How does the gut microbiome affect cancer immunotherapy?

The efficacy of immune‐checkpoint inhibitors (ICIs) such as anti‐PD‐1/PD‐L1 and anti‐CTLA‐4 therapies exhibits marked inter‐individual variability, with a substantial subset of patients failing to respond or developing severe immune‐related adverse events (irAEs). Emerging evidence indicates that the gut microbiome is a critical determinant of both therapeutic outcome and toxicity in cancer immunotherapy. Host immune priming and microbial taxa Gut microbes shape systemic immunity by modulating antigen‐presenting cell (APC) maturation and T‐cell priming. In murine models, CTLA-4 blockade requires intestinal Bacteroides species: antibiotic‐treated or germ-free mice failed to respond until reconstitution with B. fragilis or B. thetaiotaomicron, which restored antitumor T‐cell responses [1]. Similarly, colonization with Bifidobacterium spp. enhanced anti–PD-L1 efficacy via improved dendritic-cell function and CD8+ T-cell activation [1]. Taxonomic signatures of responders Clinical cohorts show that responders to anti–PD-1 often harbor a more diverse microbiome enriched in specific taxa. Patients with non–small‐cell lung cancer or renal cell carcinoma who responded to PD-1 blockade had higher abundance of Akkermansia muciniphila; antibiotic exposure prior to ICI was associated with poorer outcomes [2]. In melanoma, responders exhibited increased α-diversity and enrichment of Ruminococcaceae family members, correlating with enhanced systemic and intratumoral immunity [3]. In hepatobiliary cancers, enrichment of Lachnospiraceae and Alistipes spp. predicted longer progression‐free and overall survival on PD-1 therapy [4], while in gastrointestinal malignancies, a higher Prevotella/Bacteroides ratio and SCFA‐producing genera (e.g., Eubacterium, Lactobacillus) associated with clinical benefit [5]. Fecal microbiota transplantation Preclinical FMT studies demonstrated that transfer of feces from ICI responders to germ-free or antibiotic-treated mice converted nonresponders into responders under PD-1 blockade, with A. muciniphila supplementation rescuing efficacy in an IL-12–dependent manner [2]. First‐in‐human phase 1 trials of FMT in anti–PD-1–refractory melanoma patients reported objective responses in a subset of treated individuals, accompanied by increased CD8+ T-cell infiltration and favorable shifts in gut and tumor transcriptomes [6]. Antibiotics, diet, and probiotics Broad‐spectrum antibiotics administered within weeks of ICI initiation are linked to reduced response rates and shorter survival, likely via loss of key immunostimulatory commensals [2][7]. Conversely, dietary fiber intake correlates with improved ICI efficacy: melanoma patients consuming high‐fiber, low‐probiotic diets had superior progression‐free survival, an effect reproduced in murine models on low-fiber or probiotic regimens [8]. Thus, antibiotic stewardship and dietary counseling represent actionable levers to optimize immunotherapy. Microbial metabolites and signaling Gut bacteria produce immunomodulatory metabolites—short‐chain fatty acids (SCFAs) such as butyrate, secondary bile acids, and tryptophan catabolites—that regulate T-cell differentiation, memory formation, and cytokine profiles. Butyrate enhances CD8+ T-cell function and memory, whereas certain bile acids augment antigen cross‐presentation by dendritic cells [7][9]. Muropeptides derived from Enterococcus cell walls have recently been shown to potentiate antitumor immunity via NOD2 signaling pathways [10]. Immune‐related adverse events Microbiome composition also influences irAE risk. In CTLA-4 blockade, Bacteroides-enriched microbiota correlated with lower colitis incidence, whereas Firmicutes‐dominant profiles predicted higher rates of gastrointestinal toxicity [1]. Systematic analyses across solid tumors suggest that Firmicutes abundance associates with increased irAEs, while Bacteroidetes enrichment is protective [11]. Translational strategies Oncomicrobiotics—including next‐generation probiotics, prebiotics, fecal biotherapeutics, and dietary modulation—are under clinical investigation to augment ICI responses and mitigate toxicity [12][13]. Precision‐medicine approaches integrating microbiome profiling could stratify patients and guide adjunctive interventions, ushering in a new era of microbiome‐informed cancer immunotherapy.