Biomineralized Cu-Disulfiram nanoparticles Potentiate Colorectal cancer immunotherapy through synergistic cuproptosis and apoptosis

• ACOD achieves compartmentalized, stimuli-release codelivery of copper and disulfiram. • ACOD induces immunogenic cell death via chemo-chemodynamic apoptosis and cuproptosis. • ACOD activates robust anti-tumor immunity and potentiates αPD-L1 efficacy. • ACOD remodels tumor microenvironment potentially via chemotaxis pathways of immune cell. The aberrant tumor microenvironment (TME) in colorectal cancer (CRC) significantly limits the efficacy of current immunotherapy regimes. To address this challenge, the albumin-based copper (Cu) and Cu ionophores disulfiram (DSF) co-loaded nanoparticle (ACOD) is constructed through a biomineralization process. ACOD demonstrates tumor-targeted accumulation and releases Cu 2+ and DSF in response to acidic pH and elevated glutathione (GSH) respectively. After entering into mitochondria, Cu 2+ triggers cuproptosis, a novel and immunogenic Cu-dependent programmed cell death. Moreover, the Cu-diethyldithiocarbamate complex generated in situ by liberated Cu 2+ and DSF exerts a chemotherapeutic role. Besides, Cu 2+ can also arouse the chemodynamic therapy (CDT) via sequentially reacting with overexpressed GSH and H 2 O 2 . The chemotherapy and CDT synergistically promote tumor cell apoptosis. The combinative cuproptosis/apoptosis induction elicits robust immunogenic cell death, activates innate/adaptive immunity, and reprograms the immunosuppressive TME. Notably, ACOD upregulates tumor programmed cell death-ligand 1 (PD-L1) expression. Based on these efficacies, ACOD converts “immune-cold” CT26 tumors into “immune-hot” phenotypes and thus enhances therapeutic synergy with anti-PD-L1 antibodies. Transcriptomic analysis of tumor tissues via RNA sequencing elucidates ACOD’s anti-tumor mechanism. Along with its favorable biosafety, ACOD may serve as a multifunctional therapeutic strategy that overcomes TME-mediated immunotherapy outcome impairment in CRC through synergistic cuproptosis and apoptosis.