Phosphorus-32 microspheres: A dual-modality transarterial radioembolization approach for hepatocellular carcinoma therapy and Anti-PD1 immunotherapy potentiation

: Transarterial radioembolization (TARE) is a key therapy for hepatocellular carcinoma (HCC) management and downstaging. While 90 Y microspheres (glass/resin) are widely used, their clinical application is limited by complexity, short half-life, and high costs. Thus, novel radionuclide microspheres are crucial. This study developed phosphorus-32-loaded microspheres ( 32 P-MS). In vitro, 32 P-MS dose-dependently suppressed HCC cell proliferation, migration, and invasion while inducing apoptosis. In vivo, 32 P-MS TARE achieved tumor vascular embolization, reducing tumor volume/weight (confirmed by Positron Emission Tomography-Computed Tomography (PET-CT), Hematoxylin and Eosin (HE) staining, TUNEL/Ki67 assays without systemic toxicity. RNA sequencing and mass cytometry analyses revealed 32 P-MS upregulated FABP1 + PD-L1 + myeloid-derived suppressor cell (MDSC), linked to immunosuppression. Mechanistic investigations, including molecular docking, co-localization, and co-immunoprecipitation (Co-IP) assays, demonstrated that 32 P-MS activated the FABP1/PPARG/PD-L1 axis in MDSC. Genetic ablation of FABP1 or pharmacological inhibition with Orlistat reversed PD-L1 expression and augmented anti-tumor efficacy. Combining 32 P-MS with anti-PD1 therapy synergistically suppressed tumor growth, reduced MDSC infiltration, and reinvigorated CD8 + T cell activity, significantly improving treatment sensitivity. 32 P-MS is a promising HCC therapeutic with dual anti-tumor and immune-modulatory functions, providing a compelling rationale for integrating radioembolization with immune checkpoint blockade to counteract immunosuppressive resistance in HCC.