Gut microbiome in cutaneous T-cell lymphoma: emerging insights into systemic immunity and the gut-skin-tumor axis

The gut microbiome is a critical regulator of systemic immunity that influences cancer development, therapeutic response, and immune homeostasis beyond the gastrointestinal tract. Although microbiome research has largely focused on solid tumors and immune checkpoint blockade, growing evidence indicates intestinal microorganisms also shape hematologic malignancies through effects on microbial metabolism, epithelial barrier integrity, immune cell differentiation, and inflammatory signaling. Cutaneous T-cell lymphoma (CTCL) represents a uniquely informative model to investigate these interactions: CTCL is characterized by chronic skin inflammation, progressive barrier dysfunction, systemic immune dysregulation, and skin microbial alterations, and can be longitudinally sampled via ready microbial reservoirs from tumors, blood, stool, and skin. Recent studies have demonstrated CTCL patients harbor gut microbiota with reduced diversity, depleted short-chain fatty acid (SCFA)-producing commensals, and altered microbial metabolic pathways. Associations between intestinal dysbiosis, disease severity, and therapeutic response have been made, alongside evidence linking skin microbial dysbiosis to malignant T-cell proliferation. These findings support a model in which intestinal and cutaneous microbial ecosystems cooperate to shape systemic antitumor immunity through a gut-skin-tumor axis. Microbial metabolites, including SCFAs and tryptophan-derived metabolites, may represent key mediators connecting gut dysbiosis with immune dysfunction and tumor progression. This review synthesizes current evidence regarding the gut microbiome in CTCL within the broader context of cancer immunology, hematologic malignancies, and the gut-skin axis. We discuss mechanisms linking intestinal dysbiosis with malignant T-cell biology, highlight opportunities for integrating microbiome research with multi-omic technologies, and propose future directions for microbiome-based biomarkers and therapeutic interventions to enhance antitumor immunity in CTCL.