Metabolite to Modifier: Lactate and Lactylation in the Evolution of Tumors

Abstract

Lactate, once dismissed as a mere by-product of cancer metabolism, has emerged as a pivotal factor in tumor progression, exerting diverse effects on metabolic reprogramming and immune modulation. Lactate enhances tumor cell adaptability through sustained glycolysis and concurrently shapes the tumor microenvironment by modulating immune, stromal, and endothelial cell function. This review highlights the evolving understanding of lactate's role, extending beyond the Warburg effect to its regulatory capacity via lactylation, a recently identified post-translational modification. The complex interaction between lactate and tumor biology is examined, emphasizing its influence on the tumor microenvironment and immune dynamics. Additionally, potential therapeutic strategies targeting lactate metabolism and transport are explored, along with lactylation regulation by histone-modifying enzymes. Inhibitors targeting lactate production and transport, especially those against lactate dehydrogenase (LDH) and monocarboxylate transporters (MCTs), have shown considerable potential in preclinical and early clinical studies. Recent advancements are discussed, underscoring the potential of integrating metabolic regulation with immunotherapies, thereby offering a dual pathway in cancer treatment. These insights establish lactate and lactylation as pivotal modulators of tumor biology and highlight their potential as targets in precision oncology.

Keywords: cancer therapy; immune modulation; lactate; lactylation; metabolic reprogramming; tumor microenvironment.

FIGURE 1

The tumor microenvironment (TME) includes immune and stromal cells, with tumor cells secreting large amounts of lactate, causing an inverse pH gradient and suppressing immune cell function. Lactate, by secreting immunosuppressive molecules and enhancing Treg cell activity, disrupts the immune microenvironment. Additionally, lactate promotes the polarization of M2‐like macrophages, contributing to anti‐inflammatory effects and tumor growth.

FIGURE 2

Visualization of lactylation based on bibliometics. (A) Annual changes in the number of articles by country; (B) lactylation research papers by document type percentage; (C) distribution of different research fields of papers for lactylation; (D) collaborative relationships between different countries; (E) keyword cloud; and (F) distribution map of related diseases.

FIGURE 3

Lactylation at the histone amino terminus. The figure depicts DNA coiled around a histone octamer, forming nucleosomes composed of two each of H2A, H2B, H3, and H4 histones. The histone tails, which protrude from the nucleosomal core, are susceptible to diverse post‐translational modifications (PTMs), including lactylation (Lac). These modifications not only modulate the chromatin structure's overall compaction but also influence gene expression. Lactylation is dynamically regulated by “writers” (e.g., p300, CBP, AARS1) that catalyze the addition of lactyl groups, “erasers” (e.g., HDAC1‐3 and SIRT1‐3) that remove them, and “readers” that recognize lactylated lysines to mediate transcriptional and chromatin responses. All three classes of regulators are depicted in the figure.

FIGURE 4

The mechanism by which protein lactylation modification promotes tumor progression in several types of cancer.