Although immune checkpoint inhibitors (ICIs) have revolutionized immuno-oncology with effective clinical responses, only 30 to 40 % of patients respond to ICIs, highlighting the need for reliable biomarkers to predict and enhance therapeutic outcomes. This study investigated how amino acid, glycolysis, and bile acid metabolism affect ICI efficacy in non-small cell lung cancer (NSCLC) patients. Through targeted metabolomic profiling and machine learning analysis, we identified amino acid metabolism as a key factor, with histidine (His) linked to favorable outcomes and homocysteine (HCys), phenylalanine (Phe), and sarcosine (Sar) linked to poor outcomes. Importantly, the His/HCys+Phe+Sar ratio emerges as a robust biomarker. Furthermore, we emphasize the role of glycolysis-related metabolites, particularly lactate. Elevated lactate levels post-immunotherapy treatment correlate with poorer outcomes, underscoring lactate as a potential indicator of treatment efficacy. Moreover, specific bile acids, glycochenodeoxycholic acid (GCDCA) and taurolithocholic acid (TLCA), are associated with better survival and therapeutic response. Particularly, TLCA enhances T cell activation and anti-tumor immunity, suggesting its utility as a predictive biomarker and therapeutic agent. We also suggest a connection between gut microbiota and TLCA levels, with the Eubacterium genus modulating this relationship. Therefore, modulating specific metabolic pathways—particularly amino acid, glycolysis, and bile acid metabolism—could predict and enhance the efficacy of ICI therapy in NSCLC patients, with potential implications for personalized treatment strategies in immuno-oncology.

中文翻译：

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全面的代谢组学分析确定了 NSCLC 患者免疫治疗反应的关键生物标志物和调节因子


尽管免疫检查点抑制剂 （ICI） 以有效的临床反应彻底改变了免疫肿瘤学，但只有 30% 至 40% 的患者对 ICI 有反应，这凸显了需要可靠的生物标志物来预测和增强治疗结果。本研究调查了氨基酸、糖酵解和胆汁酸代谢如何影响非小细胞肺癌 （NSCLC） 患者的 ICI 疗效。通过靶向代谢组学分析和机器学习分析，我们确定氨基酸代谢是一个关键因素，组氨酸 （His） 与良好的结果有关，同型半胱氨酸 （HCys） 、苯丙氨酸 （Phe） 和肌氨酸 （Sar） 与不良结果有关。重要的是，His/HCys+Phe+Sar 比率成为一种强大的生物标志物。此外，我们强调糖酵解相关代谢物的作用，尤其是乳酸。免疫治疗后乳酸水平升高与较差的结果相关，强调乳酸是治疗效果的潜在指标。此外，特异性胆汁酸、糖去氧胆酸 （GCDCA） 和牛磺酰胆酸 （TLCA） 与更好的生存率和治疗反应相关。特别是，TLCA 增强了 T 细胞活化和抗肿瘤免疫力，表明其作为预测性生物标志物和治疗剂的用途。我们还提出了肠道微生物群与 TLCA 水平之间的联系，真杆菌属调节这种关系。因此，调节特定的代谢途径——特别是氨基酸、糖酵解和胆汁酸代谢——可以预测和提高 ICI 治疗对 NSCLC 患者的疗效，对免疫肿瘤学的个性化治疗策略具有潜在意义。