Disruption of mitochondrial homeostasis by bimetallic ca/cu nanocomposites against hepatocellular carcinoma.

Tumor stemness, manifesting as self-renewal capability, differentiation plasticity, and multi-differentiation potential, along with the heterogeneity of the tumor microenvironment (TME), have been identified as the culprits of tumor relapse and metastasis in hepatocellular carcinoma following hepatectomy, which inevitably result in the failures of many auxiliary therapeutic means in both preclinical studies and clinical trials. Herein, we typically designed a carboxymethyl chitosan (CMCS)-based and glucose oxidase (GOx)-loaded bimetallic Ca/Cu nanocomposites (CaCu@CS-GOx), which integrated the unique characteristics of different components, once exposed in acidic microenvironment, can succeed in oxygen generation and achieving glucose starvation-augmented cuproptosis and calcium (Ca2+) overload synergistic oncotherapy, ultimately realizing the collapse of tumor ironclad defense and stemness inhibition. Furthermore, by combining with aCTLA-4-based immunotherapy, CaCu@CS-GOx efficiently suppressed Hepa1-6 tumor growth, decreased tumor stemness and reshaped immunosuppressive TME, thus remarkably curbing tumor relapse and metastasis. In summary, an amplified anti-tumor dual-ion interference strategy united with energy deprivation is established, which is of great significance in anti-tumor therapy by stemness inhibition, activating cell-specific death channels, damaging mitochondria and disrupting cellular homeostasis. ORCID Duo Wang: https://orcid.org/0009-0004-4094-3326.