Nanoparticle‐Enhanced Radiotherapy to Trigger Robust Cancer Immunotherapy

TLDR

Radiotherapy is widely used to destroy tumors but its effectiveness is limited by hypoxia‑induced resistance and its inability to control metastatic disease. The authors fabricated core‑shell PLGA nanoparticles that encapsulate catalase to generate oxygen and load the TLR‑7 agonist imiquimod in the shell, thereby converting hypoxic tumors into an oxygenated, immunostimulatory environment. These nanoparticles markedly improve radiotherapy by alleviating hypoxia, stimulating antitumor immunity, and, when combined with CTLA‑4 blockade, producing strong abscopal effects and durable immune memory, indicating strong potential for clinical translation.

Abstract

External radiotherapy is extensively used in clinic to destruct tumors by locally applied ionizing-radiation beams. However, the efficacy of radiotherapy is usually limited by tumor hypoxia-associated radiation resistance. Moreover, as a local treatment technique, radiotherapy can hardly control tumor metastases, the major cause of cancer death. Herein, core-shell nanoparticles based poly(lactic-co-glycolic) acid (PLGA) are fabricate, by encapsulating water-soluble catalase (Cat), an enzyme that can decompose H2 O2 to generate O2 , inside the inner core, and loading hydrophobic imiquimod (R837), a Toll-like-receptor-7 agonist, within the PLGA shell. The formed PLGA-R837@Cat nanoparticles can greatly enhance radiotherapy efficacy by relieving the tumor hypoxia and modulating the immune-suppressive tumor microenvironment. The tumor-associated antigens generated postradiotherapy-induced immunogenic cell death in the presence of such R837-loaded adjuvant nanoparticles will induce strong antitumor immune responses, which together with cytotoxic T-lymphocyte associated protein 4 (CTLA-4) checkpoint blockade will be able to effectively inhibit tumor metastases by a strong abscopal effect. Moreover, a long term immunological memory effect to protect mice from tumor rechallenging is observed post such treatment. This work thus presents a unique nanomedicine approach as a next-generation radiotherapy strategy to enable synergistic whole-body therapeutic responses after local treatment, greatly promising for clinical translation.