肿瘤微环境 (TME) 中调节性 T 细胞 (Treg) 的富集已被认为是免疫检查点抑制剂耐药性启动和发展的主要因素之一。 C-C 基序趋化因子受体 8 (CCR8) 是激活的抑制性 Tregs 的标志物，对 TME 中 Tregs 的功能具有显着影响。然而，CCR8在Tregs中的调控机制仍不清楚。在此，我们揭示结直肠癌 (CRC) 微环境中高水平的 TNF-α 通过 TNFR2/NF-κB 信号通路和 FOXP3 转录因子上调 Tregs 中的 CCR8 表达。此外，在抗 PD1 反应和抗 PD1 无反应肿瘤模型中，PD1 阻断诱导 CCR8 Treg 浸润。在这两种模型中，Tnfr2 耗竭或 TNFR2 阻断通过减少 CCR8 Treg 浸润来抑制肿瘤进展，从而增强抗 PD1 治疗的疗效。最后，我们发现 TNFR2 CCR8 Tregs 而不是总 Tregs 与 CRC 和胃癌的不良预后呈正相关。我们的工作揭示了 Tregs 中 CCR8 的调控机制，并将 TNFR2 确定为免疫治疗的一个有前景的靶标。© 作者 2023。由牛津大学出版社代表上海生命科学研究院生物化学与细胞生物学研究所出版科学院。

Enrichment of regulatory T cells (Tregs) in the tumour microenvironment (TME) has been recognized as one of the major factors in the initiation and development of resistance to immune checkpoint inhibitors. C-C motif chemokine receptor 8 (CCR8), a marker of activated suppressive Tregs, has a significant impact on the functions of Tregs in the TME. However, the regulatory mechanism of CCR8 in Tregs remains unclear. Here, we reveal that a high level of TNF-α in the colorectal cancer (CRC) microenvironment upregulates CCR8 expression in Tregs via the TNFR2/NF-κB signalling pathway and the FOXP3 transcription factor. Furthermore, in both anti-PD1-responsive and anti-PD1-unresponsive tumour models, PD1 blockade induced CCR8+ Treg infiltration. In both models, Tnfr2 depletion or TNFR2 blockade suppressed tumour progression by reducing CCR8+ Treg infiltration and thus augmented the efficacy of anti-PD1 therapy. Finally, we identified that TNFR2+CCR8+ Tregs but not total Tregs are positively correlated with adverse prognosis in CRC and gastric cancer. Our work reveals the regulatory mechanisms of CCR8 in Tregs and identifies TNFR2 as a promising target for immunotherapy.© The Author(s) 2023. Published by Oxford University Press on behalf of Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences.