HDAC6 orchestrates metastatic and immunosuppressive programs in small cell lung cancer through S100A2-TGF-β/SMAD and CSF1R signaling

Small cell lung cancer (SCLC) remains a highly lethal malignancy with limited therapeutic options. The purpose of this study was to investigate the central role of histone deacetylase 6 (HDAC6) in SCLC progression and its regulatory mechanisms to identify novel therapeutic strategies. Preclinical SCLC models were utilized alongside molecular, cellular, and immunological techniques to elucidate HDAC6's mechanistic functions. The deacetylation of S100A2 and its impact on downstream signaling were analyzed, compensatory responses to HDAC6 inhibition were assessed, and the efficacy of dual-target inhibition was evaluated. HDAC6 was found to deacetylate the calcium-binding protein S100A2 at lysine 27, thereby stabilizing TGF-β/SMAD signaling to promote epithelial-mesenchymal transition (EMT) and metastatic dissemination. Simultaneously, HDAC6 polarized macrophages toward tumor-promoting M2 phenotypes, fostering an immunosuppressive microenvironment. HDAC6 inhibition triggered compensatory CSF1R upregulation, revealing a resistance mechanism. Dual blockade of HDAC6 and CSF1R synergistically suppressed primary tumor growth and metastasis while reprogramming macrophages toward anti-tumor M1 states. SCLC patients with co-high expression of HDAC6 and CSF1R exhibited worse progression-free survival (PFS). This study defines the HDAC6-S100A2-TGF-β/SMAD and HDAC6-CSF1R-macrophage axes as actionable therapeutic vulnerabilities. The dual inhibition strategy provides a translational framework to overcome stromal and immune barriers in this recalcitrant cancer.