Low-Dose Intestinal Irradiation Enhances the Efficacy and Prognosis of PD-1 Blockade in Metastatic Non-Small Cell
Baiyang Huang1, Jiarui Zhao1, Jingyu Zhu1
1Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China.
Purpose:
Intestinal low-dose irradiation (ILDR) may enhance immunotherapy efficacy by modulating the gut microbiota and metabolism; however, its role in metastatic non-small cell lung cancer (mNSCLC), particularly in the first-line setting, remains unclear.
Experimental Design:
This multicenter retrospective and prospective study included patients with mNSCLC receiving first- and second-line programmed cell death protein 1 (PD-1) inhibitors along with abdominopelvic radiotherapy between 2018 and 2025. Patients were stratified by the mean intestinal radiation dose into <1 Gy, 1 to 3 Gy, and >3 Gy groups, and treatment outcomes were compared. The blood and fecal samples were subjected to multiomics profiling.
Results:
A total of 309 patients were included in the retrospective analysis. Optimal efficacy was observed with a small intestinal mean radiation dose (SIMRD) of 1 to 3 Gy, showing longer progression-free survival (PFS, 10.2 months) and overall survival (OS, 22.8 months; P < 0.01), which was consistent across subgroups. Compared with 1 to 3 Gy, SIMRD >3 Gy [hazard ratio (HR) = 4.87; P < 0.001] and <1 Gy (HR = 1.85; P < 0.001) independently predicted worse OS. Prospective results confirmed the best disease control rate (P = 0.041) and PFS (P = 0.046) with SIMRD of 1 to 3 Gy. Responders were enriched in Bacillota, Clostridia, and indole derivatives, particularly indole-3-carboxylic acid. Moreover, the 1 to 3 Gy group exhibited increased circulating macrophage inflammatory protein-3α and reduced circulating α4β7+ regulatory T cells.
Conclusions:
ILDR influences the efficacy of PD-1 blockade in patients with mNSCLC, particularly when SIMRD is maintained within the 1 to 3 Gy range, likely through modulation of the gut microbiota-metabolite-immune axis. See related commentary by Deutsch et al., p. 3420.
