Therapeutic potential of targeting MASTL in lung adenocarcinoma.

Protein kinases play crucial roles in tumor progression and modulation of the immunosuppressive tumor microenvironment. However, the specific function of MASTL (microtubule-associated serine/threonine kinase-like) in lung adenocarcinoma (LUAD) remains poorly understood. In this study, we integrated multi-omics bioinformatic analyses with experimental validation to delineate the clinical significance and biological role of MASTL in LUAD. We found that MASTL is markedly overexpressed in LUAD tissues and exhibits substantial diagnostic value. Elevated MASTL expression served as an independent prognostic indicator of poor overall survival, particularly in early-stage patients. Comprehensive immune profiling revealed a strong association between high MASTL expression and an immunosuppressive tumor microenvironment, characterized by impaired dendritic cell function and altered Th1/Th2 balance. Notably, patients with low MASTL expression showed enhanced sensitivity to immune checkpoint blockade therapy. Phosphoproteomic analysis identified serine 370 (S370) as a novel functional phosphorylation site on MASTL, whose activation correlated with higher tumor grade and dysregulation of key oncogenic pathways, including p53, MYC, mTOR, WNT, and HIPPO signaling. Functionally, pharmacological inhibition of MASTL using MKI-1 suppressed LUAD cell proliferation, induced apoptosis and cell cycle arrest, and reduced cancer stem cell-like properties such as self-renewal and metastatic potential. Importantly, MKI-1 administration significantly inhibited tumor growth in a LUAD xenograft model with good tolerability. Collectively, our findings identify MASTL as a pivotal regulator of tumor progression and immune evasion in LUAD and underscore its potential as both a prognostic biomarker and a promising therapeutic target.