Restoration of the Immunogenicity of Tumor Cells for Enhanced Cancer Therapy via Nanoparticle‐Mediated Copper Chaperone Inhibition

Abstract

Recent progress in studying copper-dependent targets and pathways in the context of tumor treatment has provided new insights into therapeutic strategies of leveraging copper-dependent disease vulnerabilities and pharmacological manipulation of intratumor copper transportation to improve chemotherapy. Here, we developed reactive oxygen species (ROS)-sensitive nanoparticles loaded with copper chaperone inhibitor DC_AC50 and cisplatin(IV) prodrug. The released DC_AC50 can promote a remarkable accumulation of intracellular cisplatin and copper through inhibition of the Atox1-ATPase pathways, thereby enhancing the chemotherapeutic effect of cisplatin and inducing significant ROS generation. Excessive ROS then elicits intense endoplasmic reticulin (ER) stress which facilitates the immunogenic cell death (ICD) spurring a sustained immune response. Our study suggests that nanoparticle-mediated copper chaperone inhibition via DC_AC50 can restore the immunogenicity of tumor cells for enhanced chemotherapy and cancer immunotherapy.

Evaluating the Impact of Cuproptosis-Related Genes on Prognosis and the Tumor Microenvironment in Colon Cancer

“…CRGs Genetic and transcriptional alterations in CC We compiled a catalog of 19 cuproptosis-related genes (CRGs) including NFE2L2, NLRP3, ATP7B, ATP7A, SLC31A1, FDX1, LIAS, LIPT1, LIPT2, DLD, DLAT, PDHA1, PDHB, MTF1, GLS, CDKN2A, DBT, GCSH, and DLST [1,18,19] . We then explored somatic mutations in these CRGs across 447 colon cancer samples from the TCGA-COAD database.…”

Targeted nanomedicines remodeling immunosuppressive tumor microenvironment for enhanced cancer immunotherapy

“…In the work of Ding et al. 124 , reactive oxygen species (ROS)-sensitive nanoparticles loaded with copper chaperone inhibitor DC_AC50 and cisplatin(Ⅳ) prodrug were fabricated. Along with the chemotherapeutic effect of cisplatin, massive ROS generated from DC_AC50 spurred on synergistic ICD, thereby restoring the cancer immunogenicity.…”

Targeting Cell Membranes, Depleting ROS by Dithiane and Thioketal-Containing Polymers with Pendant Cholesterols Delivering Necrostatin-1 for Glaucoma Treatment

“…Herein, a glaucomatous microenvironment-responsive degradable polymer was designed (designated as P1), which was characterized by the presence of thioketal bonds and 1,4dithiane unit in the main chain as well as pendant cholesterol molecules. The introduction of thioketal bonds and 1,4dithiane unit was aimed to deplete ROS in RGCs, 19 whereas the introduction of cholesterols was aimed to target the cell membrane. Thereafter, P1 was used to encapsulate the necroptosis inhibitor NEC into nanoparticles (designated as NP1).…”