VGF ‐Derived TLQP ‐21 Ameliorates Tumor Progression, Pain, and Depression‐Like Behaviors in an Orthotopic Mouse Model of Pancreatic Ductal Adenocarcinoma

ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer associated with severe pain and depression. Neuropeptide VGF (non‐acronymic) exhibits robust expression in the pancreas and brain, known for its modulatory roles in metabolic homeostasis, nociception, and depression‐like behaviors. Despite elevated VGF expression being linked to poor prognosis in various cancers, its specific role in PDAC remains unexplored. By combining bioinformatic analysis of clinical datasets with experimental validations, we uncover that high VGF expression correlates with improved survival in PDAC patients. Notably, the administration of TLQP‐21, a C‐terminal peptide derived from VGF, significantly reduces tumor size and enhances the therapeutic efficacy of gemcitabine, resulting in a marked increase in overall survival in an orthotopic mouse model of PDAC. Mechanistically, TLQP‐21 suppresses the tumor‐promoting effects of tumor‐associated macrophages through complement receptors C3aR1 and C1qBP. Additionally, TLQP‐21 alleviates depression‐like behaviors, allodynia, and muscle wasting in PDAC mice. Collectively, these findings demonstrate the dual efficacy of TLQP‐21 in inhibiting tumor growth and mitigating nociceptive and psychiatric symptoms, highlighting the potential of TLQP‐21 as a therapeutic option for PDAC.