Tumor immunosurveillance refers to the process by which innate and adaptive immunity monitor the body for the presence of malignant cells for elimination. This process occurs continuously throughout lifetime, thereby preventing initiation, development, and progression of cancer. Effector immune cells surveil tissues using a variety of mechanisms, including pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) recognition, natural direct cytotoxicity, antigen presentation, antibody-dependent cellular cytotoxicity (ADCC), and the activation of adaptive responses (6, 7).

Immune cells interact with tumor cells through a process known as immunoediting, which consists of three phases, namely: elimination (immunosurveillance), equilibrium, and escape (6, 7). In the elimination phase, immune cells recognize and destroy early malignant cells, thereby preventing tumor formation. This phase is mediated by various types of immune cells, including natural killer (NK) cells, DCs, macrophages, B cells and T cells (6, 7). Malignant cells eventually alter the expression of relevant ligands, thereby evading immune recognition, a state in which an equilibrium with the immune system is reached. In this phase, malignant cells survive and slowly proliferate while interacting with immune cells (6, 7). Immune cells continue to eliminate malignant cells but are unable to completely produce the desired effect, a process that is believed to last for years (8). Malignant cells ultimately acquire the necessary tools to completely evade the equilibrium phase, proliferating and possibly metastasizing to adjacent tissues (9) ( Figure 1A ).

Several immune cells, including neutrophils, macrophages and T lymphocytes, are highly plastic and polarize to pro- or anti-inflammatory phenotypes depending on the environment. This is also true for other infiltrated immune cells within the TME. The influence of immune mediators such as TGF-β within the TME promotes the generation of neutrophils with a N2 phenotype, which are pro-tumoral, and the existence of type I IFN such as IFN-β reduces the presence of N1 neutrophils that are anti-tumoral (78). Regarding TAMs, the “classically activated” M1 anti-tumoral macrophages, whose differentiation is based on stimuli by lipopolysaccharide (LPS), TNF-α and IFN-γ, are replaced by the “alternatively activated” M2 pro-tumoral macrophages, which are pro-angiogenic and depend on IL-4, IL-10, PGE2 and TGF-β (79). In the case of TILs, even though they are the main effectors of the anti-tumoral immune responses, it is possible that, as the malignancies progresses, the presence of IFN-γ-producing Th1 cells reduces while the immunosuppressive Tregs, which rely on IL-2, IL-10, TGF-β and IL-35, increase (80). Taken together, the N2 neutrophils, M2 macrophages and Tregs enable the persistence and dissemination of the malignancy ( Figure 3A ).

DCs also become dysfunctional. Purportedly, immunosuppressing factors in the TME, such as IL-10, TGF-β, and Wnt5, favor the adoption of a tolerogenic phenotype through a β-catenin-mediated mechanism, whereby IDO expression is increased (56). Furthermore, both Treg and tumor cells express programmed death-ligand 1 (PD-L1) and CTLA-4. The first binds to programmed cell death protein 1 (PD1) on the surface of Teff, initiating an exhaustion program that compromises aerobic glycolysis (48). CTLA-4 blocks co-stimulation by CD80/CD86 by acting as a decoy of CD28 (81). This effectively abrogates the “second signal” in T cell activation and induces anergy ( Figure 3B ).

As Lardner A. reviewed before, the acidic extracellular pH strongly affects the activity and behavior of immune cells. Normally a drop in pH up to 6.5 is not able to impede locomotion of leukocytes in a significant way, suggesting that infiltrated immune cells still should be able to migrate to the TME and to mobilize within it. However, under acidic pH, neutrophils see their oxygen consumption reduced up to 90%, their tumor cytotoxicity and hydrogen peroxide (H₂O₂) production is limited, and their phagocytic activity is suppressed (69). Macrophages, on the other hand, release reduced amounts of TNF-α (69), IL-6, IL-10 and NO when there is a low extracellular pH (82). Also in macrophages, even though the secretion of both IL-6 and IL-10 diminishes upon low pH environments, IL-10 reduction is even higher, yielding a ratio of IL-6:IL-10 from 5:1 at pH 7.4, to 55:1 at pH 6.5 (83). In the case of lymphocytes in acidic microenvironments, IL-2 fails to work as a proliferation inductor, and such cells have a limited lytic activity against cancer cells (69).

