The intercellular communication largely relies on the information exchange via soluble factors (e.g., proteins and microRNAs) and direct cell–cell contacts. Beyond this, the shuttling of metabolites may serve as an additional form of intercellular communication and a high degree of intercellular coordination in various physio-pathological situations. As an intensive energy-consuming organ, brain efficiently utilizes nutrients/metabolites via organizing a complex intercellular shuttle of glucose, glutamine, glutamate, pyruvate, and lactate between neurons and astrocytes (1). Similar metabolic coordination exists in retina between glial cells and photoreceptor cells, in muscle between fast white fibers and slow red fibers, and in testis between sertoli cells and spermatogenic cells (2, 3). Also, emerging evidences have shown that various pathogen-derived metabolites mediate an intercellular host–pathogen interaction and critically impact on homeostasis and pathogenesis during pathogen invasion (4–7). Tumor microenvironment represents a dramatic example of metabolic derangement, where tumor-surrounding cells may either compromise or support highly metabolic demanding tumor cells by competing nutrients (a form of intercellular competition) or by forming a metabolic symbiosis (a form of intercellular collaboration), respectively. Amino acids, lactate, and lipids derived from stromal cells, adipocytes, mesenchymal stem cells, epithelial cells, or tumor cells from hypoxic regions can modulate tumor cell growth and their responses to therapy (8–15). Beyond this, the immune system, a pivotal cellular compartment presented in tumor microenvironment, is intimately involved in tumor initiation, progression, and responses to therapy.

Interaction of immune system with tumor is a complex and dynamic process. As the major component of anti-tumor immunity, tumor antigen-specific cytotoxic T (CTL) and T effector (T_eff) cells together with antibody-producing B cells and antigen-presenting dendritic cells (DC) elicit adaptive anti-tumor activity through direct recognizing and killing tumor cells and orchestrating a plethora of adaptive and innate immune responses. Also, macrophages, natural killer (NK) cells, and NK-T cells form an important layer of non-specific innate immunity to suppress tumor progression. However, tumor often co-opts and manipulates its microenvironment favoring the development of immunosuppressive cells, such as myeloid-derived suppressor cells (MDSC) and regulatory T (T_reg) cells. In addition, tumor-associated macrophages (TAMs), a pivotal immune population within the tumor microenvironment, are composed of multiple distinct pro- and anti-tumoral subpopulations. Mounting evidence indicates that strengthening the amplitude and quality of T cell-mediated adaptive response is one of the most promising approaches to enhance therapeutic anti-tumor immunity (16–19).

The shift from glucose oxidation toward aerobic glycolysis, also termed “Warburg effect,” and heightened glutamine catabolism are characteristic hallmarks of cancer cells. The metabolic rewiring of cancer cells supporting tumor growth and survival relies on a hierarchical oncogenic cascade involved in Akt/mTOR, MAPK, and essential transcriptional factors, such as HIF1α- and Myc-dependent metabolic transcriptome. Secretion of metabolic end products, such as lactate from glycolysis and glutaminolysis and CO₂ from the pentose phosphate pathway, often result in an extracellular acidification in tumor microenvironment. Hence, the Na⁺/H⁺ exchanger, the H⁺-lactate co-transporter, monocarboxylate transporters, and the proton pump (H⁺-ATPase) that are frequently activated in cancer cells play essential role in modulating the pH and ionic compositions in tumor microenvironment (20–22). Also, elevated expression of phosphoglycerate dehydrogenase (PHGDH) and it-mediated diversion of glycolysis into serine biosynthetic pathway have been found to be essential for the proliferation of certain tumor cells, such as breast cancer cells and melanoma cells (23, 24). Beyond being key precursors for biosynthesis, metabolic products of tryptophan, cysteine, serine, and glycine also contribute to tumor homeostasis through modulating anti-oxidative response and anti-tumor immunity (8, 25–28). Together, the metabolic reprograming in tumor contributes to its growth either by directly supporting cancer cell proliferation or by shaping the microenvironment potentially favoring tumor cell survival.

