Boosting Cancer Immunotherapy by Integrating Cuproptosis and Mild Photothermal Therapy in a Biomimetic Nanoplatform.

Abstract

Breast cancer remains a global health challenge with limited therapeutic options for metastatic cases. Cuproptosis, a copper-dependent cell death pathway, offers a novel anticancer strategy that is currently constrained by the poor solubility of copper complexes and lack of tumor selectivity. To overcome this limitation, a biomimetic nanoplatform was developed by co-encapsulating copper diethyldithiocarbamate (CuET) and a photothermal agent into epigallocatechin gallate-assisted nanoparticles, which was followed by coating with a hybrid cell membrane from cancer cells and programmed cell death protein 1 (PD-1)-overexpressing CTLL-2 cells. This strategy allowed synergistic induction of cuproptosis, mild photothermal therapy (PTT), and PD-1/programmed death-ligand 1 (PD-L1) checkpoint blockade. The nanoplatform exhibited excellent stability, photothermal efficiency, and tumor-targeting capability, resulting in responsive degradation within the tumor microenvironment. In vitro and in vivo studies using breast tumor models showed that these nanoparticles displayed potent cytotoxicity, causing immunogenic cell death and dendritic cell maturation. Transcriptomic analysis revealed significant enrichment of key biological pathways. Specifically, both immune-activation and cuproptosis-related pathways were markedly upregulated. The combination of mild PTT and PD-1/PD-L1 blockade enhanced CD8+ T-cell infiltration and established long-term immune memory. This multifunctional nanoplatform provides an integrated strategy for potentiating cuproptosis-augmented immunotherapy in breast cancer.