Lactate as a Signaling Molecule in the Tumor Microenvironment: Implications for Cancer Progression

Abstract

Aerobic glycolysis is a process commonly utilized by tumor cells to produce excessive lactate, acidification of the extracellular milieu and promoting tumor progression. Lactate plays its roles as a metabolic intermediate and as a signaling molecule in the tumor microenvironment (TME). In this literature review, we first describe how cancer cells alter their metabolism, focusing on the Warburg effect, LDHA-mediated lactate catalysis, and MCT1/4’s role in its removal. Next, we explain GPR81-mediated signal transduction and inhibition of HIF-1α and NF-κB degradation, which connects metabolism to oncogenic signaling pathways. We discuss lactate-driven histone lactylation as an epigenetic process that enhances gene expression for growth, angiogenesis, and immune evasion. We also examine lactate effects on Immune cells by inhibition of CD8 + T and NK cells, macrophage polarization toward the M2 phenotype, and inhibition of dendritic cell (DC) maturation. Lactate shuttling between cancer-associated fibroblasts and tumor cells promotes metabolic symbiosis and therapy resistance. Lastly, this review examines treatment options targeting LDH and MCTs, either on their own or in combination with immunotherapy. We also discuss challenges including compensatory pathway activation and off-target effects. Understanding the mechanisms of lactate ‘s effects on the TME facilitates the development of more effective metabolic and immunometabolic cancer treatments. From a clinical perspective, targeting lactate metabolism through LDHA inhibitors and MCT blockers, alone or combined with immune checkpoint inhibitors, represents a promising strategy to recondition the immunosuppressive TME and improve therapeutic outcomes. However, metabolic plasticity, pathway redundancy, and insufficient tumor selectivity remain significant translational challenges that warrant further investigation.

Graphical Abstract