Besides, an acidic TME directly stimulates immune evasion by malignant cells. For example, the increased presence of lactate in the TME significantly enhances the suppressive activities of MDSCs through the HIF-1α pathway (75). When activated, MDSCs rely on aerobic glycolysis for ATP synthesis. However, in the TME, a shift to oxidative metabolism is favored, and the MDSCs up-regulate FAO and OXPHOS greatly. This transition enforces their suppressive functions, many of which pertain to nutrient deprivation, such as arginine and cysteine (51). Along with Treg consolidation in the TME, these processes contribute to the inefficiency of the anti-tumor response (75). On the other hand, Kwon YJ et al. reported in the triple-negative breast cancer cell line MDA-MB-231 that extracellular acidosis promoted the expression of PDL-1 up to 4 times, an effect that was reverted upon returning to a normal range of pH or with the LDH inhibitor oxamate (76). Upregulated PDL-1 levels in non-small cell lung cancer (NSCLC) tumors have been associated, not only with the cancer stage in patients, but also with glucose uptake by such cells (84). A high PDL-1 expression by cancer cells is commonly seen in advanced tumors, and it binds to PD-1 in infiltrated immune cells, mainly to suppress the mTOR pathway in macrophages and to induce exhaustion in cytotoxic T lymphocytes, which eludes the anti-tumor action by immune cells (70). Additionally, an acidic pH of 6.5 disrupts IL-2 signaling by reducing STAT5 phosphorylation in pre-activated CD8+ T cells (85). STAT5 is a critical mediator for CD8+ T cell responses, since it acts as a signal transducer for the CD8+ T cell pro-survival cytokines, IL-7 and IL-15 (86). However, for Tregs even low doses of IL-2 could secure their survival and maintenance (87). Thus, it is possible that the acidic pH in the TME does not only stimulate the exhaustion of TILs, but also that by Treg enrichment and survival, it limits the presence of ATP that could be used by the newly arrived immune cells to ensure their proper anti-tumor activities. The implications of this statement deserve further investigation.

More recently, it has been shown that changes in pH within the TME could be working together with the limitations in energetic resources, to induce phenotype shifts on immune cells. Such a hostile environment depleted of nutrients, particularly glucose, demands energetic plasticity from immune cells. Certainly, while a reduced availability of glucose strongly limits glycolysis and the capacity of T cells to proliferate and to produce cytokines, minor concentrations of glutamine diminish T cell activation (49) ( Table 1 ). The restriction in nutrients within the TME has led to the concept of “metabolic competition”, and now it is known that the predatory consumption of glucose by malignant cells metabolically restricts TILs. Indeed, by using a mice model of sarcoma, the group led by Pearce E. has demonstrated that CD8+ T cells in contact with such cancer cells had a limited aerobic glycolysis capacity and produced low levels of IFN-γ, which correlated with the glucose concentration in the media. Importantly, while the relative presence of Tregs was high, the M1:M2 ratio was low in the TME of the tumors (94).

