Tumorigenesis is characterized by genetic alterations, and several findings demonstrate that high expression of specific transcription factors or oncogenic tumor pathways, principally MYC, hypoxia-inducible factor-1 alpha (HIF-1α), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and phosphatidylinositol-3-OH kinase (PI3K), can sustain the Warburg effect. As the tumor starts to grow, oxygen diffusion becomes limited and cancer cells respond to these environmental changes by upregulating HIF-1α (29). HIF-1α, in turn, induces the overexpression of key players in the conversion of glucose into lactate, such as glucose transporters (GLUTs) and hexokinase (HK) 1 and 2, which are responsible for the initial steps of glycolysis; lactate dehydrogenase A (LDHA), which transforms pyruvate into lactate (30, 31); and the lactate-extruding monocarboxylate transporter 4 (MCT4) (32). Conversely, HIF-1α blocks the entry of pyruvate into the TCA cycle by upregulating pyruvate dehydrogenase kinase 1 (PDK1), driving tumor cell energy to glycolysis (33). The major oncogene Ras, when mutated, can also induce glycolysis through the activation of the mammalian target of rapamycin complex I (mTORC1). Akt kinase activation by PI3K results in increased glucose uptake, HK2 targeting to the mitochondria, and increase in glycolytic flux (34), while the transcription factor MYC increases glutaminolysis and upregulates MCT1 expression (35). Cancer cell metabolism is also influenced by the activity of tumor suppressor genes. Loss of the p53 protein prevents expression of the synthesis of cytochrome c oxidase (SCO2) gene, decreasing mitochondrial respiration (36). Lactate can also function as a paracrine tumor molecule (37). Acidosis often precedes angiogenesis and lactate can stimulate HIF expression independently of hypoxia (38). Thus, instead of one event promoting the Warburg effect, numerous factors play a role in determining the fate of glucose in cancer cells. Also true is that somatic mutations in genes involved in metabolism either cause/predispose cells to become malignant. For instance, mutations in succinate dehydrogenase are related to paraganglioma, and mutations in fumarase can induce leiomyoma and leiomyosarcoma formation (39); isocitrate dehydrogenase mutations are related to glioma development (39).

The major oncometabolite resulting from tumor metabolic rewiring is lactate, which is abundant in the tumor microenvironment (TME). Because lactic acid is hydrophilic and a weak acid, its transport across membranes requires transporters that belong to the monocarboxylate transporter family. MCTs 1–4 facilitate the transmembrane H⁺-linked transport of monocarboxylates, including lactate, pyruvate, acetoacetate, and β-hydroxybutyrate (15), having the cell surface glycoprotein CD147 as an obligatory chaperone (40). MCT1 and MCT4 isoforms are strongly associated with the hyperglycolytic phenotype of cancer cells. These transporters display distinct affinities for monocarboxylic acids that are associated with their expression patterns within tissues (41). MCT1 expression was identified in most tissues, being associated with the uptake/extrusion of lactate, while MCT4 has an important role in the export of lactate in highly glycolytic tissues. MCTs have been widely studied by our group and others, and found to be robustly expressed in a variety of solid human tumors such as colon, glioblastoma, breast, prostate, stomach and others, as depicted in Table 1 [for a comprehensive review see (41, 72)]. MCT expression/cell localization can differ from cancer to cancer. Importantly, the prognostic potential of MCTs was found in various tumor types (Table 1). Given the key role of MCTs in cancer, these transporters are promising therapeutic targets in cancer. A less studied family of lactate transporters, also known to facilitate the transport of monocarboxylates, are the sodium-coupled monocarboxylate transporters (SMCTs), containing two members, SLC5A8 and SLC5A12 (73).

Lactate acts as a powerful regulator of multiple hallmarks of cancer, supporting cell proliferation and promoting immune suppression, angiogenesis, migration, metastasis, and resistance to therapy (20), namely chemotherapy (77), radiotherapy (78), and targeted therapy (79, 80). Cancer cells exploiting aerobic glycolysis upregulate GLUTs and MCTs, secreting large amounts of lactate (Figure 1), while deviating glycolytic intermediates to fuel alternative anabolic pathways (e.g., pentose phosphate pathway), thus sustaining rapid cell proliferation (81). Due to the metabolic heterogeneity of the TME, cancer cells are also able to engage into context-dependent metabolic affairs, similarly to what occurs in muscle (82) and brain (83). One such example is the symbiosis between well and poorly-oxygenated cancer cell populations (Figure 1): at the hypoxic, nutrient-poor/normoxic, nutrient-rich interface, lactate is released by glycolytic cancer cells through MCT4, and taken up by oxidative cancer cells through MCT1, where it fuels oxidative phosphorylation, thus sparing glucose for glycolytic cancer cells (84). Occurrence of this “two compartment model” was additionally described between lactate-avid breast cancer cells and “corruptible” glycolytic cancer-associated fibroblasts (CAF) by Lisantis's group (85), and further amplified to a “three compartment model” in the study by Curry et al. (86); in head and neck cancer samples, the authors showed that catabolic compartments composed of Warburg-adapted MCT4-expressing cancer cells and CAFs provided anabolic MCT1-expressing cancer cells with glycolysis-originating lactate (86). Since those original observations, numerous studies reported similar associations in several cancer models, such as non-Hodgkin lymphoma (87), pancreas (88), lung (89), prostate (90), and bladder (91); clinically, this metabolic phenotype has been associated with cancer aggressiveness, resistance to therapy and poor survival (89–91). Several mechanisms have been pointed out as mediators of those metabolic affairs, such as secretion of growth factors [e.g., cancer cell-secreted basic fibroblast growth factor (bFGF) in response to CAF-secreted hepatocyte growth factor (HGF) (92)], interleukins [e.g., IL-1β secretion by cancer cells (93)], and exosomal microRNAs (94). Interestingly, microRNA-containing exosomes secreted by CAFs were able to inhibit oxidative metabolism in cancer cells, while providing them with intact metabolites, namely glucose, to sustain their growth (95). In such an inverted scenario, CAFs oxidize cancer cell-derived lactate to support tumor proliferation (96); this has been correlated with resistance to targeted therapy (80).

