Radionuclide-Labeled Microspheres for Radio-Immunotherapy of Hepatocellular Carcinoma

Brachytherapy, including radioactive seed implantation (RSI) and transarterial radiation therapy embolization (TARE), is an important treatment modality for advanced hepatocellular carcinoma (HCC), but the inability of RSI and TARE to treat tumor metastasis and recurrence limits their benefits for patients in the clinic. Herein, indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors-loaded alginate microspheres (IMs) are developed as radionuclide carriers with immunomodulatory functions to achieve effective radio-immunotherapy. The size and swelling properties of IMs can be facilely tailored by adjusting the calcium source during emulsification. Small/large IMs(SIMs/LIMs) are biocompatible and available for RSI and TARE, respectively, after ¹⁷⁷ Lu labeling. Among them, ¹⁷⁷ Lu-SIMs completely eliminated subcutaneous HCC in mice after intratumoral RSI. Moreover, in combination with anti-PD-L1, ¹⁷⁷ Lu-SIMs not only eradicate primary tumors by RSI but also effectively inhibit the growth of distant tumors, wherein the potent abscopal effect can be ascribed to the immune stimulation of RSI and the modulation of the tumor immune microenvironment (TIME) by IDO1 inhibitors. In parallel, LIMs demonstrate excellent embolization efficiency, resulting in visible necrotic lesions in the central auricular artery of rabbits, which are promising for TARE in future studies. Collectively, a versatile therapeutic agent is provided to synchronously modulate the TIME during brachytherapy for efficient radio-immunotherapy of advanced HCC.