摘要
The aggressive nature of oral squamous cell carcinoma (OSCC) and its highly immunosuppressive tumor microenvironment (TME) present significant challenges for effective treatment, urgently demanding advanced multi-modal therapeutic strategies. In this study, we designed a self-reinforced dual cascade nanoreactor (A@CuCD), delivered via a thermosensitive hydrogel, to execute a synergistic therapeutic strategy. The A@CuCD nanoreactors are co-assembled from copper nanoclusters (Cu NCs) and artesunate (ART) encapsulated within γ-cyclodextrin (γ-CD). This multifunctional engineering platform operates synergistically through a bifunctional system: it leverages the thermosensitive properties of the hydrogel to enable localized, on-demand retention and controlled release of A@CuCD at the tumor site, thereby efficiently inducing cuproptosis. The resulting immunogenic cell death (ICD) then further promotes cytotoxic T lymphocyte (CTL) infiltration and induces macrophage M1 polarization, consequently reversing immunosuppression and comprehensively remodeling the tumor microenvironment. Simultaneously, the intrinsic cholesterol-scavenging capability of γ-CD within A@CuCD not only enhances OSCC cell sensitivity to cuproptosis but also significantly downregulates programmed death-ligand 1 (PD-L1) expression by disrupting lipid raft structures, effectively suppressing tumor immune evasion. Utilizing single-cell RNA sequencing, we provide a systemic understanding of the hydrogel-mediated TME reprogramming process, elucidating the intricate interplay between cuproptosis and immune activation pathways. This engineered hydrogel platform effectively translates localized precise delivery into powerful systemic anti-tumor immunity, offering a highly promising and clinically translatable strategy for overcoming OSCC therapeutic resistance, conquering “cold” immune tumors, and achieving durable anti-tumor immunity.
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