Spatially optimized 125I brachytherapy: a novel immunomodulatory approach based on spatially fractionated radiation therapy principles

Conventional ¹²⁵I brachytherapy, emphasizing uniform dose coverage, may limit its potential to activate anti-tumor immunity. We propose integrating the principles of Spatially Fractionated Radiotherapy (SFRT) into ¹²⁵I brachytherapy. Through a heterogeneous dose design featuring "co-existing high- and low-dose regions", this approach aims to synergize immunogenic cell death (ICD) with the preservation of immune cell function, thereby transforming the tumor into an "<i>in situ</i> vaccine". The inherent characteristics of ¹²⁵I sources - namely, the steep dose gradient of their low-energy gamma rays and continuous low-dose-rate delivery - provide unique advantages for the precise construction of distinct regions: a high-dose zone (to induce ICD) and a low-dose zone (to support immune cell survival).We have established a novel dose evaluation framework (incorporating metrics such as HDRI [High-Dose Region Index], LDRI [Low-Dose Region Index], DGUI [Dose Gradient Utilization Index], and SHS [Spatial Heterogeneity Score]) to replace traditional homogeneous indices like D90/V100. Furthermore, we present optimization strategies for parameters including source spacing and source activity. Finally, we systematically outline an integrated preclinical-to-clinical research pathway for combination with immunotherapy. This lays the theoretical and experimental foundation for developing tumor-type-specific, personalized treatment protocols based on the "¹²⁵I-SFRT + Immunotherapy" approach.