In addition to CAFs, the metabolic promiscuity described above involves other cells of the TME, namely immune and endothelial cells (Figure 1). Cytotoxic T cells' transition from an anergic to a fully activated state relies on an accelerated glucose metabolism (97) and, in a glucose-restricted TME, cancer cells easily succeed in such metabolic competition (98). Dampening of lymphocyte proliferation and motility, cytokine production and cytotoxic activity ultimately leads to immunosuppression, as a result of the excess cancer cell-derived lactate that blocks lactate export by immune cells (99) and might be inclusively taken up by those cells, thus impairing their glycolysis-dependent activation (100). Lactate also mediates polarization of macrophages from an M1- (anti-tumoral type) to an M2-like phenotype (pro-tumoral type) (101, 102); induction of VEGF (vascular endothelial growth factor) expression has been linked to this pro-tumoral state (103). Moreover, it was proposed that endothelial cells rely on extracellular lactate uptake, via MCT1, as a fuel source for their oxidative metabolism, promoting VEGF/VEGFR-2 production through HIF-1α stabilization, endothelial cell migration and tube formation (104–106).

Lactate stimulates motility, migration and invasion of cancer cells (38, 107), as a probable result of CD44 expression and hyaluronan production (108), as well as activation of matrix metalloproteinases (MMPs) (109), both promoted by extracellular acidosis.

As stated above, lactate can serve additional purposes beyond acting as a metabolic substrate, functioning as an intracellular signaling mediator and as an extracellular ligand. At the intracellular level (Figure 1), hypoxia adaptation is assured by lactate in HIF-1α-dependent [direct HIF-1α stabilization by prolyl hydroxylase (PHD) 2 inhibition (110)] and independent [binding to N-Myc downstream-regulated (NDRG3) protein, preventing association with PHD2 (111)] fashions. HIF-2α stabilization is also induced by lactate, which ultimately potentiates glutaminolysis in cancer cells (112). Lactate promotes HIF-1α-mediated VEGF expression in the cancer cell, and expression of bFGF and VEGFR-2 by neighboring endothelial cells (105). Apart from this HIF-1α-dependent angiogenic signals, endothelial cells are also activated by NF-κB stabilization (104) in a lactate-dependent manner. NF-κB activation in cancer cells' instructed CAFs additionally drives resistance to targeted therapies, being lactate secreted by cancer cells the instructor in such phenotype (80). Pyruvate kinase M2/HIF-1α-driven gene expression in prostate cancer cells promoted epithelial-to-mesenchymal in response to CAF-secreted lactate (113). Immune suppression is also mediated by lactate signaling, as different studies reported that this oncometabolite interferes with key tumor pathways that lead to IFN-γ production by cytotoxic T cells (114), activates the IL-23/IL-17 proinflammatory pathway (115) and promotes polarization of macrophages toward an M2-like phenotype (103). Recently, functions in histone post-translational modification, termed histone lysine lactylation, were attributed to lactate and shown to regulate gene expression in macrophages; increased lactate production led to this epigenetic modification, inducing an M2-like phenotype during wound healing (116).

The signaling functions of lactate at the extracellular space (Figure 1) are mediated by the lactate-activated G-protein-coupled receptor GPR81 (5, 117). Its expression is not limited to the plasma membrane but also to other intracellular organelles (118). GPR81 activation occurs at a lactate concentration of 0.2–1.0 mM (119), followed by cyclic AMP downregulation and inhibition of protein kinase A (PKA)-mediated signaling (120). In the physiological context, lactate binds to GPR81, which inhibits lipolysis in fat cells (121). In the cancer context, modulation of lactate-sensing proteins, such as MCTs, ultimately leads to tumor proliferation and dissemination (122), escape from the immune system (123) and therapy resistance (124). GPR81 expression is upregulated in cervical (125), breast (126) and liver cancer (122), and associated with the progression of cervical squamous carcinoma (125). GPR81 is highly expressed in different cancer cell lines including colon, breast, lung, hepatocellular, cervical, and pancreatic (122, 126). In vitro, GPR81 expression associated with cancer cell survival, proliferation, migration, invasion and resistance to chemotherapy, and is involved in the suppression of antitumor immunity by promoting the overexpression of PD-L1 in lung cancer cells lines (123, 124, 126). Knockdown of GPR81 in a xenograft cancer model resulted in reduction of tumor growth and metastasis (122, 126).

The putative lactate sensors GPR4, GPR65, GPR68, and GPR132 have been described as proton-sensitive, and are activated at the acidic TME due to the low pH levels obtained from lactic and carbonic acids (5). GPR132 and GPR65 were additionally described in macrophages and linked to their polarization toward a pro-tumoral phenotype (127, 128). It remains to be clarified whether the modulation of lactate-sensing signaling pathways occurs through a direct GPR-lactate interaction ou through a conformational modification in the receptor induced by lactic acidosis.

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. The handling editor declared a shared affiliation, though no other collaboration, with one of the authors FB.