Impact of inulin on immunotherapy efficacy in extensive-stage small cell lung cancer and on promotion of CD8+ T-cell tumor infiltration and functional activity.

Abstract

e20145 Background: Response to immune checkpoint inhibitor (ICI)–based therapy in extensive-stage small cell lung cancer (ES-SCLC) is highly heterogeneous, and robust predictive biomarkers remain scarce. Growing evidence suggests that gut microbiota-derived metabolites regulate systemic antitumor immunity by modulating CD8+ T cell function. Inulin, a dietary prebiotic, can reshape gut microbial composition, but its role in ES-SCLC immunotherapy has not been fully elucidated. This study investigated whether Inulin enhances immunotherapy efficacy in ES-SCLC through modulation of the gut microbiota-metabolite-CD8+ T cell axis. Methods: A retrospective cohort study was conducted on patients with ES-SCLC who received first-line treatment with PD-1 inhibitor. The patients were grouped based on the baseline peripheral blood CD8+ T cell level. The high group consisted of 9 patients and the low group of 15 patients. The progression-free survival (PFS) of the two groups was analyzed. Baseline fecal samples underwent metagenomic sequencing and untargeted metabolomics to characterize gut microbial and metabolic features associated with therapeutic outcomes. A SCLC mouse model was used to evaluate the antitumor effects of Inulin, anti-PD-1 therapy, and their combination. Tumor growth, immune infiltration, and cytokine production were assessed by flow cytometry and ELISA. In vitro assays examined the direct effects of Inulin on tumor cells and CD8+ T cell function. Results: Patients with higher baseline CD8+ T cell levels exhibited significantly prolonged PFS following immunotherapy. Distinct gut microbial profiles were observed between patients with favorable and poor responses. Metabolomic analysis revealed higher fecal Inulin levels in patients with elevated CD8+ T cell levels, and Inulin demonstrated predictive value for immunotherapy benefit. In vivo, Inulin significantly enhanced the antitumor efficacy of anti-PD-1 therapy, accompanied by increased tumor-infiltrating CD8+ T cells and elevated IFN-γ, TNF-α, and granzyme B production. In vitro experiments showed that Inulin had no direct cytotoxic effects on tumor cells but augmented CD8+ T cell effector function. Conclusions: Immunotherapy efficacy in ES-SCLC is closely linked to gut microbiota composition and metabolic features. Inulin enhances CD8+ T cell-mediated antitumor immunity through modulation of the gut microenvironment and synergizes with anti-PD-1 therapy, supporting its potential as both an adjunctive therapeutic strategy and a candidate biomarker for immunotherapy responsiveness.