A Novel Self-Regulated, Non-Directional Magnetic Thermos-Brachytherapy <sup>125</sup>I Seed Enhances Anticancer Efficacy by Rescuing Immune Escape.

Abstract

Integrating mild hyperthermia (MH) with ¹²⁵I brachytherapy holds potential for overcoming treatment resistance and improving anticancer efficacy. Here, magnetic nanoparticles (MNPs) with a suitable Curie temperature are constructed and incorporated with silver rods coated with ¹²⁵I to form composite seeds. In vitro simulations and in vivo validations demonstrated their effective performance in radiation dose and temperature control. Compared with traditional thermoseeds and previously reported MNPs, this composite seed exhibits direction-independent and self-regulated heating efficiency. Additionally, the titanium shell prevented MNPs leakage and enabled its repeated hyperthermia treatment capacity. Subsequently, the enhanced pancancer anticancer efficacy of the composite seed-relied ¹²⁵I@MH therapy is confirmed through cellular and animal experiments involving liver cancer and prostate cancer. Further tumor microenvironment investigations based on a subcutaneous liver cancer mouse model identified that ¹²⁵I therapy recruited Cd274/Pd-l1⁺ neutrophils and induced T-cell exhaustion, leading to immune evasion and brachytherapy resistance. The addition of MH significantly reversed this effect, restoring the function of effector T cells (IFN-γ⁺ T cells) and activating T-cell immunity. In conclusion, this study developed a novel composite seed with superior anticancer efficacy, which holds promising therapeutic potential for the treatment of malignancies, particularly solid tumors, in future clinical practice.