Oncometabolite 2-hydroxyglutarate regulates anti-tumor immunity

• Published in: Heliyon 2024-01, Vol.10 (2), p.e24454, Article e24454
• Main Authors: Cai, Mengyuan, Zhao, Jianyi, Ding, Qiang, Wei, Jifu
• Format: Article
• Language: English
• Subjects: 2-Hydroxyglutarate; Isocitrate dehydrogenase; Oncometabolite; Review; Therapeutic target; Tumor immune microenvironment
• ISSN: 2405-8440; 2405-8440
• DOI: 10.1016/j.heliyon.2024.e24454

"Oncometabolite" 2-hydroxyglutarate (2-HG) is an aberrant metabolite found in tumor cells, exerting a pivotal influence on tumor progression. Recent studies have unveiled its impact on the proliferation, activation, and differentiation of anti-tumor T cells. Moreover, 2-HG regulates the function of innate immune components, including macrophages, dendritic cells, natural killer cells, and the complement system. Elevated levels of 2-HG hinder α-KG-dependent dioxygenases (α-KGDDs), contributing to tumorigenesis by disrupting epigenetic regulation, genome integrity, hypoxia-inducible factors (HIF) signaling, and cellular metabolism. The chiral molecular structure of 2-HG produces two enantiomers: D-2-HG and L-2-HG, each with distinct origins and biological functions. Efforts to inhibit D-2-HG and leverage the potential of L-2-HG have demonstrated efficacy in cancer immunotherapy. This review delves into the metabolism, biological functions, and impacts on the tumor immune microenvironment (TIME) of 2-HG, providing a comprehensive exploration of the intricate relationship between 2-HG and antitumor immunity. Additionally, we examine the potential clinical applications of targeted therapy for 2-HG, highlighting recent breakthroughs as well as the existing challenges. •D-2-HG interferes with a wide range of immune cells and even complement system to cause “cold tumor” characteristics.•L-2-HG provokes CD8+ T cells as well as induces memory T cells.•Small molecule inhibitors and therapeutic vaccines targeted 2-HG have potential in cancer treatment.