128 A topical cream activated the skin’s immune defenses and suppressed tumour growth in two preclinical models of cutaneous squamous cell carcinoma (cSCC), one of the most common cancers in the world, according to a study published today in the Journal of Clinical Investigation. Developed by researchers at the Perelman School of Medicine at the University of Pennsylvania, the cream works by blocking LSD1, an enzyme that suppresses immune‑activating pathways in the skin. “What’s striking is that a simple topical cream can use the skin’s own machinery to recruit and activate immune cells that attack tumours,” said senior author Brian C. Capell, MD, PhD, an assistant professor of Dermatology at Penn. “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. Ideally, this cream could be used directly on cancerous and precancerous spots.” cSCC is one of the most common cancers, with about a million Americans diagnosed each year, and incidence continues to rise with an ageing population and people spending more time in the sun. While most cases are treatable with surgery, up to 5% of tumours metastasise, leading to thousands of deaths annually in the US. Many older or immunocompromised patients develop dozens of precancerous lesions across large areas of skin, making repeated procedures burdensome and, at times, unfeasible. Current options for widespread lesions, such as chemotherapy, are not targeted to the cancer, and other targeted treatments can be painful. Surgery remains effective but is invasive and carries risks such as infection and scarring. A topical approach that activates anti‑tumour immune responses locally could reduce the need for repeated procedures and help prevent progression to invasive cancer. In the study, Penn researchers formulated a low‑dose topical inhibitor of LSD1, an enzyme that normally acts as a brake on certain immune‑activating pathways in epidermal cells. By lifting the brake, the cream prompted skin cells to signal for immune help. Those cells played a key role in slowing down tumour growth. Blocking retinoic acid signalling, a naturally occurring and important type of basic cellular signalling that tells cells how to grow and develop, reversed many of the skin‑level changes induced by the cream. In addition, destroying CD4⁺ T cells (a type of immune cell) eliminated its tumour suppression. The findings suggest the therapy works by priming communication between skin cells and the immune system to enable targeted anti‑tumour responses. While treating skin cancer would be a huge benefit from this treatment, preventing cancer from forming in the first place could have an even larger impact. An estimated 58 million Americans live with skin precancers or early squamous cell carcinomas each year, and a topical treatment could reduce the need for repeated surgeries and lower the number of lesions that progress to invasive cancer. The researchers are also exploring whether taking LSD1 inhibitors orally or by injection could enhance the efficacy of immune‑checkpoint cancer therapies. These types of therapies are currently effective in only a subset of patients with advanced cSCC.