Introduction: For decades, lactate was regarded as a simple byproduct of glycolysis, tightly linked to the Warburg effect and the acidic nature of tumors. This traditional view positioned lactate as a metabolic “waste” molecule, passively accumulating in the tumor microenvironment. However, advances in metabolic research over the past two decades have radically changed this perception. Evidence from isotope tracing, metabolic flux analysis, and imaging technologies now demonstrates that lactate is not merely discarded but actively recycled as a carbon source. Remarkably, lactate can directly fuel the tricarboxylic acid (TCA) cycle and, in certain contexts, may even surpass glucose in efficiency. This finding highlights lactate as a crucial contributor to metabolic plasticity, enabling cancer cells to thrive in heterogeneous and nutrient-fluctuating microenvironments.
Methods: This study was designed as a narrative review synthesizing current evidence on the role of lactate in cancer biology, with emphasis on its metabolic, signaling, immunological, and epigenetic functions. A comprehensive literature search was conducted in PubMed, Scopus, and Web of Science databases for studies published between 2000 and 2025. Keywords included “lactate AND cancer,” “lactate shuttle,” “monocarboxylate transporters (MCT1/MCT4),” “lactylation,” “tumor metabolism,” and “oncometabolite.” Additional references were identified by screening bibliographies of relevant review and primary research articles.
Results: A central concept in this metabolic reprogramming is the lactate shuttle, whereby lactate is transported bidirectionally through monocarboxylate transporters (MCT1 and MCT4). Hypoxic tumor cells predominantly export lactate via MCT4, while oxygenated tumor cells import it through MCT1, using it as an oxidative substrate for mitochondrial metabolism. This metabolic symbiosis sustains tumor growth, preserves energy balance, and enhances survival under stress. Thus, lactate functions not as a metabolic endpoint but as a versatile fuel sustaining tumor progression.
Beyond its metabolic role, lactate exerts potent signaling functions. One key mechanism is the stabilization of hypoxia-inducible factor-1α (HIF-1α), a master regulator of angiogenesis and adaptation to hypoxia. By maintaining HIF-1α activity, lactate drives vascular endothelial growth factor (VEGF) expression and promotes neovascularization, ensuring continuous nutrient and oxygen delivery to expanding tumors. In parallel, lactate-induced acidosis remodels the extracellular matrix (ECM), activating proteases and promoting an invasive phenotype that supports metastasis.
Lactate also exerts profound immunomodulatory effects, reshaping the tumor immune landscape in favor of immune evasion. Elevated lactate concentrations inhibit cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, impairing their glycolytic metabolism and reducing effector function. Simultaneously, lactate promotes regulatory T-cell (Treg) expansion, M2-like macrophage polarization, and dendritic cell dysfunction. Collectively, these mechanisms establish a profoundly immunosuppressive tumor microenvironment, allowing cancer cells to evade immune surveillance and resist immunotherapy.
Perhaps the most transformative discovery in recent years is the identification of lactylation, a novel post-translational modification in which lactate modifies histone and non-histone proteins. This process provides a direct biochemical link between metabolism and epigenetic regulation. Through lactylation, lactate reprograms transcriptional networks involved in cell proliferation, metastasis, stemness, and therapy resistance. For example, histone lactylation in macrophages drives the expression of genes associated with wound healing and tissue remodeling, processes that cancer cells can hijack to support growth and invasion. In cancer cells themselves, lactylation alters chromatin accessibility, facilitating transcriptional programs that sustain oncogenic progression and therapeutic escape.
Collectively, these findings establish lactate as a multifunctional oncometabolite that contributes to cancer progression through metabolic, signaling, immunological, and epigenetic pathways. Lactate is no longer viewed as a waste product but as a central orchestrator of tumor biology. Importantly, this paradigm shift opens new avenues for therapeutic intervention. Inhibiting lactate production (e.g., targeting lactate dehydrogenase, LDH), blocking lactate transport (e.g., MCT inhibitors), or disrupting lactylation may represent novel strategies to dismantle tumor-supporting networks. Preclinical studies have shown that targeting lactate metabolism enhances the efficacy of chemotherapy, radiotherapy, and immunotherapy, highlighting the translational relevance of this emerging field.
Conclusion: Lactate plays a dual role in cancer as both a metabolic substrate and a molecular regulator, driving tumor progression through interconnected mechanisms. By sustaining metabolic symbiosis, promoting angiogenesis, establishing immune evasion, and reprogramming gene expression via lactylation, lactate has emerged as a central determinant of tumor aggressiveness and therapeutic resistance. Future therapies directed against lactate metabolism and signaling may serve as a powerful approach to overcome treatment resistance and improve clinical outcomes in oncology
Keywords: Lactate, Cancer metabolism, Lactate shuttle, Immune suppression, Tumor microenvironment