate immunity includes cells such as natural killer (NK) cells, macrophages, dendritic cells (DC), and neutrophils, as well as active molecules such as complement system in serum. The lymphocytes and antibodies involved in adaptive immunity have the ability to recognize the structure of non-self antigens or amino acid sequences in detail with high accuracy. In order to induce an effective immune response that can fight infectious diseases or cancer, cells or active molecules in the innate immune system and the adaptive immune system must interact in a coordinated manner. When cells from both systems respond properly at the early stage of cancer, cancer cells can be removed and the tissue returns to its normal state (Pulendran et al., 1997; Medzhitov and Janeway, 2002).

However, cancer cells grow and spontaneously proliferate faster than the immune system can handle through strategies that deceive the immune system and prevent attacks from immune cells. To do this, cancer cells begin to build a microenvironment starting at the time of cancer occurrence, and in most cases, when a cancer mass is found, a tumor microenvironment (TME) is present, making it difficult for the immune system to efficiently eliminate cancer cells (Labani-Motlagh et al., 2020).

Cancer immunology first began in 1957 when Burnet proposed the concept of tumor immunosurveillance (Burnet, 1957). Tumor immunosurveillance is when tumor cells are first recognized by T cells at the occurrence and growth stage, and then are killed by immune cells and secreted interferon-gamma (IFN-γ). In addition, tumor cells actively induce T-cell tolerance, resulting in an immunoediting process that facilitates tumor re-distribution and growth (Dunn et al., 2002). Accordingly, in cancer immunology, efforts have been made to develop immunotherapy against tumors by targeting the interactions between cancer cells and immune cells. Many recent studies have revealed that various cancers diminish normal immunity from having effective anti-cancer activity, as exemplified by findings of decreased absolute counts of lymphocytes (Kuss et al., 2005), an increasd regulatory T cells (Schaefer et al., 2005; Strauss et al., 2007) and tumor-associated macrophages (Li et al., 2002), down-regulation of antigen expression in tumor-associated cells (Grandis et al., 2000), and apoptosis of cytotoxic T cells (Whiteside, 2005). In addition, direct inhibition of the immune mechanism occurs due to vascular endothelial growth factor (Gabrilovich et al., 1996), prostaglandin E2 (Benefield et al., 1996; Schroeder et al., 2004), transforming growth factor-β (TGF- β) (Qin et al., 2001), and interleukin (IL)-10 secreted from cancer cells (Dennis et al., 2013), further decreasing the function of anti-cancer immunity. The immune response is also indirectly involved in tumor development through a reduction of the Th1 response, which induces anti-cancer effects, cytotoxic T cell differentiation, and an increase in the antagonistic Th2 response (Agada et al., 2009).

Interestingly, direct and indirect studies have reported that chemotherapy and radiation therapy, which are direct treatments for cancer and its progression, also regulate the immune system’s response against cancer cells. When external radiation therapy is performed for malignant melanoma, lymphoma, and renal cancer, improvement also occurs outside the treated area, and a recent report showed that these effects of cancer treatment might be caused by the activation of cancer-specific antibodies and T cells (Postow et al., 2012; Stamell et al., 2013). It has also been reported that the immune response is suppressed in high-dose chemotherapy, while in low-dose chemotherapy, the anti-cancer immune response is stimulated or induced (Zitvogel et al., 2008; Galluzzi et al., 2015).

Cancer immunotherapy is research on the effects of existing cytotoxic chemotherapy and radiation therapy on the host immune system based on an understanding of the relationship between cancer and the immune system. Although cancer immunotherapy has been attempted since 1990 in preclinical and early clinical studies with immunostimulating cytokine therapy, cancer vaccine therapy, and adoptive T cell therapy, it has not been introduced into practical use in clinical settings due to the local delivery of drug, systemic toxicity, and a lack of remarkable treatment results. Nevertheless, there has recently been a rapid increase in interest in immunotherapy, as exemplified by research on the involvement of immune mechanisms in the treatment of cetuximab (Holubec et al., 2016), diverse research results on immune evasion mechanisms, and early clinical studies of monoclonal antibodies to block immune checkpoints that showed satisfactory results not only for malignant melanoma, but also for head and neck cancer and non-small cell lung cancer, which is a non-immune solid cancer (Bauman and Ferris, 2014).

