HDAC inhibitors reverse YAP-driven immune resistance in NSCLC: mechanistic and translational evidence

As a key downstream effector of the Hippo signaling pathway, Yes-associated protein (YAP) has emerged as a pivotal regulator of tumor immune evasion and resistance to immune checkpoint inhibitors (ICIs). However, the relationship between YAP expression and immunotherapy outcomes in patients with non-small cell lung cancer (NSCLC), as well as its potential value as a therapeutic target, remains to be systematically investigated.

We retrospectively analyzed 141 patients with NSCLC who received immunotherapy, including 9 monoimmunotherapy and 132 immunotherapy plus chemotherapy or anti-angiogenic therapy. The expression of YAP in tumor tissues was evaluated by immunohistochemistry, and the association between YAP expression and immunotherapy resistance was assessed. Gene expression profiling following YAPand transcriptional coactivator with PDZ-binding motif (TAZ) knockdown was performed to identify potential YAP inhibitors and explore their underlying mechanisms of action. Furthermore, the therapeutic potential of a YAP inhibitor in reversing ICI resistance was evaluated in two patients with high YAP expression who had developed acquired resistance to immunotherapy.

In our cohort, which predominantly received combination immunotherapy (93.62%), high YAP expression was associated with poor clinical outcomes to immunotherapy. Notably, YAP expression outperformed Programmed Cell Death Ligand 1 (PD-L1) as a predictive biomarker for treatment response. Through screening for potential YAP inhibitors, tucidinostat (TD) was identified as a compound capable of suppressing YAP activity. In two elderly patients with advanced NSCLC who had developed acquired resistance to immunotherapy, the combination of TD with ICIs successfully restored antitumor responsiveness. Mechanistic investigations further revealed that TD suppressed YAP expression via SNAI2-mediated epigenetic regulation, thereby blocking YAP-dependent tumor proliferation and immune evasion.

YAP is a strong predictive biomarker of response to immunotherapy in NSCLC. The combination of TD and ICIs shows promise in reversing immunotherapy resistance associated with high YAP expression, offering a potential strategy to overcome acquired resistance.