靶向肿瘤浸润调节性 T (TI-Treg) 细胞是癌症治疗的潜在策略。 ATPase p97 与辅因子（例如 Npl4）复合物已被研究作为抗肿瘤药物靶标；然而，p97是否在免疫细胞或免疫治疗中具有功能尚不清楚。在这里，我们证明松宗溴化物是 p97 和 Npl4 相互作用的抑制剂，并且这种 p97-Npl4 复合物在 TI-Treg 细胞中具有关键功能。 Thonzodium bromide 可增强抗肿瘤免疫力，而不影响外周 Treg 细胞稳态。 p97-Npl4 复合物将 Stat3 与 E3 连接酶 PDLIM2 和 PDLIM5 桥接，从而促进 Stat3 降解并促进 TI-Treg 细胞发育。总的来说，这项工作显示了 p97-Npl4 复合物在控制肿瘤中 Treg-TH17 细胞平衡方面的重要作用，并确定了免疫治疗的可能靶点。© 2024。作者获得 Springer Nature America, Inc. 的独家许可。

Targeting tumor-infiltrating regulatory T (TI-Treg) cells is a potential strategy for cancer therapy. The ATPase p97 in complex with cofactors (such as Npl4) has been investigated as an antitumor drug target; however, it is unclear whether p97 has a function in immune cells or immunotherapy. Here we show that thonzonium bromide is an inhibitor of the interaction of p97 and Npl4 and that this p97-Npl4 complex has a critical function in TI-Treg cells. Thonzonium bromide boosts antitumor immunity without affecting peripheral Treg cell homeostasis. The p97-Npl4 complex bridges Stat3 with E3 ligases PDLIM2 and PDLIM5, thereby promoting Stat3 degradation and enabling TI-Treg cell development. Collectively, this work shows an important role for the p97-Npl4 complex in controlling Treg-TH17 cell balance in tumors and identifies possible targets for immunotherapy.© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.