Head and neck cancer (HNC) is prevalent worldwide, and treatment options are limited. Momordicine-I (M-I), a natural component from bitter melon, shows antitumor activity against these cancers, but its mechanism of action, especially in the tumor microenvironment (TME), remains unclear. In this study, we establish that M-I reduces HNC tumor growth in two different immunocompetent mouse models using MOC2 and SCC VII cells. We demonstrate that the anticancer activity results from modulating several molecules in the monocyte/macrophage clusters in CD45+ populations in MOC2 tumors by single-cell-RNA sequencing.. Tumor-associated macrophages (TAMs) often pose a barrier to antitumor effects, but following M-I treatment, we observed a significant reduction in the expression of Sfln4, a myeloid cell differentiation factor, and Cxcl3, a neutrophil chemoattractant, in the monocyte/macrophage populations. We further find that the macrophages must be in close contact with the tumor cells to inhibit Sfln4 and Cxcl3, suggesting that these TAMs are impacted by M-I treatment. Coculturing macrophages with tumor cells shows inhibition of Agr1 expression following M-I treatment, which is indicative of switching from M2 to M1 phenotype. Furthermore, the total B-cell population in M-I-treated tumors is significantly lower, while spleen cells also show similar results when cocultured with MOC2 cells. M-I treatment also inhibits PD1, PD-L1, and FoxP3 expression in tumors. Collectively, these results uncover the potential mechanism of M-I by modulating immune cells, and this new insight can help develop M-I as a promising candidate to treat head and neck cancers, either alone or as adjuvant therapy.

中文翻译：

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苦瓜碱-I 通过肿瘤浸润巨噬细胞和 B 淋巴细胞的重编程免疫抑制作用来抑制头颈癌的生长

头颈癌 (HNC) 在世界范围内普遍存在，但治疗选择有限。苦瓜中的天然成分苦瓜碱-I (MI) 对这些癌症具有抗肿瘤活性，但其作用机制，特别是在肿瘤微环境 (TME) 中的作用机制仍不清楚。在这项研究中，我们使用 MOC2 和 SCC VII 细胞确定 MI 可减少两种不同免疫活性小鼠模型中的 HNC 肿瘤生长。我们通过单细胞 RNA 测序证明，抗癌活性是通过调节 MOC2 肿瘤中 CD45+ 群体的单核细胞/巨噬细胞簇中的多个分子而产生的。肿瘤相关巨噬细胞 (TAM) 通常对抗肿瘤作用构成障碍，但随着 MI治疗后，我们观察到单核细胞/巨噬细胞群中 Sfln4（一种骨髓细胞分化因子）和 Cxcl3（一种中性粒细胞趋化因子）的表达显着降低。我们进一步发现巨噬细胞必须与肿瘤细胞密切接触才能抑制 Sfln4 和 Cxcl3，这表明这些 TAM 受到 MI 治疗的影响。 MI 治疗后巨噬细胞与肿瘤细胞共培养显示 Agr1 表达受到抑制，这表明从 M2 表型转变为 M1 表型。此外，MI治疗的肿瘤中的B细胞总数显着降低，而脾细胞与MOC2细胞共培养时也显示出类似的结果。 MI 治疗还抑制肿瘤中 PD1、PD-L1 和 FoxP3 的表达。总的来说，这些结果通过调节免疫细胞揭示了 MI 的潜在机制，这一新见解可以帮助将 MI 开发为治疗头颈癌的有希望的候选药物，无论是单独治疗还是作为辅助治疗。