Topical Cream Activates Skin's Immune System to Suppress Cutaneous Squamous Cell Carcinoma Growth
Key Insights
Researchers at the University of Pennsylvania developed a topical cream (search) that blocks the LSD1 (search) enzyme to activate the skin's immune defenses against cutaneous squamous cell carcinoma (search), demonstrating tumor suppression in two preclinical models.
The experimental treatment works by removing the "brake" on immune-activating pathways in skin cells, prompting them to recruit CD4+ T cells (search) that attack tumors through retinoic acid signaling (search) mechanisms.
With approximately one million Americans diagnosed with cutaneous squamous cell carcinoma (search) annually and 58 million living with precancerous lesions (search), this approach could reduce the need for repeated surgical procedures.
Researchers at the Perelman School of Medicine (search) at the University of Pennsylvania have developed a topical cream (search) that harnesses the skin's own immune system to fight cutaneous squamous cell carcinoma (search) (cSCC (search)), one of the world's most common cancers. The experimental treatment demonstrated tumor suppression in two preclinical models by blocking LSD1 (search), an enzyme that normally suppresses immune-activating pathways in the skin.
The findings, published in the Journal of Clinical Investigation, represent a potential breakthrough for treating a cancer that affects approximately one million Americans each year, with incidence continuing to rise as populations age and sun exposure increases.
Addressing a Growing Medical Challenge
Cutaneous squamous cell carcinoma (search) presents significant treatment challenges, particularly for vulnerable patient populations. While most cases can be successfully treated with surgery, up to five percent of tumors metastasize, leading to thousands of deaths annually in the United States.
The burden is especially heavy for older adults and immunocompromised patients, who often develop dozens of precancerous lesions (search) across large areas of skin. Treating each lesion individually requires repeated procedures that are both physically demanding and impractical for many patients.
Current treatment options for widespread lesions have notable limitations. Chemotherapy (search) lacks cancer-specific targeting, while some targeted therapies can cause significant pain. Surgery remains effective but carries risks including infection and scarring.
Mechanism of Action: "Lifting the Brake" on Immune Response
The Penn research team created a low-dose topical inhibitor of LSD1 (search), an enzyme that acts as a "brake" on certain immune-activating pathways in epidermal cells. By blocking this enzyme and effectively "lifting the brake," the cream encourages skin cells to send signals that recruit immune cells to attack tumors.
"What's striking is that a simple topical cream (search) can use the skin's own machinery to recruit and activate immune cells that attack tumors," said Dr. Brian Capell, MD, PhD, senior author of the study and assistant professor of Dermatology at Penn.
Further experiments revealed the specific mechanisms underlying the treatment's effectiveness. When researchers blocked retinoic acid signaling (search)—a naturally occurring cellular communication pathway that guides cell growth and development—many of the skin-level changes caused by the cream were reversed. Additionally, eliminating CD4+ T cells (search), a type of immune cell, removed the treatment's tumor-suppressing effect.
These results indicate the therapy works by strengthening communication between skin cells and the immune system, enabling a more targeted anti-tumor response.
Prevention Potential and Clinical Timeline
While treating existing skin cancer (search) would represent a major advancement, researchers believe the greatest impact could come from cancer prevention. An estimated 58 million Americans live with skin precancers or early squamous cell carcinomas each year. A topical treatment that can be applied to large areas of affected skin could significantly reduce the need for repeated surgeries and lower the number of lesions that progress to invasive cancer.
"We are carrying out some more studies to refine the formulation this coming year, and we hope to begin a phase 1 clinical trial in the next 1-2 years," Capell explained. "Ideally, this cream could be used directly on cancerous and precancerous spots."
Expanding Therapeutic Applications
The research team is also exploring whether LSD1 (search) inhibitors delivered orally or by injection could enhance the effectiveness of immune checkpoint therapies (search). These treatments are currently beneficial for only a subset of patients with advanced cSCC (search).
The study was supported by the National Institutes of Health, the Damon Runyon Cancer Research Foundation (search), the Dermatology Foundation, and the Skin Cancer (search) Foundation. First author Nina Kuprasertkul led the research alongside a multidisciplinary team of investigators.
If future clinical trials confirm these preclinical findings, the approach could offer a new strategy for using the skin's own immune system to fight one of the world's most common cancers, potentially transforming treatment paradigms for both prevention and therapy of cutaneous squamous cell carcinoma (search).