GUT MICROBIOME-MEDIATED IMMUNE REGULATION IN CANCER: LINKING MICROBIAL DYSBIOSIS TO PERSONALIZED IMMUNOTHERAPEUTIC RESPONSES

Abstract

Background: Immune checkpoint inhibitors (ICIs) have revolutionized oncology, yet primary resistance remains a major clinical challenge. While the gut microbiome influences ICI efficacy, its metabolomic mediators and predictive utility in underrepresented, non-Western populations remain poorly defined. We investigated the tripartite gut microbiota–metabolite–immune axis as a predictor of immunotherapy outcomes in a South Asian cohort. Methods: In this prospective, single-center cohort study at a tertiary hospital in Karachi, Pakistan, we enrolled 64 patients with advanced non-small cell lung cancer (NSCLC) or hepatocellular carcinoma (HCC) initiating first- or second-line ICIs. Baseline fecal shotgun metagenomics, targeted serum and fecal metabolomics (UHPLC MS/MS), and peripheral blood 14-color flow cytometry were performed. The primary endpoint was objective response rate (ORR) at 24 weeks. Findings: The ORR was 40.6% (26/64). Responders exhibited significantly higher baseline gut microbial alpha diversity and enrichment of Akkermansia muciniphila, Faecalibacterium prausnitzii, and Bifidobacterium longum. Metabolomic profiling revealed that responders had elevated fecal butyrate and serum indole-3-propionic acid (IPA), alongside reduced secondary bile acids and serum kynurenine. Immunophenotyping showed responders had higher circulating CD8+ T-cell frequencies, lower regulatory T-cell and myeloid-derived suppressor cell burdens, and diminished CD8+ T-cell exhaustion. A composite microbiome-metabolite signature (A. muciniphila ≥1%, fecal butyrate ≥10 μmol/g, serum IPA ≥5 μmol/L) independently predicted ICI response (AUROC=0.87) and was associated with markedly prolonged progression-free survival (12.1 vs. 3.2 months; HR=0.28, p<0.001). Interpretation: The gut microbiota and its specific metabolic outputs, particularly butyrate and IPA, modulate systemic anti-tumor immunity and robustly predict ICI efficacy in a South Asian population. These findings validate microbiome-metabolite signatures as actionable biomarkers for personalizing immunotherapy and highlight microbial metabolites as promising targets for adjuvant microbiome-directed therapeutics.