T helper 2 cell–directed immunotherapy eliminates precancerous skin lesions
The continuous rise in skin cancer incidence highlights an imperative for improved skin cancer prevention. Topical calcipotriol-plus–5-fluorouracil (calcipotriol-plus–5-FU) immunotherapy effectively eliminates precancerous skin lesions and prevents squamous cell carcinoma (SCC) in patients. However, its mechanism of action remains unclear. Herein, we demonstrate that calcipotriol-plus–5-FU immunotherapy induces T helper type 2 (Th2) immunity, eliminating premalignant keratinocytes in humans. CD4+ Th2 cells were required and were sufficient downstream of thymic stromal lymphopoietin cytokine induction by calcipotriol to suppress skin cancer development. Th2-associated cytokines induced IL-24 expression in cancer cells, resulting in toxic autophagy and anoikis followed by apoptosis. Calcipotriol-plus–5-FU immunotherapy was dependent on IL-24 to suppress skin carcinogenesis in vivo. Collectively, our findings establish a critical role for Th2 immunity in cancer immunoprevention and highlight the Th2/IL-24 axis as an innovative target for skin cancer prevention and therapy.
Source:
Oka, T., Smith, S. S., Son, H. G., Lee, T., Oliver-Garcia, V. S., Mortaja, M., Trerice, K. E., Isakoff, L. S., Conrad, D. N., Azin, M., Raval, N. S., Tabacchi, M., Emdad, L., Das, S. K., Fisher, P. B., Cornelius, L. A., & Demehri, S. (2025). T helper 2 cell–directed immunotherapy eliminates precancerous skin lesions. Journal of Clinical Investigation, 135(1). https://doi.org/10.1172/jci183274