IL20RB drives non-small cell lung cancer progression and immune evasion via K267‑dependent activation of JAK2 phosphorylation and STAT3 signaling.

INTRODUCTION Tumor immune evasion is a pivotal mechanism driving therapeutic resistance and poor prognosis in lung cancer. The interleukin-20 receptor β subunit (IL20RB) is implicated in chronic inflammation and oncogenesis, but its precise function and molecular basis in non-small cell lung cancer (NSCLC) require elucidation.

Methods

Multi-omics data analysis, clinical NSCLC specimens, and a series of in vitro and in vivo functional experiments were employed to investigate the role of IL20RB. Techniques included gene expression correlation, survival analysis, cell proliferation/migration/invasion assays, co-immunoprecipitation, western blotting, and pharmacologic modulation studies.

Results

IL20RB was significantly overexpressed in NSCLC tissues, correlating with advanced disease stage and inferior patient survival. Its knockdown potently suppressed NSCLC cell proliferation, migration, and invasion. High IL20RB expression was associated with reduced T cell infiltration and function within the tumor microenvironment. Mechanistically, IL20RB directly bound to JAK2 via a critical lysine residue (K267), activating JAK2-STAT3 signaling and upregulating downstream effectors including PD-L1 and BCL2, thereby coordinating tumor growth and immune escape. The commonly used drug acetaminophen (APAP) was identified to downregulate IL20RB expression via HDAC3-mediated deacetylation, inhibiting this oncogenic pathway and demonstrating synergistic activity with anti-PD-L1 therapy in vitro.

Conclusions

IL20RB drives NSCLC progression and immune evasion through a K267-dependent activation of the JAK2-STAT3 pathway. Pharmacologic suppression of IL20RB by APAP presents a novel therapeutic strategy, positioning IL20RB as a promising prognostic biomarker and therapeutic target in NSCLC.