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.