Co-delivery of sorafenib and an FSP1 inhibitor triggers dual ferroptosis in tumor cells and immunosuppressive macrophages for enhanced immunotherapy in mouse models of hepatocellular carcinoma

The prevalence of immunosuppressive, tumor-associated macrophages (TAM) in the tumor microenvironment of hepatocellular carcinoma (HCC) compromises the efficacy of sorafenib (SF)-based, ferroptosis-inducing systemic therapies. Increasing the susceptibility of tumor cells and TAMs to ferroptosis represents a promising breakthrough in improving the therapeutic outcomes of SF. Here, we show that the upregulation of ferroptosis suppressor protein 1 (FSP1) counteracts SF-induced ferroptosis independently of glutathione peroxidase 4 (GPX4) and correlates with increased immunosuppressive TAM infiltration and unfavorable prognosis. In preclinical HCC mouse models, biomimetic nanoparticles, co-loaded with SF and the FSP1 inhibitor viFSP1 and designed to simultaneously target tumor cells and immunosuppressive TAMs, enhance ferroptosis in both cell types, promoting antigen presentation and cytotoxic T cell infiltration. Furthermore, combinatorial treatment with an anti-PD-L1 antibody suppresses metastasis and tumor recurrence. Thus, our nanoparticle-based dual-target strategy induces synergistic ferroptosis-immunotherapy in HCC, and represents a promising strategy to sensitize tumors to SF treatment, driving the remodeling of the immunosuppressive tumor microenvironment.