Reprogramming of TLR-Ferroptosis Signaling and Immunometabolic Pathways Overcomes Myeloid Suppression to Improve Checkpoint Blockade in Prostate Cancer.

Nabil A Siddiqui; Li Zhang; Gabriel DeLeon; Nada Naguib; Tuo Zhang; Thomas P Quinn; Feng Chen; Virginia Aragon Sanabria; Anusha Aditya; Daniel Penarete; Sebastien Monette; Fabio Socciarelli; Miles Pourbaghi; Rachel Lee; Chan Lee; Pat B Zanzonico; Howard I Scher; Michael Overholtzer; Ulrich Wiesner; Jedd D Wolchok; Michelle S Bradbury

doi:10.1158/0008-5472.can-25-4954

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Reprogramming of TLR-Ferroptosis Signaling and Immunometabolic Pathways Overcomes Myeloid Suppression to Improve Checkpoint Blockade in Prostate Cancer.

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Abstract

UNLABELLED: The limited efficacy of immunotherapies in advanced prostate cancer stems from a tumor microenvironment (TME) in which myeloid-driven immune suppression, stromal remodeling, and metabolic barriers converge to limit antitumor immunity. In this study, we characterized the immunometabolic properties of an ultrasmall prostate-specific membrane antigen-targeting silica particle therapy as a first-in-class strategy to reprogram the Toll-like receptor (TLR)-ferroptosis axis in MYC-driven prostate cancer. As single agents, these particles suppressed lipid and steroid biosynthesis, disrupted lipid peroxidation control, and impaired nutrient flux, sensitizing tumors to ferroptosis. Coordinated redox remodeling, stromal reprogramming, and innate immune activation reversed myeloid suppression and promoted CD8+ T-cell infiltration. When combined with CSF-1R inhibition and immune checkpoint blockade, the particles suppressed tumor growth, extended survival beyond 100 days, and achieved up to 50% complete remission in MYC-overexpressing models. These findings position TLR-ferroptosis axis remodeling as a mechanistic blueprint for rational, particle-driven immunotherapies with broad translational potential in prostate cancer and other immunologically refractory malignancies. SIGNIFICANCE: Clinically validated, PSMA-targeted ultrasmall core-shell silica particles reprogram immunometabolic pathways via a TLR-ferroptosis axis, enabling tumor microenvironment remodeling and potentiating checkpoint blockade in prostate cancer, with translational implications for treatment-resistant disease.

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Male Prostatic Neoplasms Humans Animals Ferroptosis Tumor Microenvironment Signal Transduction Immune Checkpoint Inhibitors Toll-Like Receptors Mice Metabolic Reprogramming Cell Line, Tumor Journal Article Research Support, U.S. Gov't, Non-P.H.S.Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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Nabil A Siddiqui, Li Zhang, Gabriel DeLeon, Nada Naguib, Tuo Zhang, Thomas P Quinn, Feng Chen, Virginia Aragon Sanabria, Anusha Aditya, Daniel Penarete, Sebastien Monette, Fabio Socciarelli, Miles Pourbaghi, Rachel Lee, Chan Lee, Pat B Zanzonico, Howard I Scher, Michael Overholtzer, Ulrich Wiesner, Jedd D Wolchok, Michelle S Bradbury. 2026-08-14. Reprogramming of TLR-Ferroptosis Signaling and Immunometabolic Pathways Overcomes Myeloid Suppression to Improve Checkpoint Blockade in Prostate Cancer.. https://doi.org/10.1158/0008-5472.can-25-4954

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