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<p>Lactate, a key byproduct of tumor metabolic reprogramming, accumulates in the tumor microenvironment (TME) and profoundly shapes T cell-mediated anti-tumor immunity. As research into TME metabolism advances, lactate has emerged as a critical regulator with broad effects on immune function. In many cancers—including gastric cancer, hepatocellular carcinoma, lung cancer, melanoma, and pancreatic cancer—lactate suppresses or remodels anti-tumor immunity by acting on CD8⁺ T cells, regulatory T cells (Tregs), dendritic cells (DCs), and immune checkpoint molecules. The underlying mechanisms are becoming increasingly well-defined. However, major knowledge gaps remain, especially regarding how lactate-associated enzymes (e.g., LDHA), lactate transporters (e.g., MCT4), and signaling pathways impact T cell function. This review summarizes how lactate regulates anti-tumor immune responses and explores emerging immunotherapies targeting lactate metabolism, with a focus on metabolic enzymes and transporters. We cover preclinical and clinical progress on LDHA inhibitors and lactate transporter inhibitors. By comprehensively analyzing lactate’s function in the TME, we aim to build a theoretical framework for precision tumor immunotherapy and propose future directions centered on modulating the immune microenvironment through lactate-targeted strategies.</p>

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Beyond a waste product: lactate as a master metabolite dictating anti-tumor T-cell fate

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月23日

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  • Xiangyu Dai,
  • Jingjia Chang,
  • Siyue Wang,
  • Lutterodt Bentum-Ennin,
  • Jian Zhou,
  • Xiaomin Zuo,
  • Wanglai Hu

摘要

Lactate, a key byproduct of tumor metabolic reprogramming, accumulates in the tumor microenvironment (TME) and profoundly shapes T cell-mediated anti-tumor immunity. As research into TME metabolism advances, lactate has emerged as a critical regulator with broad effects on immune function. In many cancers—including gastric cancer, hepatocellular carcinoma, lung cancer, melanoma, and pancreatic cancer—lactate suppresses or remodels anti-tumor immunity by acting on CD8⁺ T cells, regulatory T cells (Tregs), dendritic cells (DCs), and immune checkpoint molecules. The underlying mechanisms are becoming increasingly well-defined. However, major knowledge gaps remain, especially regarding how lactate-associated enzymes (e.g., LDHA), lactate transporters (e.g., MCT4), and signaling pathways impact T cell function. This review summarizes how lactate regulates anti-tumor immune responses and explores emerging immunotherapies targeting lactate metabolism, with a focus on metabolic enzymes and transporters. We cover preclinical and clinical progress on LDHA inhibitors and lactate transporter inhibitors. By comprehensively analyzing lactate’s function in the TME, we aim to build a theoretical framework for precision tumor immunotherapy and propose future directions centered on modulating the immune microenvironment through lactate-targeted strategies.