Malczewski Agnieszka Beata, Coward Jermaine Ig, Ketheesan Natkunam, Navarro Severine
Icon Cancer Centre, Wesley and South Brisbane, Brisbane, Queensland, Australia.
Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia.
Clin Transl Med. 2025 Sep;15(9):e70472. doi: 10.1002/ctm2.70472.
Checkpoint inhibitor therapy is the most common type of immunotherapy used in the clinical setting, however, there are significant obstacles with treatment resistance and cancer progression. Since its introduction, there have been relatively few advances in the development of prognostic or predictive biomarkers. The field of metabolomics studies small molecules and can provide us with an understanding of the dynamic events evolving during the tumour-drug-immune-system interaction. Several key pathways have emerged as important in understanding resistance mechanisms thereby providing a rationale for targeting immunometabolism in order to enhance the immune response during checkpoint inhibitor therapy. In the first part of this review, we explore the role of gut microbiome-derived short-chain fatty acids, which are recognized as important immunoregulatory molecules shaping T-cell activation, effector and memory function. We then discuss tryptophan catabolism as a key predictor of primary checkpoint inhibitor failure. Lastly, we focus on immunometabolism as an important future target in immunotherapy. ONE SENTENCE SUMMARY: This review focusses on microbiome-derived metabolites and their role in immunometabolism and the enhancement of checkpoint inhibitor responses.
检查点抑制剂疗法是临床中使用的最常见的免疫疗法类型，然而，在治疗耐药性和癌症进展方面存在重大障碍。自引入以来，在预后或预测生物标志物的开发方面进展相对较少。代谢组学领域研究小分子，并能让我们了解肿瘤-药物-免疫系统相互作用过程中发生的动态事件。在理解耐药机制方面，几个关键途径已被证明很重要，从而为靶向免疫代谢提供了理论依据，以便在检查点抑制剂治疗期间增强免疫反应。在本综述的第一部分，我们探讨了肠道微生物群衍生的短链脂肪酸的作用，这些短链脂肪酸被认为是塑造T细胞激活、效应和记忆功能的重要免疫调节分子。然后，我们讨论色氨酸分解代谢作为原发性检查点抑制剂治疗失败的关键预测指标。最后，我们将重点放在免疫代谢作为免疫治疗未来的一个重要靶点上。一句话总结：本综述重点关注微生物群衍生的代谢物及其在免疫代谢和增强检查点抑制剂反应中的作用。
