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

Abstract

The limited efficacy of immunotherapies in advanced prostate cancer (PCa) stems from a tumor microenvironment in which myeloid-driven immune suppression, stromal remodeling, and metabolic barriers converge to limit antitumor immunity. Here, we characterized the immunometabolic properties of an ultrasmall PSMA-targeting silica particle therapy as a first-in-class strategy to reprogram the Toll-like receptor (TLR)-ferroptosis axis in Myc-driven PCa. 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 promote 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 remissions 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 PCa and other immunologically refractory malignancies.