In a breakthrough that has the potential to reshape how we understand some forms of skin cancer, doctors at the U.S. National Institutes of Health (NIH) have identified a strain of human papillomavirus (HPV), commonly found on the skin, as the direct cause of cutaneous squamous cell carcinoma in a woman with a rare immune disorder.The findings, published in the New England Journal of Medicine this week, challenge long-held assumptions about the role of HPV in skin cancer and spotlight the risks faced by immunocompromised individuals.A Case That Changed EverythingThe discovery came during treatment of a 34-year-old woman, who was suffering from a rare genetic condition that severely weakened her immune system. Over time, she developed more than 40 skin cancer lesions across her face, hands, and legs, all diagnosed as cutaneous squamous cell carcinoma, the second most common form of skin cancer after melanoma.Despite undergoing multiple surgeries and immunotherapy, her cancer kept returning. That’s when a team of doctors, led by Dr. Andrea Lisco from NIH’s National Institute of Allergy and Infectious Diseases, decided to dig deeper. What they found was shocking: her tumors were being driven by beta HPVs, a group of viruses typically seen as harmless.“The virus replicated in a somewhat uncontrolled manner and ended up integrating into the skin cells,” said Dr. Lisco. “Once they did that, they became cancerous.”HPV’s Role in Skin CancerUntil now, HPV’s link to skin cancer was considered indirect at best. Scientists believed the virus might weaken skin cells or make them more vulnerable to UV damage, but not directly cause cancer.This case flips that understanding on its head.Unlike alpha HPVs, which are known to cause cervical, anal, and throat cancers and are targeted by the Gardasil vaccine, beta HPVs live on the skin and usually stay dormant. In healthy people, they don’t integrate into DNA or cause illness.But in this woman’s case, a weakened immune system, specifically impaired T-cells, allowed the virus to behave aggressively and hijack her skin cells’ DNA, turning them malignant.A Life-Saving Treatment and New InsightsWith her immune system unable to fight the virus, doctors decided a stem cell transplant to replace her malfunctioning immune cells. Three years after the procedure, she remains cancer-free.“This case gives us valuable insight into how the immune system interacts with HPV,” said Dr. Anthony Rossi, a dermatologist at Memorial Sloan Kettering Cancer Center, who was not involved in the study. “What’s novel is that it’s the first time beta HPV has been directly linked to human skin cancer.”Dr. Lisco noted that while the finding is important, it doesn’t suggest that everyone with beta HPV is at risk. “We shake hands and we pick up those viruses,” he said. “But if our immune systems are intact, we’re fine.”A Warning for the ImmunocompromisedDoctors emphasize that this case highlights a very specific risk, one that primarily applies to people with compromised immune systems, including those with HIV, organ transplants, long-term immunosuppressive medications, or rare genetic conditions.“Immunocompromised people are up to 100 times more likely to develop this type of skin cancer,” said Dr. Rossi. “HPV can integrate and disrupt the cell cycle more easily in these individuals.”Dr. Anthony Oro, professor of dermatology at Stanford Medicine, added, “It suggests that beta HPVs could contribute to cancers in patients where the immune defense, especially T-cells, is impaired.”Does the HPV Vaccine Help?While Gardasil protects against nine strains of alpha HPV, it’s unclear whether it offers any protection against beta strains.“There is some theory that cross-protection may exist,” said Dr. Rossi, “but we need more research to know for sure.”Studies in mice had long hinted at a potential link between beta HPV and cancer, but this is the first human case to show such a direct cause-and-effect relationship.What This Means for YouExperts say the general population is not at risk from beta HPV-related skin cancer, at least not based on current evidence. Most skin cancers are still caused by sun exposure, and the best prevention is still protecting your skin.Here’s what you can do:Use sunscreen daily, even on cloudy days.Wear protective clothing when outdoors, especially during peak sun hours.Get regular skin checks, particularly if you’re immunocompromised or have a history of skin cancer.Consult your doctor about HPV vaccines and whether they may benefit you.“This case serves as a reminder,” said Dr. Oro, “that even viruses we thought were harmless can become dangerous in the wrong context. And that context is often an immune system not doing its job.”