A topical cream that wakes up the skin's immune system shrank tumors in mice

A topical cream applied directly to the skin suppressed tumor growth in two preclinical models of cutaneous squamous cell carcinoma, one of the most common cancers worldwide. The cream works by blocking a single enzyme - LSD1 - that normally keeps the skin's immune-signaling pathways turned off. Remove the brake, and the skin recruits its own immune cells to attack the tumor.

The study, published in the Journal of Clinical Investigation by researchers at Penn Medicine, is preclinical - meaning it has been tested only in mouse models, not in humans. But the researchers plan to begin a phase 1 clinical trial within one to two years.

A million diagnoses a year, and few good options for the worst cases

Cutaneous squamous cell carcinoma (cSCC) is diagnosed in roughly one million Americans annually, and incidence continues to rise with an aging population. Most cases are caught early and treated successfully with surgery. But up to 5% of tumors metastasize, causing thousands of deaths each year.

The bigger clinical problem may be volume. Many older or immunocompromised patients develop dozens of precancerous lesions - actinic keratoses and early squamous cell carcinomas - spread across large areas of sun-exposed skin. Surgically removing each one is burdensome, sometimes unfeasible, and carries risks of infection and scarring. Existing topical treatments like chemotherapy creams are not targeted to the tumor biology, and some alternatives are painful.

An estimated 58 million Americans live with skin precancers or early squamous cell carcinomas in any given year. A topical treatment that could prevent progression to invasive cancer would have enormous population-level impact.

Lifting the brake on immune signaling

LSD1 (lysine-specific demethylase 1) is an enzyme that acts as a suppressor of certain immune-activating pathways in epidermal cells. In healthy skin, this suppression serves a regulatory function - preventing unnecessary inflammation. But in the context of early cancer, it effectively hides developing tumors from the immune system.

The Penn researchers formulated a low-dose topical inhibitor of LSD1. When applied to the skin in mouse models, the cream prompted epidermal cells to send molecular signals recruiting immune cells to the area. Those recruited immune cells - specifically CD4+ T cells - played a key role in slowing tumor growth.

The mechanism was confirmed through two critical control experiments. Blocking retinoic acid signaling, which the cream activates, reversed many of the immune changes the cream produced. And destroying CD4+ T cells eliminated the tumor-suppressive effect entirely. Both results indicate the cream works by establishing a communication pathway between skin cells and the immune system, not by directly killing cancer cells.

A cream, not a systemic drug

The topical approach is a deliberate design choice. Systemic immune therapies - checkpoint inhibitors that unleash the immune system throughout the body - work for some patients with advanced cSCC but carry significant side effects and help only a subset of patients. A cream applied directly to precancerous or cancerous spots would, in theory, activate immune responses locally while minimizing systemic exposure.

The researchers are also exploring whether oral or injectable LSD1 inhibitors could enhance the efficacy of existing immune checkpoint therapies for advanced cSCC. If the cream primes the skin's immune environment and a systemic checkpoint inhibitor removes the broader suppressive signals, the combination could potentially work where neither approach succeeds alone.

Mouse model, human timeline

The study used two mouse models of cSCC, and the results were consistent across both. But preclinical cancer research has a well-documented translation gap. Many therapies that work in mice fail in humans, particularly in immunology, where mouse and human immune systems differ in important ways.

The researchers acknowledge this and are spending the next year refining the cream's formulation before moving to a phase 1 trial. If that trial confirms safety and shows preliminary efficacy, larger trials would follow - a process that typically takes several years.

The study's senior author, Brian C. Capell of Penn's Department of Dermatology, has outlined the ideal clinical scenario: a cream that can be applied directly to cancerous and precancerous spots, potentially preventing the need for surgical removal. Whether that vision survives contact with human biology remains the central question. But the preclinical proof of concept - using the skin's own immune machinery, activated by a topical formulation, to fight one of the most common cancers - is compelling enough to warrant the test.