Ferroptosis at the Metabolic-Immune Interface in Metastatic Castration-Resistant Prostate Cancer: Mechanistic Evidence, Translational Gaps, and Combination Strategies.

BACKGROUND

Immune-checkpoint inhibitors have limited activity in unselected metastatic castration-resistant prostate cancer (mCRPC), although molecularly selected subsets can respond. Androgen-receptor (AR)-linked lipid and redox remodeling creates biologically credible ferroptosis vulnerabilities, but whether ferroptosis can improve immune or radioligand therapy remains uncertain.

METHODS

We performed a structured narrative review of PubMed/MEDLINE, ClinicalTrials.gov, DOI, and publisher records through August 9, 2026. Evidence was classified as prostate cancer clinical/interventional, human observational, prostate functional preclinical, functional evidence from another cancer, general ferroptosis biology, or hypothesis.

RESULTS

Prostate models support context-specific links among AR or AR variants, SLC7A11, glutathione peroxidase 4 (GPX4), acyl-CoA synthetase long-chain family member 4 (ACSL4), 2,4-dienoyl-CoA reductase 1 (DECR1), lipid remodeling, and treatment resistance. Immune consequences are bidirectional: selected preclinical systems show T-cell-associated tumor ferroptosis and improved checkpoint-blockade activity, whereas other studies show impaired dendritic-cell cross-presentation or ferroptosis of effector lymphocytes. No direct evidence establishes that ferroptotic prostate cancer cells activate cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) in recipient dendritic cells. External-beam radiation and chemoradiotherapy provide functional evidence in non-prostate and prostate models, but ferroptosis after 177Lu-PSMA-617 remains unproven. Most combinations and biomarkers remain preclinical or exploratory.

CONCLUSIONS

AR-linked lipid and redox programs influence ferroptosis susceptibility in prostate cancer. Translation requires direct ferroptosis causality, tumor-selective delivery, preservation of immune-cell fitness, clinically relevant models, and orthogonal pharmacodynamic assessment. Clinical benefit from ferroptosis-based combinations with checkpoint inhibitors or 177Lu-PSMA radioligand therapy has not been demonstrated.