Dual-targeted alpha therapy mitigates prostate cancer and boosts immune checkpoint blockade therapy

Alpha radionuclide with a high emitting energy and short emitting range has emerged as a new tool for the treatment of advanced tumors; however, its clinical usage stringently depends on delivery vehicle. Here, we report on Sigma-1 receptor and PSMA dual-specific peptide with efficient 225‑actinium labeling (²²⁵Ac-S1R/PSMA-P) for targeted alpha therapy and alpha-immunotherapy of murine prostate tumor. ²²⁵Ac-S1R/PSMA-P with a high specific activity and radiostability exhibited upgraded cell binding and uptake while diminished efflux in RM1-PSMA⁺ cancer cells. Intriguingly, ²²⁵Ac-S1R/PSMA-P afforded a peak uptake of 34.7 ± 3.2 %ID/g and elevated the radioactivity in the tumor over 7 days, with a tumor/kidney ratio of 12.2 ± 1.2 and minimal deposition in blood and other normal tissues like liver and muscle. A single injection of ²²⁵Ac-S1R/PSMA-P effectively shrank large LNCaP-FGC tumors at 1.85 or 5.5 kBq, and completely eradicated highly malignant murine RM1-PSMA⁺/RM1 tumors at 33.3 kBq. We further showed that ²²⁵Ac-S1R/PSMA-P at a low dose of 3.7 kBq could boost immune checkpoint blockade therapy of murine RM1-PSMA⁺/RM1 tumor, leading to 5 out of 7 mice tumor-free that showed durable antitumor immune memory. ²²⁵Ac-S1R/PSMA-P with excellent targeting and immune activation ability has a great clinical potential for treating advanced prostate cancer patients.