Topical Immunotherapy Offers Long-Term Cancer Protection

New research published in the Journal of Clinical Immunology highlights the potential of topical immunotherapy with calcipotriol-plus-5-FU to effectively eliminate precancerous skin lesions and provide long-term protection against squamous cell carcinoma (SCC). This innovative approach not only reduces lesion numbers but also triggers a lasting immune response, offering hope in the fight against skin cancer.

Skin squamous cell carcinoma (SCC) is the second most common skin cancer worldwide, often developing from actinic keratosis (AK)—a precancerous skin condition caused by prolonged sun exposure. Although treatments like topical 5-fluorouracil (5-FU), photodynamic therapy, and tirbanibulin are commonly used, their long-term effectiveness in preventing SCC remains limited.

Researchers discovered that combining calcipotriol, a vitamin D analog, with 5-FU significantly enhances immune responses against AK lesions. The treatment stimulates thymic stromal lymphopoietin (TSLP) in keratinocytes, boosting CD4+ T helper type 2 (Th2) cells and generating tissue-resident memory T cells (TRM). These immune cells provide long-lasting defense against SCC progression.

In the study, 18 patients with AK were treated with a topical combination of 0.0025% calcipotriol and 2.5% 5-FU for six days. Results revealed a 95% reduction in AK lesions on the face and 82% reduction on the scalp. On the arms, reductions reached 65-68%.

The treatment activates a Th2/IL-24 pathway, where interleukin-24 (IL-24) induces toxic processes like autophagy and anoikis, ultimately causing cancer cell death. IL-24 also boosts MMP-1 enzyme activity, further enhancing its anti-cancer effects.

Interestingly, the immune response lasts over five years, providing sustained protection against SCC. Both CD4+ T cells and Th2 polarization are essential for the therapy’s success, as removing these cells in mouse models negated the benefits of treatment.

This study emphasizes that the synergy between calcipotriol and 5-FU is critical for their effectiveness, with neither agent performing as well individually.

These findings introduce the Th2/IL-24 pathway as a potential therapeutic target for future cancer prevention strategies and highlight the promise of topical immunotherapy in preventing SCC progression.

More Information: Oka, T., Smith, S. S., Son, H.. G., et al. (2025). T helper 2 cell–directed immunotherapy eliminates precancerous skin lesions. Journal of Clinical Immunology. doi: https://doi.org/10.1172/JCI183274. https://www.jci.org/articles/view/183274.