Photodynamic therapy: a promising alternative for high-grade squamous intraepithelial lesion treatment

Cervical cancer, driven by persistent infection with high-risk human papillomavirus (hrHPV), remains a major global health burden. While conventional excisional procedures such as loop electrosurgical excision (LEEP) and conization are effective in treating high-grade squamous intraepithelial lesions (HSIL), which include cervical intraepithelial neoplasia grades 2 and 3 (CIN2 and CIN3, respectively), they are associated with significant risks to cervical integrity and adverse obstetric outcomes. Photodynamic therapy (PDT), particularly using the protoporphyrin IX precursors 5-aminolevulinic acid (5-ALA) and its derivatives, hexyl aminolevulinate (HAL), and methyl aminolevulinate (MAL), has emerged as an alternative and minimally invasive strategy to treat younger women with CIN2. Here, we delineate the cellular and molecular mechanisms that underlie PDT's efficacy in the treatment of cervical lesions. We emphasize the ability of 5-ALA-PDT to selectively target dysplastic cells while preserving the anatomical and functional integrity of the cervix. Central to this therapeutic effect is the modulation of cell death pathways. Specifically, we discuss how PDT counteracts the inhibitory effects of hrHPV on autophagy, thereby facilitating viral clearance and restoring homeostatic immune responses. Furthermore, we delineate the multifaceted cell death modalities orchestrated by 5-ALA-PDT, underscoring their pivotal role in the targeted eradication of hrHPV-transformed cervical cells. Clinical data supporting the reduction of viral load and high regression rates of HSIL are summarized, alongside a critical evaluation of current treatment protocols. Finally, we propose that the future of cervical PDT lies in precision oncology. This highlights the need to focus on the identification of resistance biomarkers and the development of therapeutic strategies that exploit the synergistic combination of PDT with molecular modulators to optimize clinical outcomes and prevent recurrence.