National Institutes of Health (NIH) researchers have shown for the first time that beta-human papillomavirus (beta-HPV), commonly found on the skin, can directly cause cutaneous squamous cell carcinoma (cSCC) when certain immune cells malfunction.

cSCC is one of the most common cancers in the U.S. and globally. Until now, HPV was believed to simply aid the DNA damage caused by UV radiation—the usual main driver of cSCC. The findings were published in The New England Journal of Medicine.

“This could change how we understand and treat cSCC in immunocompromised people,” said Andrea Lisco, of NIH’s National Institute of Allergy and Infectious Diseases (NIAID). “Some patients may have an undiagnosed immune defect and could benefit from immune-targeting treatments.”

NIH researchers made this discovery while treating a 34-year-old woman with recurrent cSCC on her forehead. After multiple surgeries and immunotherapy failed, doctors suspected a combination of UV-related DNA repair issues and T cell dysfunction. The tumor was one of several HPV-related conditions, she had.

Genetic analysis revealed that beta-HPV had integrated into the DNA of her tumor cells and was producing viral proteins, contradicting the belief that beta-HPV doesn’t sustain tumors. Her cells could still repair UV-induced DNA damage, pointing to the virus as the primary cancer cause.

Researchers traced the unusual viral integration to the woman’s inherited immune disorder, which severely impaired T cell activation. This allowed the virus to spread unchecked and directly drive cSCC.

The NIH team created a personalized plan to give her a stem cell transplant to restore normal T cell function. The transplant was carefully performed due to her already weakened immune system. It was successful—and within months, all her HPV-related conditions, including the aggressive cSCC, resolved. They haven’t returned in over three years.

“This outcome was only possible thanks to collaboration among NIH experts in virology, immunology, oncology, and transplantation,” said Dr. Lisco.

Researchers say others with T cell defects may also be at risk for beta-HPV–driven cancers.