Unraveling the role of HDAC3 as an immunotherapy prognostic biomarker and therapeutic target in advanced non-small cell lung cancer.

BACKGROUND: This study investigates HDAC3 as a potential immunotherapy biomarker in advanced non-small cell lung cancer (aNSCLC), focusing on its association with treatment response to immune checkpoint inhibitors (ICIs). METHODS: We employed a multi-phase approach in 78 aNSCLC patients with 138 plasma samples, starting with a discovery phase that identified differential autoantibodies (AAbs) using proteomic analysis in responders and non-responders. In the validation phase, we assessed AAb levels at multiple time points. Additionally, immunohistochemistry and multiple immunofluorescence (n = 21) were used to validate HDAC3 expression in FFPE samples, single-cell RNA sequencing (n = 26) was performed to explore gene expression differences, cell and animal experiments were performed. RESULTS: We identified 127 differential AAbs, with five key AAbs (HDAC3, METTL21C, HSPB3, SPACA7, and SPPL2B) consistently linked to prognosis pre- and post-treatment (p < 0.05). A risk score model based on these AAbs effectively predicted progression-free survival. Furthermore, HDAC3 expression correlated with significant pathway enrichments and was associated with higher TGFβ1, PD-L1 infiltration and lower CD8(+) T cells infiltration (p < 0.05). HDAC3 knockdown significantly inhibited cell proliferation, impaired colony formation, and induced G0/G1 phase arrest in lung cancer cells. Preclinical models demonstrated that RGFP966, an HDAC3 inhibitor, combined with anti–PD-1 therapy enhanced CD8(+) T cell infiltration (p < 0.05). CONCLUSION: Our findings underscore HDAC3’s role as a biomarker for predicting ICI response in aNSCLC and suggest its potential as a therapeutic target, paving the way for future studies on HDAC3-targeted therapies to improve immunotherapy outcomes. CLINICAL TRIAL NUMBER: not applicable. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12931-025-03275-w.