Photodynamic therapy reduces the burden of small ultraviolet-induced epidermal clones in human and mouse skin.

Actinic keratoses (AKs) and keratinocyte carcinomas (KCs) arise from prolonged UV exposure, with precursor UV-induced clonal mutations (CMs) appearing in sun-damaged skin. Photodynamic therapy (PDT) is a common field treatment for AKs and early KCs, but its impact on subclinical CMs is unknown. This study examines CMs using targeted ultra-deep sequencing on epidermal samples. By comparing skin before and after PDT in five patients and a mouse model of chronic UV carcinogenesis, a significant reduction in low-frequency mutations post-treatment was revealed. These findings highlight PDT’s potential in modifying subclinical damage and propose low-variant allele frequency CMs as biomarkers for field treatment efficacy.