口腔鳞状细胞癌（OSCC）仍然是头颈癌的主要死亡原因，但 OSCC 的确切发病机制尚不清楚。来自 OSCC 患者而非健康对照（HC）的唾液显着促进大鼠模型中 OSCC 的发生和进展，代谢组学分析显示，OSCC 患者的唾液（而非 HC）和 OSCC 组织（而非邻近的非肿瘤组织）的唾液中含有较高水平的犬尿酸 (KYNA)。此外，大量变形链球菌 (S. mutans) 在 OSCC 肿瘤组织中定殖，这种瘤内变形链球菌通过利用其蛋白抗原 c (PAc) 介导 KYNA 过量产生。 KYNA 改变 OSCC 肿瘤微环境 (TME) 中的细胞类型，主要加速 S100a8highS100a9high 中性粒细胞的扩增，以产生更多白细胞介素 1β (IL-1β)，从而进一步扩增中性粒细胞并诱导 TME 中 CD8  T 细胞耗竭，从而促进 OSCC。此外，KYNA 还会损害口腔癌模型中程序性细胞死亡配体 1 (PD-L1) 和 IL-1β 阻断剂的治疗效果。此外，KYNA 介导的免疫抑制程序和芳烃受体 (AHR) 表达与抗肿瘤免疫受损和 OSCC 患者较差的生存率相关。因此，口腔微生物群的畸变和特定口腔细菌（如变形链球菌）的瘤内定植可能会增加 OSCC 患者的生存率。产生肿瘤代谢物，加剧口腔粘膜癌变，重新编程高度免疫抑制的 TME，并促进 OSCC，凸显了干扰口腔微生物群和微生物代谢在 OSCC 预防和治疗中的潜力。视频摘要。© 2024。作者。

Oral squamous cell carcinoma (OSCC) remains a major death cause in head and neck cancers, but the exact pathogenesis mechanisms of OSCC are largely unclear.Saliva derived from OSCC patients but not healthy controls (HCs) significantly promotes OSCC development and progression in rat models, and metabolomic analyses reveal saliva of OSCC patients but not HCs and OSCC tissues but not adjacent non-tumor tissues contain higher levels of kynurenic acid (KYNA). Furthermore, large amounts of Streptococcus mutans (S. mutans) colonize in OSCC tumor tissues, and such intratumoral S. mutans mediates KYNA overproductions via utilizing its protein antigen c (PAc). KYNA shifts the cellular types in the tumor microenvironment (TME) of OSCC and predominantly expedites the expansions of S100a8highS100a9high neutrophils to produce more interleukin 1β (IL-1β), which further expands neutrophils and induces CD8 + T cell exhaustion in TME and therefore promotes OSCC. Also, KYNA compromises the therapeutic effects of programmed cell death ligand 1 (PD-L1) and IL-1β blockades in oral carcinogenesis model. Moreover, KYNA-mediated immunosuppressive program and aryl hydrocarbon receptor (AHR) expression correlate with impaired anti-tumor immunity and poorer survival of OSCC patients.Thus, aberration of oral microbiota and intratumoral colonization of specific oral bacterium such as S. mutans may increase the production of onco-metabolites, exacerbate the oral mucosal carcinogenesis, reprogram a highly immunosuppressive TME, and promote OSCC, highlighting the potential of interfering with oral microbiota and microbial metabolism for OSCC preventions and therapeutics. Video Abstract.© 2024. The Author(s).