Light power density governs local and systemic responses to photodynamic therapy

Photodynamic therapy (PDT) is a promising remedy against tumor cells by light activation of a photosensitizer, and its systemic antitumor effects are commonly attributed to immunogenic cell death and the release of soluble damage-associated molecular patterns (DAMPs). Here, we show that light power density (mW/cm2), which is often treated as a mere technical parameter, determines whether PDT suppresses distant, unirradiated tumors. At an identical light dose (J/cm2), PDT at a low power density sustained singlet oxygen (1O2) generation in tumors, preserved tumor perfusion, and suppressed both irradiated and unirradiated tumors. PDT at a high power density resulted in reduced 1O2 generation, reduced tumor perfusion, and increased programmed death-ligand 1 (PD-L1) expression in unirradiated tumors without inhibiting their growth. Serum levels of soluble DAMPs did not differ between the two conditions, whereas circulating small extracellular vesicles (sEVs) carried distinct protein cargo. Power density is thus a controllable determinant of the systemic effects of PDT, and circulating sEVs are candidate mediators of these effects.