Work

Cuproptosis improves CAR-T cell therapy in osteosarcoma

Year: 2025

Type: article

Abstract: The efficacy of chimeric antigen receptor (CAR)-T cell therapy is hampered by the immunosuppressive tumor microenvironment (TME) in solid tumors, such as osteosarcoma (OS). Copper (Cu) metabolism influences the TME, suggesting that cuproptosis, a new form of programmed cell death induced by Cu, can reshape the TME and enhance immunotherapy. Here, we find that the expression of cuproptosis-related genes is positively correlated with that of CD274 (PD-1 ligand 1 [PD-L1]) in OS patients and indicates that cuproptosis reduces PD-L1 expression in human OS cells. Based on these findings, we develop a biocompatible nanodrug comprising tetrahedral framework nucleic acids (tFNAs), elesclomol-Cu, and PD-L1 antibodies to induce cuproptosis and block PD-L1. Using this nanodrug, we observe enhanced tumor infiltration and antitumor activity of CAR-T cells, leading to significant tumor inhibition in both orthotopic and rechallenge OS models. Our approach represents an immunometabolic reprogramming strategy to improve CAR-T cell therapy, showing translational potential in treating solid tumors.

Source: Cell Biomaterials

DOI: 10.1016/j.celbio.2025.100148