A research team from the Department of Clinical Oncology at the University of Hong Kong’s LKS Faculty of Medicine (HKUMed) has identified a key reason why some liver cancer patients fail to respond to immunotherapy. The team discovered that the gut bacterium Phocaeicola vulgatus disrupts the immune system, causing resistance to treatment. The findings, published in Cell Reports Medicine, open a new path toward improving immunotherapy outcomes through targeted microbiome modulation.
Gut Microbiota Strongly Influences Treatment Response
Although immunotherapy has transformed cancer care, its effectiveness in liver cancer varies widely. To understand why, the team analyzed the gut microbiota of liver cancer patients and found Phocaeicola vulgatus significantly elevated in those who showed weak or no response to treatment.
Professor Spring Kong Feng-ming, Clinical Professor at HKUMed, explained that gut microbiota differences between healthy individuals and cancer patients extend far beyond digestion. “The gut acts as an invisible control center, influencing liver tumors through the complex gut–liver axis,” she said.
The Gut–Liver Axis: A Critical Connection
The liver and gut interact continuously through the gut–liver axis, allowing metabolites produced by gut microbes to travel to the liver and regulate immune and metabolic functions. These metabolites can either fuel tumor growth or suppress it. The HKUMed study found that increased levels of Phocaeicola vulgatus correlate strongly with poor immunotherapy outcomes.
To confirm this connection, researchers transplanted P. vulgatus into mice with liver cancer. Initially responsive mice became resistant to immunotherapy after receiving the bacterium, demonstrating that it directly weakens immune defenses.
How Phocaeicola vulgatus Disrupts Immunity
As reported by medicalxpress, the team uncovered the mechanism behind this resistance. Indole Acetic Acid (IAA), a key bacterial metabolite, plays a crucial role in activating cytotoxic T cells—immune cells responsible for killing cancer cells. High levels of IAA help T cells function effectively, increasing the success of immunotherapy.
However, Phocaeicola vulgatus consumes large amounts of the precursor materials required for IAA production. As a result, IAA levels drop, impairing T-cell activation and reducing the body’s ability to fight tumors. This depletion ultimately weakens immunotherapy effectiveness.
Paving the Way for Microbiome Modulation Therapy
Based on these findings, the researchers propose using “microbiome modulation therapy” to enhance immunotherapy. This approach may include modifying the gut microenvironment or supplementing key metabolites like IAA to restore immune function.
Dr. Zhao Caining, the study’s first author, noted that measuring P. vulgatus levels in patients could help predict their response to treatment. “This discovery allows doctors to develop more effective, personalized strategies based on a patient’s gut microbiota profile,” she said. Potential approaches include targeted supplementation or gut microbiome interventions.
A New Frontier in Personalized Cancer Treatment
Professor Spring Kong emphasised the importance of integrating microbiome regulation into future cancer therapies. “Our findings show that treatment should extend beyond targeting tumors. We must also address the underlying gut microecology,” she said. With deeper understanding of gut microbiota, researchers hope to create combination therapies that significantly improve success rates in liver cancer immunotherapy.