Early research finds experimental cream targets immune pathways to fight skin cancer

What if the skin could be prompted to fight cancer on its own? New research suggests that may be possible with a topical approach that “unlocks” the body’s built-in immune defenses. Researchers from the Perelman School of Medicine at the University of Pennsylvania have identified a key epigenetic regulator that suppresses immune activity in the skin, with preclinical findings suggesting that targeted inhibition could help activate anti-tumor responses in cutaneous squamous cell carcinoma (cSCC).

Skin cancer is the most common type of cancer worldwide, and cSCC is among the most frequently diagnosed forms. While many cases can be treated successfully when caught early, advanced or recurrent disease can be more difficult to manage. Researchers have increasingly focused on ways to harness the immune system to better detect and eliminate cancer cells.

Lysine-specific demethylase 1 (LSD1) is an enzyme that helps regulate cell growth and function. It works by turning off certain genes involved in cell differentiation, allowing cells to remain in a more immature, flexible state. Because its effects are reversible, LSD1 has emerged as a potential treatment target, and inhibitors have been shown to enhance immunotherapy in breast, cervical and colon cancers.

In the skin, however, its role has been less clear. The epidermis relies on keratinocytes, immune cells and vitamin A-derived retinoids to regulate barrier function and immune responses. How these processes are controlled at the gene level remains unclear.

In a study published March 12, 2026, in The Journal of Clinical Investigation, Penn researchers led by Nina Kuprasertkul and Brian C. Capell, M.D., Ph.D., investigated the role of LSD1 in skin cells. Using a combination of molecular profiling, cellular analysis and mouse models, the team explored how inhibiting LSD1 affects immune signaling and tumor growth in the skin. They developed an inhibitor of LSD1, ORY-1001, as a topical cream. (Editors’ note: ORY-1001, iadademstat, was developed by Oryzon Genomics, and the company is conducting several clinical trials as an oral therapy for several cancers, including small cell lung cancer and acute myeloid leukemia.)

In the Penn study, investigators applied the cream or vehicle to mice. They observed that LSD1, also known as KDM1A, acts as a “brake” on immune-related gene activation in the epidermis. When this brake was lifted — either through genetic approaches or with a topical inhibitor — skin cells activated a coordinated set of pathways involved in retinoic acid signaling, lipid metabolism and immune response. These changes helped recruit immune cells, including dendritic cells and CD4-positive T cells, which are critical for mounting an effective anti-tumor response.

Genomic analyses showed that LSD1 normally occupies regions of DNA associated with immune and metabolic genes, suppressing their activation. When LSD1 was inhibited, these regions became more active, enabling what the researchers described as a “retinoid AP-1 programming” that enhances communication between skin cells and the immune system.

Importantly, the study demonstrated that this immune activation translated into meaningful anti-cancer effects. In two preclinical models of cutaneous squamous cell carcinoma, topical inhibition of LSD1 suppressed tumor growth. Further experiments confirmed that CD4-positive T cells were essential for this effect: when these immune cells were removed, the tumor-suppressing benefits were lost.

“What’s striking is that a simple topical cream can use the skin’s own machinery to recruit and activate immune cells that attack tumors,” Capell, senior author and assistant professor of dermatology, said in a press release from Penn Medicine. He added that researchers are working to refine the formulation and hope to begin early-stage clinical trials within the next one to two years.