Data from Low-Dose Intestinal Irradiation Enhances the Efficacy and Prognosis of PD-1 Blockade in Metastatic Non–Small Cell Lung Cancer

<jats:p>&lt;div&gt;Abstract Purpose:&lt;p&gt;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.&lt;/p&gt; Experimental Design:&lt;p&gt;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 &lt;1 Gy, 1 to 3 Gy, and &gt;3 Gy groups, and treatment outcomes were compared. The blood and fecal samples were subjected to multiomics profiling.&lt;/p&gt; Results:&lt;p&gt;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; &lt;i&gt;P&lt;/i&gt; &lt; 0.01), which was consistent across subgroups. Compared with 1 to 3 Gy, SIMRD &gt;3 Gy [hazard ratio (HR) = 4.87; &lt;i&gt;P&lt;/i&gt; &lt; 0.001] and &lt;1 Gy (HR = 1.85; &lt;i&gt;P&lt;/i&gt; &lt; 0.001) independently predicted worse OS. Prospective results confirmed the best disease control rate (&lt;i&gt;P&lt;/i&gt; = 0.041) and PFS (&lt;i&gt;P&lt;/i&gt; = 0.046) with SIMRD of 1 to 3 Gy. Responders were enriched in &lt;i&gt;Bacillota&lt;/i&gt;, &lt;i&gt;Clostridia&lt;/i&gt;, 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&lt;sup&gt;+&lt;/sup&gt; regulatory T cells.&lt;/p&gt; Conclusions:&lt;p&gt;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.&lt;/p&gt;&lt;p&gt;&lt;a target="_blank" href="https://aacrjournals.org/clincancerres/article-abstract/doi/10.1158/1078-0432.CCR-26-1177"&gt;&lt;i&gt;See related commentary by Deutsch et al., p. 3420&lt;/i&gt;&lt;/a&gt;&lt;/p&gt;&lt;/div&gt;</jats:p>