Tumor tissue, besides tumor cell also includes a variety of other cell types such as T cells, NK cells, macrophages, fibroblasts, dendritic cells, and adipocytes (Andrejeva and Rathmell, 2017). The tumor microenvironment is characterized by cancer cells that exhibit diverse metabolic variations due to their heterogeneity, in accordance with their proliferation and metastasis. Therefore, improvement of tumor immunotherapy is tightly linked with improvement of our understanding of the TME.

Cancer cells change through mutations or abnormal regulation, while immune cells change through specific mechanisms related to external invasion. In addition, cancer cells require sufficient nutrient uptake to maintain their metabolism and regulate their growth, whereas immune cells are relatively flexible compared to cancer cells because they can maintain their function through a balance of various metabolic systems. Thus, studies aiming to inhibit cancer metabolism by regulating the signaling pathway of immune cells through interactions between immune cells and cancer cells have recently been highlighted. Cancer cells affect the metabolism of T cells through the activation and proliferation of immune cells, depletion of glucose (Kleffel et al., 2015; Shi et al., 2019) and amino acids (e.g., leucine (Sinclair et al., 2013; Patel et al., 2019), serin (Munn et al., 1998; Munn et al., 1999; Srivastava et al., 2010), tryptophan (Munn et al., 1999; Munn et al., 2005), and glutamine (Cheng et al., 2011; Wang et al., 2011; Leone et al., 2019)), conditions of high acidity and high lactic acid levels, and up-regulation of immune checkpoints.

Cancer cells affect the metabolism of T cells in various ways, and through the activation and proliferation of immune cells, the depletion of glucose and amino acids, high acidity and lactate, and upregulated immune checkpoint, consequently inhibiting glycolysis, thereby affecting the metabolism of T cells. To summarize the metabolic mechanism between cancer cells and immune cells, M1 macrophages, effector T cells, and normal cancer cells regulate proliferation and anabolism using a high proportion of glycolysis and glutaminolysis to synthesize proteins, nucleic acids, and amino acids, while M2 macrophages, regulatory T cells, and quiescent cancer cells regulate catabolism using the oxidation of fatty acids to synthesize ATP (Andrejeva and Rathmell, 2017; Kouidhi et al., 2018). Among them, tumor-associated macrophages, corresponding to M2 macrophages, are the most abundant immune cells in the TME (accounting for 50%), and mainly affect cancer progression and resistance by supplying or supporting nutrients to malignant cancer cells. In particular, because tumor-associated macrophages are responsive to pharmacological agents that improve bacterial and oxidative function (Hossain et al., 2015; Jayaprakash et al., 2018; Duan and Luo, 2021), mechanisms of regulating their metabolism are highly promising targets for novel cancer treatment. Therefore, recent studies have considered the mechanisms through which tumor-associated macrophages are involved in the overall metabolism of the TME for this goal (Vitale et al., 2019).

