Carboxypeptidase E (CPE) is a metallocarboxypeptidase with dual roles in neuroendocrine cells and cancer biology. In normal physiology, CPE functions as a sorting receptor directing prohormones to the regulated secretory pathway and processes prohormone precursors by removing dibasic C-terminal residues after endoprotease cleavage [UniProt]. The protein localizes to the Golgi apparatus and plasma membrane, participating in peptide metabolic processes and neuropeptide signaling [GO annotations]. In cancer pathology, CPE represents an emerging oncogenic driver. CPE is enriched in exosomes released from high-metastatic hepatocellular carcinoma cells compared to low-metastatic counterparts, with elevated CPE mRNA copy numbers detected in serum exosomes from cancer patients versus healthy subjects 1. Exosomal CPE delivery promotes proliferation and invasion of low-metastatic HCC cells through Cyclin D1 and c-MYC upregulation, while CPE-shRNA-loaded exosomes suppress these malignant phenotypes 1. In osteosarcoma, CPE deficiency suppresses tumor progression by upregulating PANoptosis—a form of programmed cell death—through stabilization of HYOU1 protein and activation of Hippo-YAP signaling 2. CPE knockdown markedly reduces osteosarcoma growth in vitro and in vivo 2. These findings identify CPE as a key player in exosome-mediated tumor progression and a potential therapeutic target, with CPE-shRNA-loaded exosomes offering promise as an anti-cancer treatment modality.