Epigenetic suppression of Nrf2–Slc40a1 axis induces ferroptosis and enhances immunotherapy in pancreatic cancer

Background Despite progress in immunotherapy for several solid tumors, pancreatic ductal adenocarcinoma (PDAC) remains largely unresponsive, primarily due to its profoundly immunosuppressive tumor microenvironment (TME) characterized by limited CD8 + T cell infiltration. Novel strategies are needed to overcome this immune resistance and enhance the efficacy of checkpoint blockade. Methods We established a patient-derived organoid (PDO)-autologous T cell co-culture platform using endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) specimens from patients with PDAC unresponsive to anti-programmed cell death protein-1 (PD-1) therapy. This high-throughput system was used to screen a focused library of epigenetic compounds. The effects of candidate drugs were validated in orthotopic PDAC models, integrating functional assays, sequencing analyses, and patient data. Results Through screening, we identified the histone demethylase inhibitor JIB04, which synergized with anti-PD-1 therapy to enhance T cell cytotoxicity in PDO-T cell co-cultures. Mechanistically, JIB04 suppressed nuclear-factor-E2-related factor 2 (Nrf2) and reduced chromatin accessibility at distal regulatory regions of its downstream target solute carrier family 40 member 1 (Slc40a1), impairing iron efflux and promoting ferroptosis in tumor cells. This ferroptotic stress facilitated CD8 + T cell infiltration and activation, thereby converting the PDAC TME from “cold” to “hot.” Patients with PDAC with lower Nrf2 and Slc40a1 expression exhibited higher CD8 + T cell infiltration and improved responses to anti-PD-1 therapy. Conclusions Our findings establish a PDO-T cell platform for precision immunotherapy screening and identify JIB04 as a promising epigenetic agent that induces ferroptosis and sensitizes PDAC to immune checkpoint blockade. This ferroptosis-based reprogramming provides a potential strategy to overcome resistance and improve clinical outcomes in PDAC.