In recent years, substantial advances have been made in various immune-based treatments, including the administration of specific cytokines, antibodies to immune checkpoints, and cell therapies such as CAR-T and CAR-NK, as a new paradigm of cancer treatment. These advances can be mainly summarized as attempts to modulate immune cell activity through the regulation of T cells using adoptive cell delivery and monoclonal antibodies (Hosseinkhani et al., 2020; Marofi et al., 2021). To date, among these immune-based treatments, immune checkpoint inhibitors are most widely used as an effective immunotherapy for a variety of solid tumors and malignant hematologic tumors. Immune checkpoint inhibitors are defined as drugs that upregulate the immune response using monoclonal antibodies targeting CTLA4 and PD-1, which are located on the cellular membrane of T cells and cancer cells (Waldman et al., 2020). Although there have been many studies on the mechanism and utilization of immunotherapy with immune checkpoint inhibitors, immunotherapy targeting only these single antigens has limitations due to the high immunosuppression of the TME and the low immunogenicity of cancer cells. A recent study showed that a combination of anti-PD1 and anti-CTLA4 to treat metastatic melanoma and non-small cell lung carcinoma (NSCLC) resulted in a better response than was achieved with conventional single antibody immunotherapy, as shown by increased patient life expectancy and the inhibition of new metastasis (Antonia et al., 2016; Hellmann et al., 2017). In addition, combination of immune checkpoint inhibitors with other chemotherapy agents, has recently attracted attention as a new strategy for anti-cancer treatment (Lee et al., 2020a). Nevertheless, tumor-infiltrating lymphocytes (TILs) need to overcome not only the immune checkpoints, but also a wide range of metabolic checkpoints within the TME that weaken their functions (Kouidhi et al., 2018). Thus, it is important to improve our comprehensive understanding of the mechanisms that reduce anti-cancer immunity within the metabolically hostile TME.

In fact, cancer cells can regulate immune cells by upregulating nutrient uptake and metabolite production, and as a result, constructing an immunosuppressive TME that promotes cancer cell growth and immune evasion. However, some recent studies have suggested that combining the immune checkpoint inhibitors and metabolic regulating agents can decrease cancer cell metabolism more effectively than either approach used in isolation (Murciano-Goroff et al., 2020; Weng et al., 2021). Caution is needed to ensure that treatments of this type only target specific tumor sites to prevent side effects such as systemic toxicity. Although cancer metabolism has been studied long enough to be considered the basis of cancer, active research is still undergoing and the mechanisms of cancer metabolism remain to be fully elucidated. Therefore, various aspects of cancer metabolism and its metabolites are noteworthy for future cancer research (Stine et al., 2022).

In order for an anti-cancer immune response to effectively kill cancer cells, a series of steps must be repeated and amplified. This series of steps is called the cancer-immune cycle: 1) Neoantigens produced during tumor formation are released from dead cancer cells, and dendritic cells (DCs) acquire them and move to the nearest draining lymph node (DLN). 2) DCs present the acquired antigen to T cells through major histocompatibility class I (MHC-I) and MHC-II molecules. 3) Effector T cells are activated by recognizing this antigen (Chen and Mellman, 2013; Motz and Coukos, 2013; Kim and Chen, 2016; Chen and Mellman, 2017; Patel and Minn, 2018). 4) Antigen-recognizing cancer-specific T cells in the DLN express the cell adhesion molecules and chemokine receptors necessary for migration and infiltration into the tumor, and then leave the DLN and move through the blood toward the tumor tissue. 5) These T cells then infiltrate into the tumor and 6) recognize and bind the MHC-I–antigen complex presented by cancer cells through the T cell receptor (TCR). 7) Through these processes, cancer cells are finally killed. CD8⁺ T cells kill cancer cells through granule-exocytosis mechanisms mediated by perforin and granzyme and interactions between apoptotic ligands-receptors such as FasL-Fas. When cancer cells die and additional neoantigens are released, the immune reaction continues the cycle again from the first step, and it is amplified compared to the previous reaction; for this reason, this mechanism is termed the cancer-immune cycle (Figure 1) (Chen and Mellman, 2013; Motz and Coukos, 2013; Kim and Chen, 2016; Patel and Minn, 2018). In cancer patients, at least one of these steps is defective and the cancer-immune cycle does not work properly.

Successful antigen recognition and activation (steps 1–3) of T cells, which are the early stages of the cancer-immune cycle, and infiltration (steps 4–5) of T cells into the tumor are essential conditions for “hot” tumors. This type of immune infiltration is usually characterized by reactivity to immune checkpoint inhibitors. In contrast, in “cold” tumors, characterized by immune non-infiltration, there is a defect in the initial stage of the cancer-immune cycle, and most cold tumors do not respond to immune checkpoint inhibitors. Therefore, antigen recognition and migration of T cells to the tumor can be assumed to be the main factors influencing reactivity to immune checkpoint inhibitors.

