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  • Lactate-Mediated Mechanisms of Cancer Therapy Resistance

  • Parnian Hajiloo,1,*
    1. Islamic Azad University, Tehran Medical Sciences


  • Introduction: Therapeutic resistance remains a major challenge in cancer treatment and contributes to tumor progression, recurrence, and poor clinical outcomes. Increasing evidence indicates that lactate is not merely a metabolic by-product but an active signaling metabolite and regulator of the tumor microenvironment (TME). Elevated lactate can promote metabolic adaptation, extracellular acidification, immune suppression, and protein lactylation, allowing tumor cells to survive therapeutic stress. This review summarizes the major mechanisms through which lactate contributes to cancer therapy resistance and discusses potential strategies for overcoming this resistance.
  • Methods: Recent literature investigating lactate, lactylation, the TME, and cancer therapy resistance was reviewed. Four recent review articles were selected and analyzed, focusing on mechanisms connecting lactate accumulation with resistance to immunotherapy, chemotherapy, radiotherapy, targeted therapy, and anti-angiogenic treatment.
  • Results: Lactate and Immunotherapy Resistance: Elevated lactate contributes to an immunosuppressive TME and may reduce the effectiveness of immune checkpoint blockade. Lactate promotes M2-like macrophage polarization and impairs dendritic-cell antigen presentation. It also suppresses CD8+ T-cell activation, migration, cytokine production, and cytotoxicity, while supporting regulatory T-cell activity and reducing natural killer (NK) cell function. These changes weaken antitumor immunity and can contribute to resistance to anti-PD-1/PD-L1 therapy. Lactate-associated signaling and lactylation may further modify immune-related gene expression, strengthening immune evasion. Lactate and Chemotherapy Resistance: Lactate may promote chemotherapy resistance through metabolic and epigenetic mechanisms. Lactate-associated lysine lactylation of histone and non-histone proteins can regulate gene expression, cell survival, and DNA repair. Enhanced DNA repair may allow tumor cells to better tolerate treatment-induced DNA damage and survive cytotoxic therapy. In particular, lactylation of DNA-repair-related proteins, including MRE11, has been associated with increased repair capacity and resistance to DNA-damaging treatments and PARP inhibition. Lactate and Radiotherapy Resistance: Radiotherapy produces DNA damage that can lead to tumor-cell death. Lactate-related signaling and lactylation may support DNA damage repair and cellular survival, allowing tumor cells to recover from radiation-induced injury. Lactate-mediated remodeling of the TME may additionally create a protective environment that favors tumor survival during treatment. These mechanisms may therefore contribute to radioresistance. Lactate and Targeted and Anti-angiogenic Therapy Resistance: Lactate can promote adaptive survival responses that allow tumor cells to persist despite inhibition of oncogenic pathways. It may also alter communication between tumor cells and stromal components of the TME, supporting continued survival under therapeutic pressure. Lactylation has been linked to resistance to anti-angiogenic therapy; for example, increased H3K18 lactylation can promote expression of survival-related genes and has been associated with resistance to bevacizumab. Therapeutic Targeting of Lactate-Mediated Resistance: Because lactate contributes to resistance through several interconnected pathways, targeting lactate metabolism and lactylation represents a promising therapeutic strategy. Potential approaches include inhibition of lactate production through lactate dehydrogenase (LDH), blockade of monocarboxylate transporters (MCTs), modulation of lactate-related signaling, and targeting lactylation regulators. Combining these approaches with chemotherapy, radiotherapy, targeted therapy, or immune checkpoint inhibitors may improve tumor sensitivity and potentially overcome therapeutic resistance.
  • Conclusion: Lactate is a multifunctional mediator of cancer therapy resistance rather than simply a metabolic waste product. Through TME remodeling, immune suppression, metabolic adaptation, extracellular acidification, and protein lactylation, lactate can support tumor-cell survival and reduce the effectiveness of different therapeutic approaches. Targeting lactate production, transport, signaling, or lactylation may therefore provide a promising strategy for resensitizing resistant tumors to existing treatments. However, much of the current evidence remains preclinical, and further research is needed to determine the safety, efficacy, and optimal clinical combinations of lactate-targeted therapies.
  • Keywords: Lactate, Lactylation, Cancer, Therapy Resistance, Tumor Microenvironment

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