Immune checkpoint inhibitors (ICIs) improve outcomes in advanced melanoma, but many patients are refractory or experience relapse. The gut microbiota modulates antitumor responses. However, inconsistent baseline predictors point to heterogeneity in responses and inadequacy of cross-sectional data. We followed patients with unresectable melanoma from baseline and during anti-PD-1 therapy, collecting fecal and blood samples that were surveyed for changes in the gut microbiota and immune markers. Varying patient responses were linked to different gut microbiota dynamics during ICI treatment. We select complete responders by their stable microbiota functions and validate them using multiple external cohorts and experimentally. We identify major histocompatibility complex class I (MHC class I)-restricted peptides derived from flagellin-related genes of Lachnospiraceae (FLach) as structural homologs of tumor-associated antigens, detect FLach-reactive CD8⁺ T cells in complete responders before ICI therapy, and demonstrate that FLach peptides improve antitumor immunity. These findings highlight the prognostic value of microbial functions and therapeutic potential of tumor-mimicking microbial peptides.

中文翻译：

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抗 PD-1 治疗期间肠道微生物群的纵向分析揭示了黑色素瘤患者反应的稳定微生物特征


免疫检查点抑制剂 （ICI） 可改善晚期黑色素瘤的预后，但许多患者难治性或复发。肠道微生物群调节抗肿瘤反应。然而，不一致的基线预测因子指出反应的异质性和横断面数据的不足。我们从基线和抗 PD-1 治疗期间跟踪了不可切除的黑色素瘤患者，收集了粪便和血液样本，这些样本被调查了肠道微生物群和免疫标志物的变化。在 ICI 治疗期间，不同的患者反应与不同的肠道微生物群动力学有关。我们根据稳定的微生物群功能选择完全反应者，并使用多个外部队列和实验对其进行验证。我们鉴定了源自毛螺菌科鞭毛蛋白相关基因 （FLach） 的主要组织相容性复合物 I 类 （MHC I） 限制性肽，作为肿瘤相关抗原的结构同源物，在 ICI 治疗前检测完全应答者中的 FLach 反应性 CD8⁺ T 细胞，并证明 FLach肽可提高抗肿瘤免疫力。这些发现突出了微生物功能的预后价值和模拟肿瘤的微生物肽的治疗潜力。