Low-dose intestinal irradiation to enhance the efficacy and prognosis of PD-1 blockade in metastatic non-small cell lung cancer.

Abstract

2627 Background: Intestinal low-dose irradiation (ILDR) has been shown to enhance the efficacy of immunotherapy in advanced solid tumors by modulating the gut microbiota and metabolism. However, its role in metastatic non-small cell lung cancer (mNSCLC), particularly in the first-line treatment setting, remains unclear. Therefore, this study investigated the impact of intestinal radiation dose on the efficacy and prognosis of programmed cell death protein 1 (PD-1) blockade in patients with mNSCLC. Methods: This multicenter retrospective and prospective study included patients with mNSCLC who received first- or second-line PD-1 inhibitors combined with abdominopelvic radiotherapy between 2018 and 2025. Patients were stratified into three groups according to the mean intestinal radiation dose: <1 Gy, 1–3 Gy, and >3 Gy, and treatment outcomes were compared among groups. In addition, blood and fecal samples prospectively collected were subjected to multi-omics analyses. Results: A total of 301 patients were included in the retrospective analysis, among whom 105 patients (34.9%) had a small intestinal mean radiation dose (SIMRD) <1 Gy, and 84 patients (27.9%) had a SIMRD of 1–3 Gy. Overall, 183 patients (60.8%) received first-line PD-1 blockade, and 118 patients (39.2%) received second-line treatment. The median follow-up time was 27.2 months. The results showed that patients with a SIMRD of 1–3 Gy achieved the highest objective response rate (21.0% vs. 48.8% vs. 6.3%). Compared with the <1 Gy and >3 Gy groups, the 1–3 Gy group also demonstrated significantly prolonged progression-free survival (PFS, 10.2 months) and overall survival (OS, 23.7 months) (P < 0.01), with consistent findings across all subgroup analyses. Compared with the 1–3 Gy group, SIMRD >3 Gy (HR = 4.96, P < 0.001) and SIMRD <1 Gy (HR = 1.90, P < 0.001) were both independent predictors of worse OS. Thirty patients who recevied first-line PD-1 inhibitors combined with abdominopelvic radiotherapy were included in the prospective analyses. With a median follow-up of 17.5 months, patients with a SIMRD of 1–3 Gy achieved the best disease control rate (1-3 Gy vs. <1 Gy vs. >3 Gy: 90.0% vs. 63.7% vs. 33.3%; P = 0.041) and the longest median PFS (1-3 Gy vs. <1 Gy vs. >3 Gy: not reached vs. 9.3 months vs. 5.8 months; P = 0.120). Multi-omics analyses revealed that responders were enriched in Bacillota , Clostridia , and indole-derived metabolites, particularly indole-3-carboxylic acid. Moreover, patients in the 1–3 Gy group exhibited increased circulating macrophage inflammatory protein-3α levels and a reduced proportion of α4β7 + regulatory T cells. Conclusions: ILDR influences the efficacy of PD-1 inhibitor therapy in patients with mNSCLC, with the most pronounced benefit observed when SIMRD is maintained within the 1–3 Gy range. This effect may be mediated through modulation of the gut microbiota–metabolite–immune axis.