Epigenetic reprogramming of mast and cancer cells modifies tumor-promoting cytokine networks.

Mast cells (MC) play a crucial role in the tumor microenvironment (TME) by promoting tumor progression and immune evasion through the secretion of inflammatory mediators. Here, we investigate the impact of epigenetic reprogramming using a drug repurposing combination-hydralazine, a DNA methylation inhibitor, and valproate, a histone deacetylase inhibitor (HDACi)-on MC-cancer cell interactions. Human cancer cell lines (Ca Ski, MDA-MB-468, and A549) that secrete stem cell factor (SCF) were selected from a panel of tumor lines. The HMC-I MC line and the selected cancer cell lines were treated with hydralazine + valproate (HV) for 72 h, and viability assessed via trypan blue exclusion assay revealed consistent reduction across all lines. Conditioned medium (CM) from HV-treated MCs was applied to cancer cells, with MDA-MB-468 displaying resistance. CM from HV-treated cancer cells was then used to evaluate MC migration and chemotaxis, showing reduced mobility in MCs exposed to supernatants from Ca Ski and MDA-MB-468, but not A549. Flow cytometry analysis revealed that HV epigenetically suppressed the expression of pro-tumoral cytokines and MC chemoattractants, with ITAC being the only consistently upregulated cytokine. These findings demonstrate that pharmacological epigenetic reprogramming via HV modulates MC-driven tumor progression and reshapes the cytokine network, highlighting its potential as a novel immunoepigenetic therapeutic strategy in cancer.