(1) Decrease in tumor immunogenicity (evasion of step 1): During tumor formation, immunosurveillance removes cancer clones that express strong immunogenic neoantigens. At this point, the tumor evades anti-cancer immune responses by eliminating immunogenic antigens or maintaining cancer clones without cancer antigens so that they are not recognized by T cells. In other words, cancer clones that evade immunosurveillance have fewer immunogenic antigens (Dunn et al., 2004; Coulie et al., 2014; Kim and Chen, 2016).

When the initial 5 stages of the cancer-immune cycle are successfully performed, immune infiltration into the TME is formed. Similar to the initial stage of the cancer-immune cycle, the mechanism of immune evasion of the last stage also takes place in the TME. PD-L1:PD-1 interactions are only one of several causes of immunosuppression, so reactivity to immune checkpoint inhibitors is sometimes absent even when the TME has immune infiltration. In addition, even in patients who initially respond to an immune checkpoint inhibitor, secondary immune evasion can occur when the tumor inhibits immune reaction in response to attacks by T cells.

(1) Inhibition of recognition by immune cells (evasion of step 6): Cancer cells remove, reduce, or transform MHC-I on the surface of cancer cells as a mechanism to evade recognition by T cells. Cancer cells directly regulate MHC-I genes or proteins or indirectly inhibit peptide-MHC components (Dhatchinamoorthy et al., 2021). In addition, cancer cells downregulate the expression of antigens, proteasome components, TAP1/TAP2, MHC-I, and β2-microglobulin through mutation, genetic loss, transcription inhibition, or epigenetic inhibition of gene expression (Taylor and Balko, 2022). Recent cancer genome studies have confirmed that the reduction of peptide-MHC-I expression on the surface of cancer cells due to somatic mutations in human leukocyte antigen (Campoli and Ferrone, 2008; Lawrence et al., 2013). Even if cancer cells can evade recognition by T cells through reduced MHC-I expression, NK cells cannot be evaded. This is because NK cells can induce an immune response to abnormal cells by recognizing the degree of MHC-I expression on the cell surface. As an alternative to this, cancer cells release ligands to NKG2D, an active receptor of NK cells, to evade lysis by NK cells (Ljunggren and Kärre, 1990; Groh et al., 2002; Terry et al., 2019; Hu et al., 2020).

Cancer transforms its own metabolic processes to maintain rapid growth and survival. Normal cells generate energy through oxidative phosphorylation (OXPHOS) in mitochondria, while cancer cells generate ATP through aerobic glycolysis even in an environment with sufficient oxygen, which is known as the Warburg effect (Warburg et al., 1927). The Warburg effect promotes the growth and survival of cancer cells, facilitates adaptation to changes in oxygen concentration in tissues, and uses intermediate products of glycolysis to maintain cell proliferation. In addition, lactate produced through glycolysis maintains TME oxidized, contributing to cancer infiltration and immune evasion (de la Cruz-López et al., 2019). However, recent studies have shown that OXPHOS and mitochondrial metabolic processes are also important for cancer metabolism. Some tumors increase OXPHOS by oxidation of glucose, protein, amino acids (e.g., glutamine or tryptophan), and fatty acids, and some tumors use waste products such as ammonia and lactate as energy sources (LeBleu et al., 2014; Yang et al., 2014; Hensley et al., 2016; Qu et al., 2016; Faubert et al., 2017; Spinelli et al., 2017; Badur and au, 2018; Corbet et al., 2018; Kuo and Ann, 2018; Pavlova et al., 2018; Porporato et al., 2018). These changes in cancer metabolism are controlled by carcinogenic mutations (e.g., MYC, phosphatase and tensin homologue; PTEN, AKT serine/threonine kinase, and phosphoinositide 3-kinase; PI3K). In addition, carcinogenic mutations are controlled by changes in surrounding factors or specific metabolic enzymes (e.g., isocitrate dehydrogenase 1; IDH1, succinate dehydrogenase; SDH, and IDO) (Buescher and Driggers, 2016; Maj et al., 2017; Reznik et al., 2018; Wellenstein and de Visser, 2018). Changes in metabolite concentration activate specific metabolic pathways, affect cell function through metabolite-mediated signaling pathways, and change the epigenetics of cancer cells. For this reason, even within a single tumor tissue, metabolic changes vary from cancer cell to cancer cell, and the use of nutrients in the TME is also quite different (Lane et al., 2020). These complex and diverse tumor metabolic changes construct a TME that threatens the survival of immune cells, and in response, immune cells activate specific metabolism to control their own survival and cancer cell growth. Therefore, further research should aim to elucidate the diversity of tumor metabolism in order to develop effective anti-cancer immunotherapy (Hu et al., 2013; Crompton et al., 2015; Hensley et al., 2016; Pavlova and Thompson, 2016; Grzes et al., 2017; Palm et al., 2017; Reid et al., 2017; Badur and au, 2018; Wellenstein and de Visser, 2018).

