Tuning Immune‐Cold Tumor by Suppressing USP10/B7‐H4 Proteolytic Axis Reinvigorates Therapeutic Efficacy of ADCs

Abstract 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 USP10^high/B7‐H7^high signature. Collectively, these findings uncover a novel strategy for targeting the immunosuppressive molecule B7‐H4 for cancer therapy.