HO-3867 reprograms the tumor microenvironment through extracellular vesicle regulation in ovarian cancer

Introduction: Ovarian cancer (OC) remains the most lethal gynecologic malignancy. It has poor long-term survival, largely because it is commonly diagnosed at advanced stages and has a high rate of recurrence with resistance to platinum therapies. This study evaluates the therapeutic efficacy of HO-3867, a STAT3 inhibitor, and bevacizumab, an anti-VEGF antibody, alone and in combination in an immunocompetent (IC) syngeneic ovarian cancer progression model. Materials and methods: The ability of HO-3867 to induce macrophage polarization was assessed in RAW264.7 cells, and its impact on anti-tumor immunity was evaluated in splenocytes co-cultured with ID8 and OC ascites cells. Immune modulation factors, including cytokine induction, extracellular vesicle (EV) release, and endosomal sorting complex required for transport (ESCRT) protein expression, was analyzed using an in vivo OC model. The therapeutic effects of HO-3867 and bevacizumab were examined in vivo by measuring ascites volume, EV secretion levels, and immune cell populations via flow cytometry. Results: Our study shows that combination therapy significantly reduced ascites and limited peritoneal tumor spread in mouse models of ovarian cancer. EV analysis showed decreased total and CD9+ve EVs, correlating with ESCRT proteins, implicating EVs in tumor progression and immune modulation. Flow cytometry revealed reduced myeloid-derived suppressor cells (MDSCs) and PD-L1 expression with increased CD8+ T cell cytotoxicity. Cytokine profiling indicated enhanced anti-tumor immunity, with higher IFN-γ and lower IL-6, IL-10, and CXCL-2 levels. HO-3867 promoted M1 macrophage polarization and reduced MDSC expansion in vitro. Conclusions: Together, HO-3867 and bevacizumab reprogram the tumor microenvironment, inhibit EV-driven progression, and boost anti-tumor immunity, offering a promising therapeutic strategy in ovarian cancer.