Absorbable microspheres co-delivering HIF-1α inhibitor augment transarterial chemoembolization by reversing tumor hypoxia and immunosuppression

Transarterial chemoembolization (TACE) is a primary treatment option for unresectable hepatocellular carcinoma (HCC). Its clinical efficacy is, however, challenged by hypoxic and immunosuppressive tumor microenvironment. Herein, we report that absorbable microspheres (Asphere) with sustained co-delivery of hypoxia-inducible factor 1 (HIF-1) inhibitor, acriflavine (ACF), effectively reverse tumor hypoxia and boost TACE therapy of advanced HCC. Interestingly, Asphere demonstrates nearly quantitative loading of both epirubicin (EPI) and ACF within 1 min, while achieving sustained release of the dual drugs over 8 weeks. EPI/ACF-loaded Aspheres (EA@Asphere) greatly inhibit hypoxia-associated proteins and augment immunogenic cell death in HCC cells under hypoxic conditions, which in turn triggers maturation of dendritic cells (DCs) and secretion of pro-inflammatory cytokines. In H22 murine hepatoma model, EA@Asphere markedly boosts DC maturation, CD8 + T cell infiltration, and macrophage polarization from M2 to M1, achieving complete tumor regression in 2 out of 7 mice. EA@Asphere further blocks tumor vasculature in orthotopic VX2 liver tumor in rabbits, alleviates hypoxia, and suppresses tumor progression and metastasis. Thus, Asphere co-delivering HIF-1 inhibitors holds significant translational potential to boost TACE therapy in advanced HCC. Statement of Significance This work introduces an approach to enhance transarterial chemoembolization (TACE) for advanced hepatocellular carcinoma (HCC) by co-delivering HIF-1 inhibitor acriflavine (ACF) and epirubicin (EPI) via absorbable microspheres (Asphere). Asphere demonstrates swift dual drug loading, sustained 8-week release, and simultaneous reversal of hypoxia and immunosuppression, addressing critical challenges of current TACE therapy. In preclinical studies, EA@Asphere significantly suppresses hypoxia-associated protein expression, enhances immunogenic cell death, promotes dendritic cell maturation, and reprograms tumor microenvironment, achieving significant inhibition of the tumor progression and metastasis. These findings offer transformative potential to improve clinical outcomes in advanced HCC, holding broad interest for researchers and clinicians in oncology and drug delivery.