Ferroptosis, an iron-dependent form of regulated cell death characterized by lipid peroxidation and oxidative damage, has emerged as a potential mechanism to overcome the resistance of pancreatic ductal adenocarcinoma (PDAC) to immunotherapy. PDAC tumors are typically immune-cold, exhibiting poor CD8+ T-cell infiltration and resistance to immune checkpoint blockade (ICB), such as anti-PD-1 therapy.
Ferroptosis, an iron-dependent form of regulated cell death characterized by lipid peroxidation and oxidative damage, has emerged as a potential mechanism to overcome the resistance of pancreatic ductal adenocarcinoma (PDAC) to immunotherapy. PDAC tumors are typically immune-cold, exhibiting poor CD8+ T-cell infiltration and resistance to immune checkpoint blockade (ICB), such as anti-PD-1 therapy. However, inducing ferroptosis can enhance tumor immunogenicity and sensitize PDAC to immunotherapy.
Recent research has revealed that epigenetic regulation of the Nrf2–Slc40a1 axis plays a critical role in driving ferroptosis and improving immunotherapy outcomes in PDAC. The study utilized a patient-derived organoid (PDO) and autologous T-cell co-culture platform to identify compounds that synergize with anti-PD-1 therapy. Among 177 screened epigenetic modifiers, the histone demethylase inhibitor JIB04 emerged as the most effective agent, demonstrating the ability to enhance T-cell-mediated killing of PDAC cells.
Mechanistically, JIB04 suppresses nuclear factor erythroid 2-related factor 2 (Nrf2), reducing chromatin accessibility of its downstream gene Slc40a1, which regulates iron efflux. This leads to intracellular iron accumulation, oxidative lipid damage, and ferroptosis. Ferroptotic cells exhibit markers such as malondialdehyde (MDA), reactive oxygen species (ROS), and lipid peroxidation, and release immunogenic signals (HMGB1, ATP, calreticulin) that activate dendritic cells and prime T-cells.
In vivo studies confirmed that JIB04 enhances CD8+ T-cell infiltration, converts immune-cold PDAC tumors to immune-hot phenotypes, and improves anti-PD-1 efficacy without systemic toxicity. This ferroptosis-based epigenetic strategy represents a promising therapeutic avenue for sensitizing PDAC to immunotherapy and improving patient outcomes.
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