Liver cancer remains a highly prevalent malignancy both in Taiwan and globally. While combination immunotherapy has become the standard of care for advanced hepatocellular carcinoma (HCC), identifying which patients will truly benefit from this treatment remains a critical challenge in modern medicine. Supported by long-term funding from the National Science and Technology Council (NSTC), a research team led by Prof. Yi-Hsiang Huang, Director of the Department of Medical Research at Taipei Veterans General Hospital, and Dr. Pei-Chang Lee of the Division of Gastroenterology and Hepatology, Department of Medicine, recently published a breakthrough study in the prestigious international journal “Hepatology”. The study reveals for the first time that while gut microbiota compositions vary significantly across different liver cancer etiologies, they produce a common fecal metabolite: acetic acid. The concentration of acetic acid was found not only to predict the efficacy of combination immunotherapy but also to be closely associated with long-term patient survival.

Conducted over several years, this study prospectively collected clinical specimens from patients with metabolic dysfunction-associated steatotic liver disease-related hepatocellular carcinoma (MASLD-HCC) and viral hepatitis-related HCC (V-HCC) undergoing first-line combination immunotherapy. By analyzing pre-treatment gut microbiota, fecal metabolites, and systemic immune biomarkers, and correlating them with tumor response and survival outcomes, the results demonstrated marked differences in gut microbiota composition between MASLD-HCC and V-HCC patients.

The study observed that the gut microbiota of MASLD-HCC patients is enriched with inflammation-related pathogenic taxa. In contrast, V-HCC patients exhibit a higher abundance of commensal bacteria. Despite these distinct microbial profiles, elevated fecal acetic acid concentrations were consistently associated with superior therapeutic response and improved survival outcomes across both patient cohorts. These findings demonstrate that acetic acid serves as an independent predictor of immunotherapy response and survival, highlighting its potential as a novel, non-invasive biomarker.

Further analysis revealed that in the MASLD-HCC cohort, patients with favorable therapeutic outcomes exhibited an enrichment of Mediterraneibacter gnavus, a bacterium capable of producing bile acids and short-chain fatty acids. Conversely, the V-HCC cohort was characterized by an abundance of Bifidobacterium. While the dominant microbial species differed between the two types of liver cancer, both were found to produce 'acetic acid'—a common metabolite with potent immunomodulatory effects. This suggests that 'functional redundancy'—the ability of different gut microbes to perform overlapping metabolic roles—may be the key mechanism determining the success of combination immunotherapy.

This research marks a paradigm shift away from the traditional focus on 'which microbes are present' toward a more functional understanding. It demonstrates that the actual metabolic capacity of the gut microbiota is the true determinant of combination immunotherapy efficacy. Short-chain fatty acids such as acetic acid are not only significantly correlated with tumor response but also hold immense potential as a clinical basis for decision-making in liver cancer immunotherapy.

These findings establish a cross-etiology biomarker for liver cancer patients undergoing combination immunotherapy, paving the way for more precise treatment strategies. Furthermore, this research opens new avenues for enhancing immunotherapy efficacy through dietary interventions, microbiota modulation, or metabolic therapies. This breakthrough not only demonstrates Taiwan’s international competitiveness in liver cancer clinical research and the integration of gut microbiota with translational medicine but also underscores the significant impact of the National Science and Technology Council’s long-term support for clinically oriented and interdisciplinary research.

Note: The research findings above are for reference only. For the treatment of liver cancer, please follow professional medical advice and prescribed treatment plans.

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