Gut microbiota-associated nutritional-immune status predicts prognosis in postoperative NSCLC patients.

[BACKGROUND] Surgical resection is the primary treatment for non-small cell lung cancer (NSCLC) patients with stages I and II; however, the postoperative prognosis varies among individuals. The prognostic nutritional index (PNI) reflects the nutritional-immune status of patients, but its microbial determinants remain unclear.

[METHODS] PNI was analyzed in a cohort of 372 retrospective and 139 prospective NSCLC patients. This analysis integrated gut microbiota signatures using 16S rRNA sequencing, fecal metabolomics, and murine fecal microbiota transplantation (FMT) models.

[RESULTS] A PNI value of ≥46.2 stratified postoperative NSCLC patients with improved 5-y survival (HR = 0.3889, 95% CI 0.2840-0.5356,  < 0.001). Patients with a high PNI showed enrichment of short-chain fatty acid (SCFA)-producing taxa, such as and , and elevated butyrate/isovalerate levels, correlating with increased infiltration of CD8 T cells (Pearson  = 0.51,  = 0.02). FMT from high-PNI patients reduced lung tumor growth in mice compared with FMT from low-PNI patients (7.2 vs 18 nodules,  = 0.01). Oral administration of or/and or butyrate suppressed tumor growth and enhanced CD8 tumor-infiltrating lymphocytes (TILs) ( < 0.001).

[CONCLUSION] PNI and its linked gut microbiota‒SCFA axis are clinically prognostic biomarkers and potential immunomodulatory targets for early-stage NSCLC. Targeting this axis may serve as a promising coadjuvant strategy for NSCLC patients undergoing surgical resection.