SCI

28 August 2024

Targeting p97-Npl4 interaction inhibits tumor Tregcell development to enhance tumor immunity

(nature immunology; if=27.7)

  • Nie P, Cao Z, Yu R, Dong C, Zhang W, Meng Y, Zhang H, Pan Y, Tong Z, Jiang X, Wang S, Zhu M, Han Y, Wang W, Zhang Y, Tan L, Li C, Xu Y, An L, Li B, Jiao S, Zhou Z.

  • Correspondence: jiaoshi@fudan.edu.cn; zhouzhaocai@fudan.edu.cn 

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.

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（如Npl4）复合物已被研究为抗肿瘤药物靶点；然而，目前尚不清楚p97是否在免疫细胞或免疫治疗中发挥作用。在这里，我们表明溴化甲苯是p97和Npl4相互作用的抑制剂，这种p97-Npl4复合物在TI Treg细胞中具有关键作用。溴化甲苯铵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降解并使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。