Ferroptosis-driven in situ vaccine-like antitumor effects: NIR-triggered IFBM hydrogel synergizes with sorafenib to unleash systemic antitumor immunity.

The immunosuppressive tumor microenvironment and immune evasion mechanisms inhibit the development of effective antitumor responses and enduring immune memory, thereby diminishing the efficacy of cancer immunotherapy. In situ vaccines (ISVs) have been developed to overcome these challenges by inducing localized immunogenic cell death (ICD) and activating systemic immunity via dendritic cells (DCs) and CD8+ T cells. In this study, we engineered ferrous sulfide-bovine serum albumin-cell membrane nanoclusters to trigger ferroptosis, which were co-encapsulated with the photothermal agent indocyanine green in a thermosensitive hydrogel. This platform enables near-infrared-responsive drug release and works with sorafenib to boost ferroptosis. Mechanistic studies revealed that this combined regimen markedly enhanced DC-mediated antigen presentation and CD8+ T-cell infiltration, leading to substantial antitumor efficacy and complete eradication of distant liver metastases. Ultimately, the indocyanine green-ferrous sulfide-bovine serum albumin-cell membrane hydrogel-sorafenib system induces ferroptosis-driven ICD, promoting an ISV-like effect that activates systemic antitumor immunity and demonstrates strong therapeutic efficacy, suggesting its potential as a novel cancer treatment strategy.