The concentration of metabolites such as glucose, lactate, and glutamine in the TME affects the function and activity of tumor-infiltrating immune cells. Cancer cells deplete glucose in the TME, inhibiting the anticancer immunity of T cells, NK cells, macrophages, and DCs that use glucose for anti-cancer activity (Renner et al., 2017; Xia et al., 2021). Mechanistically, glycolysis is necessary to regulate IFNγ production by T cells, and the restricted use of glucose in the TME limits Ca²⁺ signaling, glycolysis, and cytokine production of TILs (Rangel Rivera et al., 2021; Zhang et al., 2021). In fact, resistance to T cell therapy appears in cancer patients with overexpressed glycolysis enzymes. If the available glucose concentration is increased by inhibiting glycolysis in the tumor, T_eff cells are activated, and the production of immunosuppressive cytokines by cancer cells is inhibited, thereby improving anticancer immunity (Maj et al., 2017; Le Bourgeois et al., 2018; Leone and Powell, 2021; Traba et al., 2021; Watson et al., 2021; Kumagai et al., 2022). Like glucose, lactate produced by the glycolysis of cancer cells or immune cells also inhibits immune cell function. Lactate inhibits the function of T_eff cells, but not T_reg cells, ultimately inducing an immunosuppressive environment. Glutamine in the TME also allows T_reg cells to accumulate, rather than the Th1 response, if its concentration is limited. Reducing glucose and glutamine in the TME limits UDP-GlcNAc synthesis by T cells and promotes differentiation into T_reg rather than Th17 (Chang et al., 2015; Angelin et al., 2017; Le Bourgeois et al., 2018; Watson et al., 2021; Xia et al., 2021; Kumagai et al., 2022; Watson and Delgoffe, 2022). Since cytotoxic cells such as CD8⁺ T cells and NK cells are sensitive to amino acid restrictions, their function is suppressed when glutamine, serine, and glycine are depleted or when branched-chain amino acids, especially leucine and isoleucine, are restricted (Gentles et al., 2015; Badur and au, 2018). Therefore, restrictions on the use of nutrients in immune cells are immunologically associated with cancers that do not undergo immune infiltration (cold tumors) or malignant tumors.

Tumor-infiltrated immunosuppressive cells (T_reg cells, tolerogenic DCs, and MDSCs) and cancer vascular endothelial cells also reduce nutrients in the TME, potentially contributing to an immunosuppressive environment. T_reg cells act competitively against glucose, inducing replicative senescence of CD4⁺ and CD8⁺ T cells. The activity of TLR8 hinders the corresponding action of T_reg cells, thereby improving anticancer immunity. In addition, T_reg cells in the TME convert ATP into adenosine, inhibiting the activity of immune cells in tumors (Lindau et al., 2013; Peixoto et al., 2019; Haist et al., 2021).

Taken together, the immune state in the TME is determined by the competitive action against nutrients, the accumulation of metabolites that inhibit immune response, and cellular signaling that changes metabolic processes. These changes in the TME ultimately induce the recruitment of tumor-associated macrophages, which secrete various cytokines that induce angiogenesis, metastasis of cancer cells, and immunosuppression. Understanding this process will be important for the success of anti-cancer immunotherapy.