Black Phosphorus as a Targeting PPAR‐γ Agonist to Reverse Chemoresistance in Patient‐derived Organoids, Mice, and Pancreatic Tumor Cells

Abstract Black phosphorus (BP) exhibits significant potential for clinical applications. However, further research is necessary to uncover the unknown biological functions of BP and broaden its applications across various fields. This study investigates the potential of BP as a targeting PPAR‐γ agonist to overcome chemoresistance in the treatment of pancreatic adenocarcinoma (PAAD) using 2D and 3D cell lines, patient‐derived organoids (PDOs), and mouse models. RNA‐sequencing analysis shows that BP treatment enriches differentially expressed genes in the PPAR pathway, and molecular modeling predicts the potential docking site between BP and PPAR‐γ. Transcriptional activity assays are further to verify the activation of PPAR‐γ. BP‐activated PPAR‐γ inhibits cancer stem cell (CSC) properties and expression of biomarkers such as CD44 and c‐Myc, which are involved in chemoresistance. Notably, CD44 overexpression in tumor cells renders them susceptible to BP while insensitive to gemcitabine. This indicates that BP preferentially targets stem‐like cells, which exhibit heightened resistance to chemotherapeutic drugs. A combination treatment strategy involving BP and gemcitabine is developed, demonstrating enhanced treatment efficacy of PAAD in both in vitro and in vivo models. Thus, BP serves as a PPAR‐γ agonist capable of reversing chemoresistance, establishing it as a potent anti‐tumor approach for the treatment of PAAD.