Targeted tumor starvation strategy augments radiosensitivity and enhances radioactive iodine-mediated tumor immunotherapy.

Radiopharmaceutical therapy (RPT) represents a critical approach in oncology, nevertheless its efficacy may be limited by tumor resistance mechanisms associated with metabolic reprogramming. Enhancing tumor radiosensitivity remains a major challenge. Engineered bi-functional starvation probes (CRT3LP and CRT4LP) that simultaneously target ecto-CRT and exert L-ASNase activity are explored for disrupting tumor amino acid metabolism. Herein, we systematically evaluate the ability of targeted starvation probes to enhance antitumor efficacy in radioactive iodine (RAI) therapy. In vitro, the probes upregulated p53 expression while downregulating Rev1 and SOD2, thereby impairing ROS scavenging and sensitizing tumor cells to RAI-induced oxidative stress. In vivo, the combination treatment elevated intratumoral ROS levels, increased CD4⁺ and CD8⁺ T cell infiltration, upregulated pro-inflammatory cytokines (IFN-γ and TNF-α), and reduced regulatory T cell populations. Additionally, markers of tumor proliferation (Ki67 and CD31) were suppressed, while apoptotic markers (TUNEL and p21) were increased. Co-administration of the immune checkpoint inhibitor αPD-L1 further improved therapeutic efficacy. These findings suggest that targeted tumor starvation probes boost radiosensitivity and anti-tumor immunity, and this strategy shows improved efficacy in combination with αPD-L1 therapy.