USP10 activity as sensitizer of lung adenocarcinoma to immune checkpoint inhibitors: Upregulating PD-L1 via the ANT3-mediated activation of the cGAS-STING pathway.

Abstract

8542 Background: Although immune checkpoint inhibitors (ICIs) have reshaped the treatment landscape for advanced lung adenocarcinoma (LUAD), response heterogeneity remains substantial. The cGAS–STING pathway plays a pivotal role in activating antitumor immune responses, yet its upstream regulatory mechanisms remain poorly defined. This study investigated the role of the deubiquitinating enzyme USP10 in remodeling the LUAD immune microenvironment and its mechanistic link to PD-L1 expression via the cGAS-STING axis to establish its potential as a predictive biomarker for ICIs efficacy. Methods: Interactions between USP10 and the mitochondrial protein ANT3 were characterized using Co-IP, LC-MS/MS, and in vitro deubiquitination assays. Mitochondrial DNA (mtDNA) leakage and cGAS-STING activation were assessed via immunofluorescence and qPCR. The therapeutic impact of USP10 on PD-1 blockade was evaluated in an orthotopic murine LUAD model. Furthermore, Furthermore, a clinical cohort of 228 patients with advanced driver-gene negative LUAD receiving first-line ICIs treatment was analyzed to correlate USP10 expression with objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS). Results: Mechanistically, USP10 directly interacts with mitochondrial adenine nucleotide translocase 3 (ANT3) and stabilizes its protein level by removing K48-linked ubiquitin chains. USP10-mediated ANT3 accumulation triggers mitochondrial stress and promotes mtDNA release into the cytosol, thereby activating the cGAS-STING-TBK1-IRF3 signaling pathway and ultimately driving transcriptional upregulation of PD-L1. In orthotopic LUAD models, USP10-overexpressing tumors exhibited an "inflamed" phenotype characterized by a significant increase in CD8+ T cell infiltration. USP10 expression levels sensitized tumors to immunotherapy; USP10-high tumors demonstrated dramatic regression upon anti-PD-1 treatment compared to controls. In the cohort of 228 patients, high USP10 expression was identified as a robust predictor of superior clinical benefit to first-line ICIs treatment . Patients in the USP10-high group achieved significantly prolonged PFS (p = 0.028), higher ORR (p = 0.037), and improved DCR (p = 0.041) compared to the USP10-low group. Conclusions: Our study identifies a novel USP10-ANT3-cGAS-STING-PD-L1 regulatory axis that converts "cold" tumors into "hot" tumors. By inducing a pro-inflammatory TIME, USP10 enhances the sensitivity of LUAD to ICIs. These findings establish USP10 as a promising predictive biomarker and a potential therapeutic target to optimize immunotherapy strategies in lung adenocarcinoma.