调节免疫冷肿瘤热在很大程度上引起了人们对改善癌症治疗的关注，包括免疫疗法和抗体药物偶联物（ADC）。利用多组学分析和实验验证，这项工作确定了 USP10/B7-H4 蛋白水解轴在介导肿瘤免疫反应和 ADC 功效之间相互作用中的关键作用，特别是对于 sacituzumab govitecan (SG) 在治疗三阴性乳腺癌 (TNBC) 中的作用。从机制上讲，去泛素酶 USP10 抑制自分泌运动因子受体 (AMFR) 介导的 B7-H4 泛素化导致 B7-H4 稳定，从而抑制肿瘤免疫活性并降低 SG 治疗效果。 USP10的药理抑制促进B7-H4的降解，增强肿瘤免疫原性，从而提高SG的杀肿瘤功效。在临床前TNBC模型中，抑制USP10/B7-H4蛋白水解轴可有效提高SG杀伤功效并减少肿瘤生长，特别是对于具有USP10high/B7-H7high特征的肿瘤。总的来说，这些发现揭示了一种靶向免疫抑制分子 B7-H4 进行癌症治疗的新策略。© 2024 作者。 《Advanced Science》由 Wiley‐VCH GmbH 出版。

Tuning immune-cold tumor hot has largely attracted attention to improve cancer treatment, including immunotherapy and antibody-drug conjugates (ADCs). Utilizing multiomic analyses and experimental validation, this work identifies a pivotal role for the USP10/B7-H4 proteolytic axis in mediating the interplay between tumor immune responses and ADC efficacy, particularly for sacituzumab govitecan (SG) in treating triple negative breast cancers (TNBCs). Mechanistically, the inhibition of autocrine motility factor receptor (AMFR)-mediated ubiquitylation of B7-H4 by the deubiquitinase USP10 leads to the stabilization of B7-H4, which suppresses tumor immune activity and reduces SG treatment effectiveness. Pharmacological inhibition of USP10 promotes the degradation of B7-H4, enhancing tumor immunogenicity and consequently improving the tumor-killing efficacy of SG. In preclinical TNBC models, suppression of USP10/B7-H4 proteolytic axis is effective in increasing SG killing efficacy and reducing tumor growth, especially for the tumors with the USP10high/B7-H7high signature. Collectively, these findings uncover a novel strategy for targeting the immunosuppressive molecule B7-H4 for cancer therapy.© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.