Recent studies from us and others have indicated that metabolic regulation and cell signaling are tightly and ubiquitously linked with immune responses (29–34). The distinct metabolic profiles of lymphocytes are intimately linked to their status and function (Table 1). Naïve T lymphocytes rely mainly on fatty acid oxidation and some glycolysis to fulfill their energy demand for survival. Upon stimulation, activated T lymphocyte “reprograms” its metabolism, by dramatically increasing aerobic glycolysis and glutaminolysis meanwhile decreasing lipid oxidation to meet its requirements for cell size growth, cell division, and cytokine production (35–38). In contrast, stimulation of B lymphocytes leads to a balanced increase in aerobic glycolysis and oxygen consumption (39, 40). As T lymphocytes begin to proliferate, they also undergo differentiation into functional subsets in response to extracellular signals, and these subsets determine the nature of the immune response. According to the nature of initial antigen challenge and specific cytokine signals, activated CD4 T cells differentiate into T_eff, including T helper Th1, Th2, Th9, and Th17, follicular helper Tfh, and T_reg. Th1 cells mediate responses to intracellular pathogens. Th2 cells control responses to extracellular bacteria and helminthes. Th9 cells play a role in the pathogenesis of asthma and resolution of parasitic infections. Th17 cells are important in anti-fungal defense and inflammation. Tfh cells are the specialized B cell helper. T_reg cells dampen immune responses by suppressing T cell activation and inflammatory response. The predominant metabolic program in T_reg cells is mitochondrial-dependent oxidation of lipid and potentially other mitochondrial-dependent metabolites. It has been indicated that forcing proliferating T cells to utilize free fatty acids for energy tends to drive enhanced T_reg differentiation (41). In contrast, increased aerobic glycolysis is seen in Th1, Th2, and Th17 cells, and partially due to activation of PI3K/Akt/mTOR pathway. The transcription factor HIF1 (hypoxia-inducible factor 1) has also been characterized as a key regulator of the anabolic metabolism in differentiating Th17 cells (42, 43). Similar to CD4 T cells, CD8 T cells also switch from fatty acid oxidation to aerobic glycolysis upon activation. The glycolysis and anabolic metabolism are essential for CD8 T cell growth and differentiation into cytotoxic T cells (34). After the peak of the primary T cell response, the metabolic state in CD8 T cells shifts from glycolysis back to lipid oxidation, which is pivotal for cell survival and the generation of CD8 T memory cells (44, 45).

Dendritic cells and macrophages are first-line effectors of innate immunity. DC maturation is concomitant with a metabolic switch to aerobic glycolysis (46, 47). Aerobic glycolysis fulfills bioenergetic need and also provides building blocks for the biosynthesis of macromolecules, such as lipids, a proper balance between uptake and synthesis of which is required for immunogenicity of DCs (48, 49). As functionally plastic cells, macrophages are capable of tightly coordinating their metabolic programs with their functional properties. This allows macrophages to grow, survive, and properly respond to a variety of pathophysiological signals in their changing microenvironments. Within the tumor microenvironment, TAMs are often identified as pro-tumoral M2 type macrophage (50, 51). Mounting evidences have showed that switching the TAM phenotype from M2 to M1 may promote anti-tumor activity, implicating a phenotypic plasticity of TAM (52–57). To mount a rapid inflammatory response, M1 macrophages coordinately engage aerobic glycolysis, pentose phosphate shunt (PPP), glutamine, and arginine catabolism to produce nitric oxide (NO) and reactive oxygen species (ROS) (58–60). However, anti-inflammatory M2 macrophages largely utilize lipid oxidation (61–63) meanwhile shift arginine catabolism from iNOS-mediated production of NO to the production of urea and ornithine (64–68). Similar to macrophage, the polarization of MDSC, a heterogeneous immunosuppressive population in tumor microenvironment, toward a pro-inflammatory phenotype (often referred as M1) is associated with heightened glycolysis meanwhile reduced immunosuppressive function (69). Beyond this, metabolic regulation in NK and neutrophils are largely unknown.

Aerobic glycolysis and glutaminolysis are dominant cancer metabolic routes. Heightened glucose and glutamine consumption often results in the depletion of nutrients (glucose, glutamine, etc.) whereas accumulates metabolic end- or by-products (lactate, proton, etc.) in tumor microenvironment (70, 71). In addition to the above general metabolic features that are required to support the needs of proliferation and other neoplastic features, tumor cells also exhibit diverse metabolic phenotypes that are often due to the adaptation of pre-existing cell/tissue lineage specific metabolic network. It is well documented that in tumor cells, biosynthesis, and catabolism of glycine and serine, as well as catabolism of tryptophan and cysteine, are essential to support tumor cell survival (25, 72–74). Acidic extracellular pH, which is resulted from the accumulation of lactate and CO₂ production, has been demonstrated to be important for cancer progression (75, 76). Recent studies have demonstrated that anti-tumoral immune population, such as CTL and T_eff cells, engage robust aerobic glycolysis and glutaminolysis, suggesting a potential metabolic antagonism (competition) for nutrients between tumor and those immune cells. On the contrary, pro-tumoral immune suppressive cells may preferentially utilize metabolic products of tumor to form a potential metabolic symbiosis in tumor microenvironment (Figure 1).

The metabolites that present in tumor microenvironment may also have signaling functions independent of their roles of bioenergetics fuels. This may represent a general feature of the intercellular metabolic crosstalk mediated by metabolites. To fully understand the underlying complexity of intercellular metabolic interplay, new techniques that allow us to quantitative measure metabolites, assess metabolic flux in situ, and detect physical interaction between metabolites and cell surface proteins are warranted. The fast moving cancer metabolism field and immunotherapy field have generated tremendous excitement regarding new therapeutic strategies and will likely change the paradigm of therapeutic interventions for cancer. However, the perturbed metabolic landscape of the tumor microenvironment can have a profound impact on anti-tumor immunity. As such, understanding the metabolic interplay between tumor and immune system will guide the development of optimal metabolic interventions on cancer without compromising anti-tumor immunity. Beyond this, intercellular metabolic interplay may also play an essential role in forming a pro-tumoral inflammatory microenvironment.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.