Synthetic α-galactosylceramide (αGalCer) and its analogues as powerful agonists for natural killer T (NKT) cell manipulation have received significant attention in immunotherapy and adjuvant development. However, identifying new potent NKT cell agonists, especially those with Th1 selectivity that promote anticancer effects, remains a challenging task. In this work, we introduced a sulfonamide group into the acyl chain of αGalCer to form additional hydrogen bonds to intensify the glycolipid/CD1d interaction. Two compounds GCS-11 and GCS-12 demonstrated remarkable potency while exhibiting different cytokine induction patterns. Compared to αGalCer, the Th1-biased GCS-11 exhibited a 6-fold increase in IFN-γ but not IL-4, while the Th1/2-balanced GCS-12 elicited 7- and 5-fold increase in IFN-γ and IL-4, respectively, in vivo. These findings place them among the most potent NKT cell agonists, with superior antitumor effects. Therefore, hydrogen-bond-involved derivatization could be a powerful strategy to develop potent and polarized NKT cell agonists for various immunotherapies.

中文翻译：

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合理设计的高效 NKT 细胞激动剂，通过氢键相互作用具有不同的细胞因子选择性


合成 α-半乳糖神经酰胺 (αGalCer) 及其类似物作为自然杀伤 T (NKT) 细胞操作的强大激动剂，在免疫治疗和佐剂开发中受到了极大的关注。然而，鉴定新的有效 NKT 细胞激动剂，特别是那些具有 Th1 选择性、促进抗癌作用的激动剂，仍然是一项具有挑战性的任务。在这项工作中，我们将磺酰胺基引入 αGalCer 的酰基链中，形成额外的氢键，从而增强糖脂/CD1d 相互作用。两种化合物 GCS-11 和 GCS-12 显示出显着的效力，同时表现出不同的细胞因子诱导模式。与αGalCer相比，Th1偏向的GCS-11的IFN-γ增加了6倍，但IL-4没有增加，而Th1/2平衡的GCS-12则引起了IFN-γ和IL-4的7倍和5倍增加。 IL-4，分别在体内。这些发现使它们成为最有效的 NKT 细胞激动剂之一，具有卓越的抗肿瘤作用。因此，氢键衍生化可能是开发用于各种免疫疗法的有效且极化的 NKT 细胞激动剂的强大策略。