Biomimetic Ti3C2 nanosheets for synergistically overcoming chemoresistance and boosting immunotherapy via enhanced cuproptosis in cancer

Chemoresistance and the immunosuppressive tumor microenvironment (TME) severely constrain the current cancer therapy, which is a global clinical challenge. To address these issues, we engineered TPEC@CM, a biomimetic nanoplatform that synergizes chemotherapy with cuproptosis induction. This system employs homologous cancer cell membrane-coated Ti 3 C 2 nanosheets for targeted delivery, co-loaded with a cisplatin (DDP) prodrug succinato diamminedichloroplatinum (SDDP) and a copper ionophore complex (Elesclomol-Cu). The biomimetic coating ensures tumor-specific accumulation of the payloads while minimizing off-target toxicity. Upon reaching the tumor site, SDDP depletes intracellular glutathione (GSH), thereby reducing copper chelation and unleashing Pt (II)-mediated DNA damage and apoptosis. Concurrently, Elesclomol-Cu disrupts mitochondrial copper homeostasis, inducing cuproptosis via dihydrolipoamide S -acetyltransferase (DLAT) oligomerization and Fe S cluster protein degradation, ultimately collapsing mitochondrial integrity and metabolic activity. Crucially, the synergistic chemo-cuproptosis effect provokes immunogenic cell death (ICD), releasing damage-associated molecular patterns (DAMPs) that drive dendritic cell maturation and reprogram the immunosuppressive TME. RNA-seq analysis of DDP-resistant MC38 cells revealed heightened mitochondrial metabolic pathways, sensitizing the tumor cells to cuproptosis, resulting in reversed DDP resistance by TPEC@CM. Furthermore, TPEC@CM treatment with anti-programmed death-ligand 1 (anti-PD-L1) checkpoint blockade amplified anti-tumor efficacy, highlighting its potential for combinatorial tumor therapy. This study pioneers a dual-pathway strategy—combining chemotherapy and cuproptosis—to dismantle chemoresistance and amplify immune responses, presenting a clinically translatable paradigm for cancer therapy.