Abstract
Hepatocellular carcinoma (HCC) is commonly classified as a "cold tumor" due to its low immunogenicity and poor response to conventional immunotherapies. Reprogramming the tumor immune microenvironment (TIME) via cuproptosis presents a promising strategy to enhance immunotherapies. Herein, sono-activatable N,N,N',N'-tetrakis(2-pyridinylmethyl)-1,2-ethanediamine (TPEN)-encapsulated cancer-targeted nanoparticles (STCNs) designed to modulate the TIME and potentiate immunotherapy through endogenous cuproptosis are reported, termed "endogenous cuproptosis immunopromotion". STCNs are rapidly internalized by HCC via folate-mediated endocytosis, and ultrasound irradiation triggers the release of TPEN. TPEN then chelates Cu2⁺ from superoxide dismutase, initiating a Fenton-like reaction induced by glutathione that produces reactive oxygen species (ROS) and Cu⁺. This cascade induces cuproptosis and immunogenic cell death (ICD), promoting robust cytotoxic T lymphocyte infiltration in HCC. The combination of STCNs with anti-programmed cell death protein 1 (PD1) therapy demonstrates significant anti-tumor efficacy in vivo. Moreover, this strategy exhibits similar effectiveness in other solid tumor models, underscoring its broad therapeutic potential. These findings provide a promising framework for enhancing immunotherapy in cold tumors, paving the way for future cancer treatments.