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

作者：Chuanyu Tang, Cheng He, Decheng Wang, Jie Guo, Xiangyi Yin, Hanjie Ye, Lei Wu, Yulin Zhang, Silüe Zeng, Xiaojun Zeng, Chengbo Liu, Jingqin Chen, Chihua Fang · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-65056-9 · 被引用次数：22 · 研究领域：Ferroptosis and cancer prognosis、Immune cells in cancer、Cancer Immunotherapy and Biomarkers

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. The high abundance of immunosuppressive, tumor-associated macrophages limits the efficacy of treatments against hepatocellular carcinoma. Here, the authors develop a nanoplatform for the co-delivery of FSP1 inhibitor an...