A single patient case leads to a breakthrough in cancer and antiviral immunity research
A new study has uncovered a genetic cause that may explain why some people develop Kaposi sarcoma despite having no apparent immune deficiency. The rare cancer, which forms in the cells lining blood vessels, is caused by human herpesvirus 8 (HHV-8), also known as Kaposi sarcoma-associated herpesvirus.
Published in the Journal of Allergy and Clinical Immunology and conducted by researchers at the Research Institute of the McGill University Health Centre (The Institute), the study describes the first known human case of RIG-I deficiency-a key player in antiviral immunity-and shows that this defect, caused by a mutation in the DDX58 gene, prevents the body from detecting the virus responsible for the disease and controlling the infection. This discovery paves the way for more targeted and potentially more effective treatments for this cancer, and possibly for other diseases or cancers caused by viruses.
Kaposi sarcoma primarily affects people with weakened immune systems, such as those living with HIV or organ transplant recipients on immunosuppressive therapy. For reasons that remain poorly understood, it can also occur in older individuals with no apparent immune problems, particularly in men of Mediterranean, Middle Eastern or Eastern European descent, as well as in certain populations in Central Asia, South America, and among Inuit communities.
"By studying a single patient in depth, we identified a hidden genetic cause and understood why some people, without known immunodeficiency and seemingly in good health, are nonetheless vulnerable to Kaposi sarcoma," says the senior author of the study, Dr. Don Vinh, an infectious-disease specialist and microbiologist, and a scientist in the Infectious Diseases and Immunity in Global Health Program at The Institute.
How one patient led to a fundamental discovery
This discovery began with the study of a patient of Inuit origin who was referred to the McGill University Health Centre (MUHC) at age 72 for violaceous nodules of the feet and lower legs-typical symptoms of Kaposi sarcoma.
Once the diagnosis was confirmed, his case raised a fundamental question: how can someone who appears immunologically healthy and is HIV-negative develop a cancer typically associated with immune suppression?
To answer this question, Dr. Vinh's team used whole-exome sequencing, an advanced technique used to identify genetic mutations responsible for rare or unexplained diseases. This first step allowed them to pinpoint the underlying cause of the disease: a mutation in the DDX58 gene that prevents the expression of the RIG-I protein.
The team then developed unique experimental systems using the patient's cells and a fluorescent Kaposi sarcoma virus to track infection in real time and assess how well the cells could detect and fight the virus. These experiments showed that the cells responded abnormally, allowing the virus to persist and driving their transformation into cancerous cells.
"One of the most striking findings is that this genetic defect doesn't just weaken the immune response-it directly changes how the virus behaves. In the absence of RIG-I, the virus is able to hide within cells and promote cancer development by reprogramming them to survive and multiply," explains Dr. Vinh.
This discovery challenges longstanding assumptions about the role of the RIG-I protein in antiviral defence.
"RIG-I was previously known for its ability to detect RNA viruses, such as those that cause influenza or COVID-19. Our work shows that it also plays a critical role in defending against Kaposi sarcoma-associated herpesvirus, which is a DNA virus," adds Dr. Vinh. "In doing so, our findings redefine its role in human antiviral immunity."
A discovery that opens new avenues
This work has several important implications. First, it may support the use of genetic testing in patients with unexplained Kaposi sarcoma or other cancers caused by DNA viruses (such as human papillomavirus, or HPV), helping them obtain a precise diagnosis. Screening could also help determine how frequently RIG-I deficiency occurs in these diseases.
Second, the findings open the door to improving treatments for Kaposi sarcoma. They suggest that certain immunotherapies, such as interferon-beta-and potentially interferon-omega-could be more effective and better tolerated than interferon-alpha, which is currently used with variable results and significant side effects for patients. The researchers found that these interferons may more effectively target the underlying biology of the disease, opening the door to more precise, mechanism-based treatment strategies.
The study also opens new avenues for research.
"We will explore whether other components of the body's innate virus-detection mechanisms may also make some people more vulnerable to cancers caused by viruses," says Dr. Vinh. "We also hope to better understand whether genetic differences help explain why these diseases are more common in certain populations, so we can improve screening and care."
About the study
"Human retinoic acid-inducible gene I (RIG-I) deficiency associated with susceptibility to classic Kaposi sarcoma" by Lucie Roussel, Stéphane Bernier, Mélanie Langelier, Yichun Sun, Benjamin Mak, Yongbiao Li, Anna Perez, Alexi Wloski, Isabelle Angers, Lily-Rose Vinh, Annie Beauchamp, Sarah Boissel, A. Kevin Watters, Simon Rousseau, Jean-Pierre Routy, Virginie Calderon, Carolina Arias and Donald C. Vinh was published in the Journal of Allergy and Clinical Immunology.
DOI: 10.1016/j.jaci.2026.02.027
This work was supported by the Fonds de recherche du Québec and the MUHC Foundation (Shawnea Roberts/SDR Project).
