Shedding light on the cancer cell death mechanism in photodynamic therapy

Photodynamic therapy (PDT) employs the interaction of a photosensitizer, light, and molecular oxygen to generate reactive oxygen species, which induce regulated cell death pathways that contribute to tumor eradication and immune modulation. Despite its clinical utility, the determinants of tumor selectivity remain incompletely understood. Current evidence suggests that PDT selectivity does not arise from a single mechanism but rather from the dynamic interplay among photosensitizer properties, tumor architecture, microenvironmental heterogeneity, and host immune responses. Here, we integrate current mechanistic understanding of PDT-induced cell death and discuss how tumor-specific factors, including enhanced permeability and retention, differential transporter expression, and microenvironmental heterogeneity, modulate photosensitizer accumulation. We further examine how photosensitizer subcellular localization, tumor biology, and immune microenvironment shape therapeutic outcomes. This integrated perspective highlights opportunities to guide the selection and optimization of PDT agents and treatment strategies toward improved selectivity and immunogenicity, while reinforcing PDT as a versatile modality within modern cancer therapy.