SAHA induces immunogenic cell death in triple negative breast cancer cells and its efficacy is enhanced by SOCS3 functional replacement

Triple negative breast cancer (TNBC) is an aggressive subtype associated with poor prognosis and limited therapeutic options. Epigenetic changes contribute to TNBC tumorigenesis, and histone deacetylase inhibitors (HDACi) have emerged as promising therapeutic agents. However, their efficacy as monotherapy in solid tumors remains limited. Recent evidence highlights their immunomodulatory potential, supporting the development of combination strategies. We investigated the effect of the HDACi suberoylanilide hydroxamic acid (SAHA) on cell viability and immunogenic cell death (ICD), as well as its combinatory potential with a SOCS3 peptidomimetic (KIRCONG chim PEG), designed to inhibit STAT3 phosphorylation (pSTAT3), in TNBC cell lines. SAHA reduced TNBC cell viability and, at its IC 25 , induced ICD hallmarks in MDA-MB-231 cells, including ATP release, calreticulin surface exposure, and increased HMGB1 levels, accompanied by enhanced IL-6 secretion. In contrast, MDA-MB-468 cells showed limited ICD features under the same conditions. The higher IL-6 secretion observed in untreated MDA-MB-231 cells was associated with lower basal SOCS3 expression compared to MDA-MB-468 cells. Given the potential role of IL-6/JAK/STAT3 signaling in limiting HDACi efficacy, SAHA was combined with the SOCS3 peptidomimetic KIRCONG chim PEG. In MDA-MB-231 cells, co-treatment reduced pSTAT3 levels and increased BAK expression. Moreover, the combination shifted the IC 25 of SAHA, indicating enhanced sensitivity to sub-toxic concentrations. Conditioned media from co-treated MDA-MB-231 cells promoted CD4 + T cell activation, as shown by increased HLA-DR and CD69 expression. Overall, these findings indicate that SOCS3 functional replacement enhances SAHA anti-cancer and immunogenic effects in IL-6 high TNBC cells, supporting a context-dependent combinatory strategy targeting the IL-6/STAT3 axis. • SAHA triggers immunogenic cell death in IL-6–high TNBC cells. • IL-6/SOCS3 imbalance limits HDAC inhibitor efficacy in TNBC. • SOCS3 mimetic suppresses STAT3 and overcomes resistance to SAHA. • Combination enhances apoptosis and sensitivity at sub-toxic doses. • Dual targeting boosts CD4 + T cell activation and tumor immunogenicity.