The Lactate–Lactylation Axis in Tumor Radioresistance: From Metabolic Adaptation to Therapeutic Targeting
核心洞察
Lactate (搜索) metabolism and protein lactylation are increasingly recognized as context-dependent regulators of tumor adaptation to radiotherapy, extending beyond their traditional role as glycolytic byproducts.
Histone lactylation can reshape chromatin accessibility and transcriptional programs associated with DNA damage repair, while non-histone lactylation of proteins such as NBS1 (搜索) and Ku80 (搜索) may directly modulate repair complex function.
Lactate (搜索)-rich and acidic tumor microenvironments suppress post-irradiation effector T-cell and NK-cell function while promoting M2 macrophage polarization, undermining the immunostimulatory effects of radiotherapy.
Radiotherapy remains a cornerstone treatment for solid tumors (搜索), with approximately half of all cancer patients receiving it during the course of their disease. Yet its effectiveness is frequently limited by intrinsic and acquired radioresistance, which leads to local recurrence and poor clinical outcomes. A growing body of evidence now positions the lactate (搜索)–lactylation axis as a central mediator of this resistance, linking metabolic reprogramming, epigenetic regulation, and immune suppression in ways that are reshaping the oncology research landscape.
The emerging understanding, detailed in a comprehensive review published in Frontiers in Immunology, moves lactate (搜索) far beyond its historical characterization as a metabolic waste product. Instead, lactate is now recognized as a multifunctional molecule that can serve as a carbon source for oxidative metabolism, act as a signaling metabolite, and provide the biochemical context for lysine lactylation—a post-translational modification first described by Zhang and colleagues in 2019 that connects metabolic state directly to gene expression.
Metabolic Rewiring and DNA Damage Repair
A defining metabolic feature of many cancers is the Warburg effect—high glycolytic flux even in the presence of oxygen—resulting in substantial lactate (搜索) accumulation within the tumor microenvironment. In many solid tumors (搜索), intratumoral lactate concentrations can reach levels far exceeding those in normal tissues, and elevated lactate has been associated with aggressive tumor behavior, metastatic potential, and adverse clinical outcomes.
Critically, tumors with lower lactate (搜索) production tend to be more radiosensitive, whereas tumors characterized by marked lactate accumulation are often more refractory to irradiation. The review authors note that lactate can function as a major oxidative carbon source, with isotope-tracing studies in human lung cancer xenografts showing that lactate-derived carbon contributed more prominently to TCA cycle intermediates than glucose-derived carbon.
Lactate (搜索)-supported oxidative phosphorylation may serve dual functions in irradiated tumor cells: supporting energetic homeostasis and promoting redox-adaptive defenses that reduce the accumulation of lethal reactive oxygen species and DNA damage. In non-small cell lung cancer (搜索) models, pharmacologic inhibition of LDHA (搜索) reduced lactate production and significantly impaired post-irradiation DNA damage repair, leading to greater residual DNA breaks and diminished clonogenic survival.
Lactate (搜索) treatment has also been reported to upregulate DNA repair-related genes, including RAD51 (搜索), a central mediator of homologous recombination. The review emphasizes that lactate-supported radioresistance is better viewed as a layered model involving metabolic flexibility, redox control, chromatin regulation, and DDR signaling rather than as a single lactate-oxidation-ATP pathway.
Lactylation: An Epigenetic Bridge in DNA Damage Response
The discovery of histone lysine lactylation introduced a new dimension to the understanding of how metabolism interfaces with epigenetic control. Histone lactylation is generally thought to neutralize the positive charge of lysine residues, thereby loosening local chromatin structure and facilitating transcriptional activation. In tumor cells, lactate (搜索)-driven chromatin remodeling appears capable of inducing cell-state-specific gene expression programs, with elevated lactylation linked to increased RAD51 (搜索) expression.
Beyond histones, lactylation has been identified on non-histone proteins including DNA repair factors themselves. One of the most compelling examples involves NBS1 (搜索), a component of the MRE11-RAD50-NBS1 (MRN) complex essential for early sensing and processing of DNA double-strand breaks. A recent study showed that lactate (搜索) accumulation promotes lactylation of NBS1 at lysine 388, a modification installed by Tip60 and removed by HDAC3 (搜索). Lactylated NBS1 displayed enhanced recruitment to sites of DNA damage and improved stabilization of the MRN complex.
Additional evidence suggests that non-histone lactylation may influence non-homologous end joining. In radioresistant lung cancer cells, multiple lactylation sites have been identified on Ku80 (搜索) (XRCC5), and lactylation inhibition has been associated with reduced Ku70/80-dependent end-joining efficiency and increased radiosensitivity.
