The Warburg effect describes how cancer cells switch from oxidative phosphorylation to glycolysis even in oxygen-rich conditions, producing massive amounts of lactate that accumulate in the tumor microenvironment. This metabolic reprogramming creates an acidic milieu that suppresses immune function while fueling tumor growth and metastasis. Beyond serving as a waste product, lactate functions as a powerful signaling molecule that reshapes immune responses through multiple mechanisms, including direct receptor binding, transporter-mediated cellular reprogramming, and post-translational protein modifications known as lactylation.
Lactate exerts immunosuppressive effects by binding to specific membrane receptors such as GPR81 and GPR132, triggering downstream signaling cascades that dampen anti-tumor immunity. Through these receptors, lactate inhibits dendritic cell maturation, suppresses T-cell activation and proliferation, and promotes the differentiation of regulatory T cells that further suppress immune responses. The monocarboxylate transporter system enables lactate shuttling between cells, allowing cancer cells to export lactate while importing it into immune cells, thereby reprogramming their metabolism and function. This metabolic symbiosis creates a vicious cycle where lactate-producing tumor cells simultaneously disable immune effector cells while supporting the survival and function of immunosuppressive cell populations.
Recent discoveries reveal that lactate serves as a substrate for histone lactylation, a novel epigenetic modification that directly links cellular metabolism to gene expression. Histone lactylation occurs on lysine residues, competing with acetylation and other modifications to regulate chromatin structure and transcriptional programs. In macrophages, lactylation drives the expression of genes associated with wound healing and tissue repair rather than pro-inflammatory responses, effectively polarizing these cells toward an immunosuppressive M2 phenotype. This metabolic-epigenetic axis explains how lactate fundamentally alters immune cell identity and function at the transcriptional level, establishing a persistent state of immune tolerance within tumors.
Non-histone proteins also undergo lactylation, representing a widespread post-translational modification that affects protein stability, localization, and activity. Key metabolic enzymes, transcription factors, and signaling molecules are subject to lactylation, creating a complex regulatory network that fine-tunes cellular responses to metabolic stress. In cancer cells, lactylation of enzymes involved in glycolysis creates positive feedback loops that sustain high lactate production while simultaneously protecting tumor cells from oxidative damage. For immune cells, protein lactylation affects cytokine production, antigen presentation, and cytotoxic function, systematically undermining their ability to mount effective anti-tumor responses.
Targeting lactate metabolism and lactylation pathways represents a promising therapeutic strategy for cancer immunotherapy. Small molecule inhibitors of lactate dehydrogenase, monocarboxylate transporters, and lactylation-modifying enzymes are being developed to disrupt the immunosuppressive tumor microenvironment. Combination approaches that block lactate production while enhancing immune cell function show particular promise, as they simultaneously starve tumors of their preferred metabolic fuel and unleash anti-tumor immunity. Clinical trials investigating lactate-targeting agents in combination with immune checkpoint inhibitors may reveal new opportunities for treating previously resistant cancers, offering hope for patients who fail conventional immunotherapies.
Understanding lactate's multifaceted roles in tumor immunity provides crucial insights into cancer biology and opens new avenues for therapeutic intervention. The integration of metabolism, epigenetics, and immunology through lactate signaling represents a paradigm shift in how cellular energy production influences immune responses. As research continues to unravel the complex mechanisms underlying lactate-mediated immunosuppression, novel therapeutic targets will emerge, potentially transforming cancer treatment by converting cold, immune-excluded tumors into hot, immune-infiltrated lesions that respond to immunotherapy.
DOI:10.1007/s11684-025-1148-0