The epigenetic regulation of immune response has been demonstrated in recent studies. Nonetheless, potential roles of RNA N6-methyladenosine (m6A) modification in tumor microenvironment (TME) cell infiltration remain unknown. We comprehensively evaluated the m6A modification patterns of 1938 gastric cancer samples based on 21 m6A regulators, and systematically correlated these modification patterns with TME cell-infiltrating characteristics. The m6Ascore was constructed to quantify m6A modification patterns of individual tumors using principal component analysis algorithms. Three distinct m6A modification patterns were determined. The TME cell-infiltrating characteristics under these three patterns were highly consistent with the three immune phenotypes of tumors including immune-excluded, immune-inflamed and immune-desert phenotypes. We demonstrated the evaluation of m6A modification patterns within individual tumors could predict stages of tumor inflammation, subtypes, TME stromal activity, genetic variation, and patient prognosis. Low m6Ascore, characterized by increased mutation burden and activation of immunity, indicated an inflamed TME phenotype, with 69.4% 5-year survival. Activation of stroma and lack of effective immune infiltration were observed in the high m6Ascore subtype, indicating a non-inflamed and immune-exclusion TME phenotype, with poorer survival. Low m6Ascore was also linked to increased neoantigen load and enhanced response to anti-PD-1/L1 immunotherapy. Two immunotherapy cohorts confirmed patients with lower m6Ascore demonstrated significant therapeutic advantages and clinical benefits. This work revealed the m6A modification played a nonnegligible role in formation of TME diversity and complexity. Evaluating the m6A modification pattern of individual tumor will contribute to enhancing our cognition of TME infiltration characterization and guiding more effective immunotherapy strategies.

中文翻译：

---

胃癌中m6A调节剂介导的甲基化修饰模式和肿瘤微环境浸润特征

最近的研究已经证明了免疫反应的表观遗传调控。尽管如此，RNA N6-甲基腺苷（m6A）修饰在肿瘤微环境（TME）细胞浸润中的潜在作用仍然未知。我们基于 21 个 m6A 调节剂综合评估了 1938 个胃癌样本的 m6A 修饰模式，并将这些修饰模式与 TME 细胞浸润特征系统地关联起来。构建 m6Ascore 以使用主成分分析算法量化单个肿瘤的 m6A 修饰模式。确定了三种不同的 m6A 修饰模式。这三种模式下的TME细胞浸润特征与肿瘤的三种免疫表型高度一致，包括免疫排斥、免疫炎症和免疫沙漠表型。我们证明了对单个肿瘤内 m6A 修饰模式的评估可以预测肿瘤炎症的阶段、亚型、TME 基质活性、遗传变异和患者预后。低 m6Ascore 的特点是突变负荷增加和免疫激活，表明 TME 表型发炎，5 年生存率为 69.4%。在高 m6Ascore 亚型中观察到基质激活和缺乏有效的免疫浸润，表明非炎症和免疫排斥 TME 表型，存活率较差。低 m6Ascore 还与新抗原负荷增加和对抗 PD-1/L1 免疫疗法的反应增强有关。两个免疫治疗队列证实 m6Ascore 较低的患者表现出显着的治疗优势和临床益处。这项工作揭示了 m6A 修饰在 TME 多样性和复杂性的形成中发挥了不可忽视的作用。评估个体肿瘤的 m6A 修饰模式将有助于增强我们对 TME 浸润特征的认知并指导更有效的免疫治疗策略。