PPP4C restores YAP1 activity by modulating MST4 phosphorylation to enhance immunosuppression and augment tumor growth in non-small cell lung cancer

Abnormal expression of mammalian sterile 20-like kinase 4 (MST4) has been frequently linked to cancer development. This study explores the function of MST4 in non-small cell lung cancer (NSCLC) and delves into its functional mechanism. The expression and clinical indicative values of MST4 in NSCLC were analyzed using tissue microarrays. Gain- and loss-of-function experiments of MST4 were conducted in NSCLC cell lines to identify its effects on cell growth in vitro . Transfected NSCLC cells were co-cultured with natural killer (NK) cells to analyze immune resistance. Mouse NSCLC cells 3LL were transplanted into C57BL/6 mice to generate subcutaneous or orthotopic isograft tumor models. Upstream and downstream factors of MST4 were identified using bioinformatics. MST4 was under-expressed in NSCLC tissue microarrays and human NSCLC cells. MST4 overexpression suppressed growth activity of NSCLC cells in vitro , reduced expression of immune checkpoint genes, and reduced cell resistance to NK cell cytotoxicity. Reverse trends were observed in cells MST4 silencing. In vivo , MST4 overexpression inhibited tumorigenic activity of 3LL cells in mice and reduced immunosuppressive factors in tumor tissues. Regarding the mechanism, MST4 induced phosphorylation and cytoplasm degradation of YAP1 by influencing the MAP4K2-LATS1/2 cascade. Protein phosphatase 4 catalytic subunit (PPP4C) was found to interact with MST4 and reduce its function, thus promoting growth and immunosuppression in NSCLC by activating YAP1. This study demonstrates that PPP4C-mediated MST4 degradation contributes to growth activity and immunosuppression in NSCLC by restoring YAP1 activity, suggesting PPP4C and MST4 as potential targets for NSCLC management. • MST4 is downregulated in NSCLC and suppresses tumor growth in vitro/in vivo. • MST4 activates MAP4K2–LATS1/2 to phosphorylate and degrade YAP1. • MST4 lowers PD-L1/TIM3/HHLA2, enhancing NK and CD8+ T-cell activity. • PPP4C binds MST4, reduces MST4 phosphorylation and stability, restoring YAP1. • Targeting the PPP4C–MST4 axis may overcome immunosuppression in NSCLC.