Mechanistic insights into hepatic metastasis of pancreatic cancer: molecular perspectives.

Pancreatic cancer (PC) is characterized by its aggressive nature and delayed diagnosis, with hepatic metastasis significantly worsening patient prognosis. Recent studies have unveiled multi-layered molecular mechanisms underlying liver metastasis (LM), offering novel perspectives for clinical intervention. Firstly, dysregulation of key genes critically influences metastatic progression. Secondly, metabolic reprogramming fuels metastatic processes, suggesting metabolic targeting as a potential strategy. Additionally, the tumor microenvironment (TME) plays a pivotal role: cancer-associated fibroblasts (CAFs) remodel the niche via extracellular matrix (ECM) and growth factor secretion, while neutrophil extracellular traps (NETs) foster pre-metastatic niches through high-mobility group box 1 (HMGB1) signaling. Immune suppression is further exacerbated by dysfunctional effector T cells and immunosuppressive cells, though targeting insulin-like growth factor I receptor (IGF-IR) or programmed cell death protein 1 (PD-1) may reverse immune tolerance. Key signaling pathways, including aberrant signal transducers and activators of transcription (STAT) family activation, Yes-associated protein (YAP)/transcriptional coactivator (TAZ)-mediated mechanotransduction, and dysregulated phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) pathways, are intricately linked to metastasis. Epithelial-mesenchymal transition (EMT), a central mechanism, is regulated by p21-activated kinase 2 (PAK2)/transforming growth factor (TGF)-β and sex determining region Y-box 2 (SOX2)/Slug pathways, with combined targeting of metabolism and EMT offering therapeutic promise. Future research should focus on elucidating the spatiotemporal dynamics of these mechanisms and integrating immunotherapy with molecular targeting to improve outcomes for PC patients with hepatic metastasis. This review aims to provide a reference for the mechanism research and therapeutic intervention of hepatic metastasis of pancreatic cancer (HMPC).