Intestinal Candida albicans promotes HCC progression and anti-PD-1 resistance via IL-17A and Trem2(+) macrophages.

Higher fecal Candida albicans abundance in patients with hepatocellular carcinoma is linked to advanced disease, shorter overall survival, and reduced durable benefit from anti–PD-1 therapy.

• Why it matters: It remains unclear whether intestinal fungal dysbiosis contributes to HCC progression and immune checkpoint inhibitor resistance, limiting microbiome-informed biomarker and therapeutic strategies.
• What they did: In four autochthonous murine HCC models, Candida albicans gavage increased tumor burden and induced a Th17/IL-17A-skewed microenvironment with Trem2+ macrophage accumulation; antifungal treatment, IL-17A blockade/deficiency, and IL-17A signaling perturbations were tested alongside single-cell/bulk RNA-seq and Kaede trafficking.
• The result: IL-17A blockade or deficiency largely abrogated Candida albicans-associated tumor promotion, and IL-17A drove MCP-1 via ACT1-TRAF6-TAK1 and PAI-1 to promote immunosuppressive Trem2+ macrophages that impaired CD8+ T cell infiltration/function and reduced anti–PD-1 efficacy in vivo.