HDAC6 as a convergent oncogenic and immunoregulatory hub across multiple cancer types

Histone deacetylase 6 (HDAC6) has emerged as a critical regulator of tumor progression across multiple malignancies. Our integrated analyses reveal that environmental phthalates (BBP, DBP) drive oncogenic processes in breast epithelial stem cells and ER-negative breast cancer by activating ER-EGFR-PKA or AhR-cAMP-PKA-CREB1 signaling, leading to HDAC6 upregulation, beta-catenin/LEF1-TCF4 activation, epithelial-mesenchymal transition (EMT), and enhanced metastatic potential. Beyond breast cancer, clinical datasets and functional studies demonstrate that elevated HDAC6 expression correlates with advanced stage, higher tumor grade, and poor survival in lung cancer, oral squamous cell carcinoma (OSCC), and endometriosis-associated ovarian carcinoma (EAOC). Mechanistically, HDAC6 promotes tumor progression by regulating HIF-1alpha/BNIP3-mediated autophagy in lung cancer, driving AP-1-dependent IL-13 expression and M2 macrophage polarization in OSCC, and mediating ARID1A mutation-associated IL-10-driven immunosuppressive macrophage programming in EAOC. Importantly, pharmacologic HDAC inhibition (TSA, vorinostat) suppresses autophagy, reverses macrophage polarization, reduces EMT, and markedly inhibits tumor growth in relevant in vitro and in vivo models. Together, these findings position HDAC6 as a convergent oncogenic and immunoregulatory hub across environmentally induced, hormone-independent, and mutation-associated cancers, supporting HDAC6-targeted therapies as a promising strategy for limiting tumor progression and reshaping the tumor immune microenvironment.