PATHY-inspired partial tumor irradiation on a small-animal irradiator: workflow development and first therapeutic evaluation in glioma

Partial tumor irradiation targeting hypoxic/hypovascularized/hypometabolic tumor segment (PATHY) while sparing the peritumoral immune microenvironment has emerged as an innovative radiotherapy strategy designed to exploit non-targeted and immune-mediated effects. Although promising clinical responses have been reported, the limited availability and technical complexity of preclinical PATHY implementations have constrained mechanistic investigation and rational optimization of treatment parameters. Here, we establish a PATHY-inspired partial tumor irradiation (PTI) workflow on a Small Animal Radiation Research Platform (SARRP) and evaluate its therapeutic efficacy in a rat glioma model. A protocol was developed integrating MRI-based target delineation, millimetric small-field dosimetry, and in vivo quality assurance to selectively irradiate the tumor core using orthovoltage photons. Tumor-bearing rats were assigned to one of three PTI regimens differing in temporal fractionation-conventional fractionation (15 Gy × 3, Δt = 24 h), accelerated fractionation (15 Gy × 3, Δt = 8 h), or single-fraction PTI (30 Gy × 1)-or to a non-irradiated control group. All PTI regimens significantly prolonged overall survival compared with controls, yielding median survival increases ranging from 32% to 62%. No statistically significant differences were observed among the irradiated groups, indicating that, under the investigated dose and fractionation conditions, interfraction timing did not significantly influence survival outcome in this highly radioresistant and immunosuppressive glioma model. This study establishes a robust and reproducible preclinical framework for PTI and provides the first in vivo evidence of its therapeutic potential in glioma. By enabling systematic investigation of partial tumor high-dose irradiation, this platform lays the groundwork for future studies incorporating hypoxia-guided targeting and immune mechanistic endpoints to refine and translate PATHY-based radiotherapy strategies.