Targeting lysosomal protease CTSL promotes anti-tumor immunity and sensitizes HNSCC to PD-1 blockade by stabilizing PDK1 and activating Akt-PD-L1 axis.

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.