Abstract 2826: Celastrol-Cu nanoparticles induce self-amplified cuproptosis augmented cancer immunotherapy

Abstract Cuproptosis, a recently identified copper-dependent programmed cell death pathway, has emerged as a promising strategy in cancer therapy. Its effectiveness is closely linked to intracellular copper accumulation but is mitigated by elevated levels of glutathione (GSH) in tumor cells. A significant barrier to its clinical application lies in the challenge of facilitating the cellular uptake of copper ions. Additionally, intracellular copper ions rapidly bind with GSH, further complicating the induction of tumor cell death. Notably, no existing ionophore drug simultaneously acts as both a copper ionophore and a GSH scavenger to effectively induce cuproptosis. In summary, we have developed a celastrol-based nanomedicine that, upon complexation with copper ions, effectively promotes cuproptosis in a self-amplifying manner, as validated in both 4T1 subcutaneous and metastatic breast cancer models. This Cel-Cu NP platform provides a novel option with significant translational potential for the integrated programmed therapy of triple-negative breast cancer (TNBC) in immunologically “cold” tumors. Citation Format: Huawei Pan, Liuxian Meng, Yifan Li, Tj (Tiejun) Bing. Celastrol-Cu nanoparticles induce self-amplified cuproptosis augmented cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2826.