<i>NFE2L2</i>-Associated Ferroptosis Resistance Reshapes the Tumor Immune Microenvironment and Guides Therapeutic Strategies in Prostate Cancer

Prostate adenocarcinoma (PRAD) poses a significant challenge due to therapy resistance and an immunosuppressive tumor microenvironment (TME). Ferroptosis has emerged as a therapeutic vulnerability, yet its immunomodulatory role in PRAD remains elusive. Here, we employed a multi-omics approach-integrating bulk RNA-seq (498 tumors), single-cell RNA-seq (68,322 cells), and spatial transcriptomics (19,483 spots)-to decode the ferroptosis-immune landscape. We derived a robust 16-gene ferroptosis signature that predicted biochemical recurrence (C-index = 0.76) and validated it in two independent cohorts. Crucially, high-risk tumors exhibited a "cold" immunosuppressive TME enriched in regulatory T cells and M2 macrophages, alongside elevated immune checkpoints (HAVCR2, CTLA4, PDCD1). Single-cell and virtual knockout analyses revealed that cancer epithelial cells evade ferroptosis via <i>NFE2L2</i>-associated antioxidant defenses, which strongly correlates with immune exclusion. Spatial transcriptomics further demonstrated spatially organized vulnerabilities, with ferroptosis-resistant tumor cores and immune-infiltrated invasive margins. To identify therapeutic interventions, we utilized drug response modeling and molecular docking, prioritizing RSL3, Atovaquone (targeting <i>NOX4</i> (NADPH oxidase 4)/<i>DHODH</i>), and Sorafenib (targeting <i>TrxR1</i> (thioredoxin reductase 1, encoded by <i>TXNRD1</i>)) as potent agents with potential ferroptosis-modulatory activity. Collectively, our findings demonstrate that <i>NFE2L2</i>-associated ferroptosis resistance shapes immune evasion in PRAD. Targeting ferroptosis regulators provides a compelling therapeutic rationale to remodel the TME and synergize with immune checkpoint blockade.