Just as with glucose, glutamine utilization by immune cells in the TME is restricted. Given the pleiotropic routes of glutamine as an anaplerotic source for OXPHOS and as an intermediate for the biosynthesis of other molecules, some tumor cells are highly dependent on it and termed “glutamine addicted”. The detailed description of the glutamine metabolism in cancer cells is outside of the scope of this review, but outstanding explanations of this topic can be seen in (95, 96). Briefly, it is known that activated T cells require both a high glycolytic rate and glutamine metabolism to ensure fast energy, to proliferate and synthesize proteins, and in fact, their ratio of glutamine intake is similar or even higher than that of glucose (97). Among other roles in lymphocytes, glutamine is required for the expression of surface markers, for proliferation, and for the production of IFN-γ, TNF-α and even IL-6 (97). Under glutamine deprivation states, such as in the TME, TCR-activated naïve CD4+ T cells differentiate to Tregs through the inhibition of the mTOR activity, and just as under low glucose concentrations, the generated Tregs demonstrate low levels of glycolysis concomitantly limiting their ATP levels (98). By reducing the presence of glucose and glutamine in the TME, effector TILs are unable to proliferate and to exert anti-tumor activities, and instead are differentiated into Tregs to maintain a tolerogenic pro-tumor environment. Thus, the induction of Tregs is also favored by the TME. Tregs do not rely on glucose for ATP production, and they are highly resistant to the toxic effects of elevated lactate concentrations. As such, Tregs are capable of surviving and even thriving within the TME.

It is not surprising that infiltrated immune cells must reprogram their metabolism according to the presence of FA, glutamine and glucose in the TME ( Table 1 ). There is a particular interest in the research of lipids, because both cancer cells and cancer-associated fibroblasts (CAFs) within the TME activate adipocytes to lipolyze their triglyceride depots (99), making the TME particularly enriched in lipids. Importantly, some malignant cells such as those from breast cancer have been suggested to exist in a somewhat “parasitic” association with adipocytes and the lipids inside them, and when adipocytes are activated, they also secrete IL-6 which then activates STAT3 and ultimately the membrane lipid transporter CD36 (99). IL-6 facilitates the recruitment of T cells into the TME but also drives chronic inflammation in cancer, and its overexpression is seen as a prognostic indicator of poor outcomes for cancer patients because it drives tumor progression through the activation of the cell cycle regulator cyclin D1, the proto-oncogene c-Myc, and the master metabolic regulator mTOR complex 1 (mTORC1) (100). TILs, such as those found within the TME, have been shown to upregulate their CD36 and their lipid chaperone FABP4/5, both of which ensure the uptake of exogenous lipids (101). Lipids being used by T cells represent a hallmark of Tregs, which then use them as a fuel for OXPHOS through FAO (102). In fact, the transcription factor PPAR-γ, which promotes the transcription of FOXP3 and therefore induces the establishment of Tregs, also stimulates FAO in Tregs (102). This series of events are maintained by IL-2, which just like IL-6, activates mTORC1 signaling in Tregs (103). mTORC1, in turn, couples an increase in the metabolism of cholesterol and other lipids and ensures the expression of the immunosuppressive molecule CTLA-4 on Tregs (48, 103). Thus, the TME shapes the metabolic adaptations of immune cells and impacts tumor development.

Changes in metabolism are crucial in granting immune cells plasticity, that is, the ability to change functional activity depending on a given situation. Helminths, like tumor cells, can modify metabolic features of infiltrated immune cells. For example, M1 macrophages under the activation of PRRs, like the TLR4 by LPS, increase the expression of HIF1-α and therefore obtain energy in a fast way through glycolysis (5). However, IL-4, a marker of type 2 immune responses, promotes OXPHOS and mitochondrial respiration in M2 macrophages surrounding the parasite. Helminths promote IL-4 production and M2 differentiation (5, 105) ( Table 2 ). Less glycolysis implies a reduced availability of intermediates for nucleotide synthesis, and thus less capacity for replication in macrophages ( Figure 4 ). In some sense, certain similarities can be seen when comparing the infected regions by helminths against the TME. In both cases, the M1/Th1 phenotypes are blocked, in detriment of the energetic requirements of infiltrated immune cells.

