Particle Reprogramming of the TLR–Ferroptosis Axis and Immunometabolic Pathways Inhibits Myeloid Suppression to Improve Checkpoint Blockade in Prostate Cancer

The limited efficacy of immunotherapies (IT) in advanced prostate cancer (PCa) stems from a tumor microenvironment where myeloid-driven immune suppression, stromal remodeling, and metabolic barriers converge to limit antitumor immunity. We highlight the immuno-metabolic 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 suppress lipid and steroid biosynthesis, disrupt lipid peroxidation control, and impair nutrient flux, sensitizing tumors to ferroptosis. Coordinated redox remodeling, stromal reprogramming, and innate immune activation reverse myeloid suppression and promote CD8⁺ T cell infiltration. When combined with CSF-1R inhibition and/or immune checkpoint blockade, particles suppress tumor growth, extend survival beyond 100 days, and achieve up to 50% complete remissions in Myc-overexpressing models. These findings position TLR–ferroptosis axis remodeling as a mechanistic blueprint for rational, particle-driven ITs with broad translational potential in PCa and other immunologically refractory malignancies.