Necroptosis in pancreatic cancer: Molecular mechanisms and therapeutic implications.

Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal cancer due to its strong resistance to chemotherapeutic agents that induce apoptosis. As conventional treatments gradually lose their effectiveness over time, necroptosis has become a key therapeutic target worth exploiting. Necroptosis is a regulated cell death independent of caspases. It is driven by the receptor-interacting protein kinase 1/3 (RIPK1/3) and mixed lineage kinase domain-like pseudokinase (MLKL) signaling axis. This systematic review summarizes the complex role of necroptosis in PDAC. We clarify how necroptosis can be triggered or manipulated pharmacologically, and how it can be induced by accumulating reactive oxygen species (ROS). We also critically analyze its tumor-promoting side. Persistent necroptotic signaling reshapes the tumor microenvironment (TME) by releasing damage-associated molecular patterns (DAMPs) and activating inflammatory cascades. We also highlight the growing clinical significance of necroptosis-related genes (NRGs), long non-coding RNAs (lncRNAs), and specific biomarkers such as fermitin family member 1 (FERMT1). Finally, we propose a new, context-dependent therapeutic framework. This framework proposes a combination of strategies for controlling necroptosis induction and immunomodulatory agents, offering a reasonable strategy for PDAC management.