The review authors caution, however, that the lactylation machinery remains incompletely defined. Current evidence suggests that p300/CBP (搜索) can catalyze lactylation under conditions in which lactyl-CoA is available, but this activity is best interpreted as promiscuous acyltransferase activity rather than proof of a dedicated lactyltransferase. Several class I histone deacetylases, particularly HDAC1–3, as well as SIRT1–3, have been reported to possess delactylase activity.
Immune Microenvironment Remodeling After Radiotherapy
Anti-tumor immunity is an important contributor to the therapeutic efficacy of radiotherapy, yet lactate (搜索)-rich and acidic tumor niches can substantially weaken this component of the response. The review distinguishes between proton-driven extracellular acidosis, which impairs immune-cell function through low-pH biophysics, and lactate-anion signaling through transporters and receptors such as GPR81.
Under acidic conditions, cytotoxic T cells exhibit reduced proliferation, cytokine production, and tumor-killing activity, while NK-cell cytotoxicity is likewise diminished. Dendritic cell antigen-presenting capacity is reduced, co-stimulatory signaling is weakened, and efficient T-cell priming becomes more difficult to achieve.
Elevated lactate (搜索) concentrations also promote polarization of tumor-associated macrophages toward an M2-like state. In the landmark 2019 study, high-lactate conditions induced H3K18la in macrophages and promoted transcription of M2-associated genes such as Arg1 and Vegfa. M2-polarized TAMs secrete immunosuppressive mediators including IL-10 and TGF-β, and can suppress T-cell proliferation by depleting L-arginine via ARG1 expression.
While effector T cells and NK cells are functionally inhibited under high-lactate (搜索) conditions, regulatory T cells appear comparatively more tolerant and may even expand, reinforcing a locally immunosuppressive niche. The review notes that lactate-rich and proton-rich niches can counterbalance the immunogenic effects of radiotherapy by imposing metabolically and biophysically driven programs of immune evasion.
Therapeutic Strategies and Translational Barriers
Several therapeutic approaches targeting the lactate (搜索)–lactylation axis are under investigation, though progress remains uneven across different classes of intervention.
MCT inhibition represents one of the most direct strategies. The selective MCT1 (搜索) inhibitor AZD3965 is the most clinically advanced representative, having shown tolerability in Phase I trials in advanced solid tumors (搜索) and lymphomas, with reversible electroretinographic changes and mild metabolic disturbances among the main reported toxicities. When combined with radiotherapy, MCT1 inhibition has demonstrated enhanced tumor control and prolonged survival in preclinical models. However, a major limitation is compensatory MCT4 (搜索) expression, which can preserve lactate (搜索) export and reduce susceptibility to MCT1-targeted therapy.
LDH inhibitors, including oxamate, NHI-1/2 derivatives, and GSK2837808A, have shown radiosensitizing effects preclinically. In xenograft models, the combination of oxamate and radiotherapy has shown greater tumor growth inhibition than radiotherapy alone. Yet systemic toxicity remains a major translational concern, as LDH is essential to normal metabolic physiology.
OXPHOS inhibitors such as phenformin and IACS-010759 have attracted interest, particularly in tumors with strong mitochondrial dependence. Triple combination strategies integrating OXPHOS inhibition, radiotherapy, and anti-PD-1 therapy have produced strong anti-tumor effects in preclinical models. However, both agents have encountered toxicity-related limitations in clinical development.
Lactate (搜索)-depleting nanoplatforms using lactate oxidase-based systems have been reported to reduce intratumoral lactate levels, inhibit tumor growth, and remodel the immune microenvironment in preclinical models, though most remain at the proof-of-concept stage.
Future Directions and Unresolved Questions
The review authors identify several major questions requiring resolution. The enzymatic machinery of lactylation is still incompletely defined, and it remains unclear whether additional substrate-selective writers and erasers exist. The spatiotemporal relationship between lactate (搜索) metabolism, lactylation dynamics, and DNA damage repair requires more refined approaches, including time-resolved metabolic tracing and integrated multi-omics strategies.
Reliable biomarkers will be necessary to identify patients most likely to benefit from lactate (搜索)-targeted radiosensitization. While FDG-PET provides an indirect measure of glycolytic activity, more direct methods for assessing intratumoral lactate dependence may ultimately prove more informative. Tissue- and blood-based biomarkers such as LDHA (搜索), MCT1 (搜索), MCT4 (搜索), and H3K18la may help define tumors with high lactate flux, but these candidates still require rigorous validation in large, clinically annotated cohorts.
The review emphasizes that RNA-processing-related mechanisms, including m6A-dependent transcript stability and non-coding RNA-associated regulatory circuits, remain promising but incompletely causal and should be treated primarily as future research directions. The next phase of the field, the authors conclude, should move beyond descriptive association toward mechanism-based intervention, biomarker-guided patient selection, and rational combination design.