Dual-Targeted Radionuclide Therapy with 161Tb Instigates Anticancer Immunity in “Cold” Murine Prostate Tumor

Targeted radionuclide therapy (TRT) with 177Lu holds a huge clinical success in treating advanced prostate cancer patients. It is noted, however, that 177Lu with moderate radiation energy achieves effective tumor inhibition at a relatively high dose and has a low capacity to activate "cold" prostate tumor. In this study, we report that Sigma-1 receptor and prostate-specific membrane antigen (PSMA) dual-targeted peptide (S1R/PSMA-P) labeled with 161Tb, which emits locally high linear energy transfer (LET) Auger electrons, effectively inhibits prostate tumor and energizes anticancer immunity. 161Tb-S1R/PSMA-P exhibited significantly enhanced cytotoxicity and immunogenic cell death over 177Lu-labeled counterpart by inducing more DNA double-strand breaks and reactive oxygen species. Of note, 161Tb-S1R/PSMA-P achieved high tumor uptake and selectivity, induced a complete regression rate of 60% at a single dose of 7.4 MBq in RM1-PSMA+/RM1 tumor model, and sensitized RM1-PSMA+/RM1 tumor to αPD1 immune checkpoint blockade therapy at a dose of 3.7 MBq resulting in a cure rate of 50% and durable antitumor immunity. Overall, 161Tb-S1R/PSMA-P emerges as a promising theranostic agent that is capable of mitigating prostate tumor by boosting anticancer immunity.