Inducing Cuproptosis with Copper Ion‐Loaded Aloe Emodin Self‐Assembled Nanoparticles for Enhanced Tumor Photodynamic Immunotherapy

At the tumor sites, NPs can responsively release copper ions and AE. Copper ions accumulates within the tumor, triggering cytotoxic stress responses and initiating the mechanism of cuproptosis. Upon 450 nm laser irradiation, AE generates ROS to eradicate tumor cells and induce ICD, DCs maturation and effector T cell activation, thereby achieving a synergistic enhancement of antitumor immunotherapy effects.

Abstract

Immunotherapy has fundamentally transformed the clinical treatment landscape for non-small cell lung cancer (NSCLC). While its effectiveness is ultimately limited by patient heterogeneity and immunosuppressive tumor microenvironment. Photodynamic therapy (PDT), as an emerging antitumor immunotherapy, has shown its unique therapeutic advantages. However, previous studies often overlooked the potential toxicity of photosensitizers (PS), making the discovery of safe and effective PS a pressing clinical need. In this study, Aloe Emodin (AE), a medicinal plant natural compound, was loaded with copper ions (Cu), and self-assembled into nanoparticles (NPs) under the modification of PEG_2k-DSPE-FA. NPs can target, accumulate, and reside within tumor sites, responsively releasing copper ions and AE, thus dual-functioning by inducing tumor cell death via cuproptosis and enhancing PDT effects. The LLC tumor-bearing mouse model demonstrated that NPs induce the maturation of dendritic cells (DCs) in vivo, promote lymphocyte infiltration, transform “cold tumors” into “hot tumors” and significantly enhance the efficacy of immune checkpoint blockade (ICB). This study provides experimental evidence of AE as a clinically promising PDT agent and offers a novel perspective for the synergistic treatment of clinical NSCLC.