Although M2-like regulatory macrophages develop in both the tumor and helminth environments, in the TME conditions of hypoxia and glycolysis usually prevail, while in helminth infection sites, IL-4 causes activation of OXPHOS, suggesting that regulatory TAMs and helminth-derived M2 macrophages may have different metabolic needs. Indeed, different helminth-derived molecules use diverse mechanisms for metabolic reprograming. A helminth product secreted by the liver fluke Fasciola hepatica, the helminth defense molecule-1 (FhHDM-1) can reprogram macrophages by inducing OXPHOS fueled by FA with a concomitant elevation of glutaminolysis that result in inhibition of pro-inflammatory cytokines independent of M2 polarization, as no changes in M2 markers were observed. Besides, FhHDM-1 inhibits lysosomal vacuolar ATPase in contrast to IL-4 metabolic reprogramming (107). In contrast, IL-4-induced M2 differentiation depends on FAO, specifically lysosomal lipolysis through activation of lysosomal acid lipase (LAL) and by intake of FA by the scavenger CD36 for activation of OXPHOS and M2 polarization. Furthermore, IL-4 is a potent inductor of CD36 expression and lysosomal function, which is responsible for endocytosis of low-density lipoproteins (LDLs) and very low-density lipoproteins (VLDLs) (108). The lipid lysophosphatidylcholine from S. mansoni can induce M2 polarization in a PPARγ‐dependent manner (115). This is relevant in the context of metabolic reprogramming since PPARγ is induced by IL-4 and is considered a link between M2 macrophage activation and glutamine metabolism (116). Infection with S. japonicum or its products, like soluble egg antigens up-regulate mRNA of enzymes involved in FA synthesis and oxidation, and thus promote M2 polarization (68, 117). In this case, inhibition of lipolysis results in diminished protective immunity in a mouse model of helminth infection ( Table 2 ).

FA synthesis and mitochondrial function are important for DC generation and immune phenotype (118). Tolerogenic DCs are dependent on glycolysis, OXPHOS and increased FAO. Helminth infections are associated with tolerogenic DCs, and similarly to helminth-derived M2 macrophages, OXPHOS and FAO are upregulated (119). Microfilariae from the nematode Brugia malayi can inhibit phosphorylation of mTOR, which is involved in FA synthesis and oxidation, and interfere with DC function, suggesting that this mechanism could also promote the differentiation of Tregs (109) ( Table 2 ).

Glutamine deprivation is significant in the context of parasitism. In helminths, glutamine acts as an important metabolite for production of energy, mainly through gluconeogenesis, as well as a regulator of the synthesis of nucleic acids (120). Motility of multicellular parasites was enhanced when grown in a glutamine-rich medium and reduced when the amino acid was depleted (121). A role in the defense against xenobiotics and other stressors has been suggested for glutamine, given that glutamine synthase, the enzyme which catalyzes the conversion of glutamate and ammonia to glutamine, is upregulated in S. japonicum specimens exposed to antiparasitic drugs (122). Helminths have also been shown to skew the immune response in their favor by modifying glutamine metabolism. In a F. hepatica model, the use of the peptide FhHDM-1 resulted in accentuated glutaminolysis in macrophages (107), resulting in a tolerogenic phenotype that favored parasite survival.

Activation of T cells, with concomitant proliferation and cytokine production, is energy-dependent and consumes glucose. Indeed, T cells over-express GLUT1. OXPHOS and cytochrome c in mitochondria, as well as glutamine import, are elevated upon activation (123). Under glutamine deprivation T cells differentiate into Tregs. This has been shown in the TME as well, where activated CD4+ T cells differentiate to Tregs through the inhibition of its mTOR activity (98). FAO, on the other hand, modulates effector T cells versus Treg generation, favoring the latter (124). These findings are consistent with the adipose tissue decrease observed in helminth-infected obesity mouse models (see below).

T cell exhaustion is not only characteristic of the immune cells found in the TME. Exhaustion has been reported in microbial infections as well, limiting the ability of immune cells to control pathogens (124). However, in helminth infections, T cell exhaustion has been poorly studied. One study showed that most Wuchereria bancrofti-infected individuals have asymptomatic disease. However, some patients develop lymphedema, characterized by constant immune activation and exhausted CD8+ T cell phenotypes (125).

