Yaodong Ding , Haoyu Zhang , Xueying Wang , Jiaqi Tan , Minghao Wang , Yuhan Chen , Imadoudini Hassimi Safia , Gangcai Zhu , Xin Zhang , Yong Liu
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引用次数: 0
Abstract
Cathepsin L (CTSL) is expressed in head and neck squamous cell carcinoma (HNSCC), yet its role in immune escape is unclear. Here we show that CTSL directly binds PDK1, blocks its ubiquitin and restrains NEDD4L-mediated ubiquitination, thereby stabilizing PDK1, sustaining AKT phosphorylation, and increasing PD-L1 on tumor cells. This establishes a non-proteolytic scaffolding function, and suppresses tumor growth in xenograft and immunocompetent mouse models; these effects synergize with anti-PD-1 therapy. Clinically, high CTSL expression correlates with increased PD-L1, scarce CD8+ T-cell infiltration, and poor prognosis in multiple HNSCC cohorts. Collectively, our data identify CTSL as a key driver of PD-L1-dependent immune evasion through the CTSL–PDK1–AKT axis and highlight CTSL inhibition as a promising therapeutic strategy and predictive biomarker for PD-1/PD-L1 blockade in HNSCC.
期刊介绍:
Neoplasia publishes the results of novel investigations in all areas of oncology research. The title Neoplasia was chosen to convey the journal’s breadth, which encompasses the traditional disciplines of cancer research as well as emerging fields and interdisciplinary investigations. Neoplasia is interested in studies describing new molecular and genetic findings relating to the neoplastic phenotype and in laboratory and clinical studies demonstrating creative applications of advances in the basic sciences to risk assessment, prognostic indications, detection, diagnosis, and treatment. In addition to regular Research Reports, Neoplasia also publishes Reviews and Meeting Reports. Neoplasia is committed to ensuring a thorough, fair, and rapid review and publication schedule to further its mission of serving both the scientific and clinical communities by disseminating important data and ideas in cancer research.