Tumor Microenvironment Lactate: Is It a Cancer Progression Marker, Immunosuppressant, and Therapeutic Target?

Abstract

The "Warburg effect" is a term coined a century ago for the preferential use of glycolysis over aerobic respiration in tumor cells for energy production, even under aerobic conditions. Although this is a less efficient mechanism of generating energy from glucose, aerobic glycolysis, in addition to the canonical anaerobic glycolysis, is an effective means of lactate production. The abundant waste product, lactate, yielded by the dual glycolysis in a tumor, has been discovered to be a major biomolecule that drives cancer progression. Lactate is a metabolic energy source that, via cell membrane lactate transporters, shuttles in and out of cancer cells as well as cancer cell-associated stromal cells and immune cells within the tumor microenvironment (TME). Additionally, lactate serves as a pH tuner, signaling ligand and transducer, epigenetic and gene transcription regulator, TME modifier, immune suppressor, chemoresistance modulator, and prognostic marker. With such broad functionalities, the production-consumption-reproduction of TME lactate fuels tumor growth and dissemination. Here, we elaborate on the lactate sources that contribute to the pool of lactate in the TME, the functions of TME lactate, the influence of the TME lactate on immune cell function and local tissue immunity, and anticancer therapeutic approaches adopting lactate manipulations and their efficacies. By scrutinizing these properties of the TME lactate and others that have been well addressed in the field, it is expected that a better weighing of the influence of the TME lactate on cancer development, progression, prognosis, and therapeutic efficacy can be achieved.

Keywords: cell metabolism; immune regulation; lactate; posttranslational modification; signaling and gene regulation; tumor microenvironment (TME).

Figure 1

Warburg effect and reverse Warburg effect form a core symbiotic mechanism supporting cancer cell thriving in the TME. Glycolytic cancer cells or stromal cells living in the TME of a growing tumor produce and release lactate for the growth of oxidative cancer cells or stromal cells. In turn, the oxidative cancer cells or stromal cells utilize the imported lactate to generate pyruvate or other metabolites and release them for the survival and propagation of the glycolytic cancer cells or stromal cells.

Figure 2

Model of lactate sources supplying the TME for tumor progression. Both tumor cells and stromal cells utilize the Warburg effect, reverse Warburg effect, canonical glycolysis, and glutaminolysis to lactate production. The reverse Warburg effect that happens in the same type of cells that are under either glycolytic or oxidative status is considered a homo-intercellular mechanism, and the Warburg effect that happens between two different types of cells is considered an allo-intercellular mechanism. Tumor-generated lactate and systemically generated circulating lactate are mutually exchangeable and available for tumor growth.

Figure 3

Systemic LOX administration impaired tumor growth in mice without affecting tumor lactate levels. (a) IVIS image of mice treated with saline or 4.8 U/mL LOX via tail vein injection. (b) Tumor size quantification. The excised tumors at Wk5 were measured with calipers, and their sizes in terms of volume were calculated with the equation (length × width²)/2. ∅: p = 0.055. (c) Tumor and circulating lactate levels in the mice treated with saline or LOX (previously unpublished data).

Figure 4

TME lactate signaling. Lactates produced from ALDH1A3/PKM2 activation or secreted from CAFs, other stromal cells, and cancer cells can either shuttle through MCT1/4 lactate transporters or functions as a signaling molecule by binding to GRP132 or HCAR1. Downstream effects of these signaling include activating immune cells and inducing their differentiation, stimulating cancer cell EMT, triggering angiogenesis, enhancing chemoresistance, and enabling cancer cell escape from immune surveillance. The question mark represents yet to be verified signaling pathway triggered by lactate.

Figure 5

Lactate and lactylation regulate gene expression and protein and fatty acid functions. Increased intracellular lactate levels can activate Snail/EZH2/STAT3 to initiate HCAR1 transcription. Histone lactylation activates gene transcription, such as for Arg1, Vegfa, IDH3G, YTHDF2, and GCLC, or inhibits HK-1 transcription. TP53K120/139 lactylation by AARS1 can inhibit the p53 response element, while increased production of YTHDF2 from H3K18la can cause degradation of TP53 and PER1 mRNA. PTBP1K436la can stabilize PFKFB4 mRNA to increase glycolysis. ALDOAK230/322la allows the release of DDX17 and its translocation into the nucleus to interact with SOX2 to activate genes important for maintaining cancer cell stemness. Lactylation of APOC2 at K70 increases secretion of FFA.

Figure 6

The major functions of TME lactate. The TME lactate is a pH tuner, signaling molecule, epigenetic and transcription regulator, and ECM modifier.

Figure 7

Lactate in the TME promotes overall immunosuppression. Cancer cells overexpress IGF2BP3 to increase lactate production, and lactate is secreted into the TME via MCT1 and MCT4. Lactate is then transported into various immune cells within the TME through various transporters, such as MCT1, MCT11, and SLC15A12, and also interacts with HCAR1 and GPR132. The overall effect is to prevent a pro-inflammatory environment by inhibiting IFN-γ-producing CD4+ T cells and preventing monocytes from differentiating into M1 macrophages and DCs, while promoting anti-inflammatory environment by inducing monocytic MDSCs into M2 macrophages, promoting Treg differentiation and enhancing their function, and inhibiting cytotoxic CD8+ T cell function through the various mechanisms described above. This allows cancer cells to escape from immune surveillance.