ILC2 are important innate immune cells induced during helminth infections. Due to their size and nutritional requirements, helminths can compete for nutrients with the host. Helminths use glucose as their main nutritional source. As mentioned throughout this review, helminths impact, not only glucose metabolism but also FAO and amino acid metabolism, and affect ILC2 and other immune cell functions. ILC2 catabolize externally derived FA through FAO to induce OXPHOS and ATP synthesis. The use of internal FA, derived from autophagy, also fuels this pathway in mitochondria. In addition, mTOR controls amino acid metabolism that supports ILC2-mediated immune responses (126) ( Table 2 ).

From an intuitive perspective, one way in which parasites could alter the metabolism of the immune cells is through nutrient depletion. Multicellular parasites, such as gastrointestinal nematodes, have been shown to divert nutrients and modify the host’s appetite in order to promote their development and growth (127). Heligmosomoides polygyrus, for instance, reduces glucose transport across the intestinal mucosa, ensuring the monosaccharide’s availability in the intestinal lumen (128).

Thus, an additional convergence point can be found between the restriction in nutrients within the TME that implies “metabolic competition” between cancer and immune cells as mentioned above, and the “nutritional competition” posed by the large parasite and the surrounding immune cells. In both cases, restrictions of immune cell physiology and differentiation cues need to adapt to the microenvironment.

In rodent models, helminth infection and their products can induce changes in global metabolism. Some of the modifications include improvement in insulin sensitivity and glucose tolerance, decrease in body weight, decrease in hepatic steatosis, white adipose tissue (WAT) beigeing, and an increase in WAT eosinophils and M2 macrophages with increased expression of M2 markers (Ym1 and Arg1). However, in humans there is no evidence of causality of the metabolic changes. The main associations observed through epidemiological cross-sectional studies in endemic areas, are the decrease in the homeostatic model assessment for insulin resistance (HOMA-IR), reduced prevalence of metabolic syndrome, obesity and type two diabetes mellitus (T2DM) (41). These results suggest that helminth infection could improve insulin sensitivity and glucose homeostasis, two aspects strongly related to cancer development.

There is still no information on the cellular mechanisms by which helminths induce these metabolic changes in humans. Diverse studies in rodents show that the metabolic changes induced by helminth infection and their secretory/excretory products, could be due to a change in microbiota species and eosinophil and M2 accumulation in mesenteric lymph nodes, adipose tissue, small bowel and liver (129). However, the possible mechanisms involved in these metabolic changes largely remain unknown, as well as the direct role of eosinophils and Th2 cytokines on insulin resistance.

Some parasitic infections in mouse models regulate adipogenesis. For example, Echinoccoccus granulosus infection promotes lipolysis and H. polygyrus attenuates obesity at least in part through enhanced arginine metabolism and PPAR-γ pathway activation that are associated with M2/Th2 polarization in adipose tissue contributing to an anti-inflammatory environment in infected mice (111, 124). Nevertheless, the effects of helminth infection on carcinogenesis have contradictory results, with some studies showing protection of cancer development, while others have either no effect or cancer-promoting activities. These discrepancies may be due to the different helminth species used in the studies, as well as the timing of infection and tumor progression (130).

Regarding the changes in immunometabolism, a broadly studied phenomenon is macrophage modifications by Schistosoma products (mainly eggs and their related antigens) that reprogram metabolism-related genes when they drive a M2 phenotype in rodent models. Schistosoma up‐regulates FAO and diminishes lipid accumulation in the liver through the up‐regulation of AKT and mTORC1 (modulators of catabolism and glucose metabolism). Additionally, this macrophage reprogramming seems to bring protection from high‐fat diet induced weight gain, type 2 diabetes and atherosclerosis (116). Further studies are needed to understand the mechanisms involved in helminth-induced metabolic changes that have potential therapeutic value.