Photodynamic therapy (PDT) requires a medical device, a photosensitizing drug and adequate use of both to trigger biological mechanisms that can rapidly destroy the primary tumour and provide long-lasting protection against metastasis. We present a multidisciplinary view of the issues raised by the development of PDT. We show how spectroscopy, photophysics, photochemistry and pharmacokinetics of photosensitizers determine the mechanism of cell death and clinical protocols. Various examples of combinations with chemotherapies and immunotherapies illustrate the opportunities to potentiate the outcome of PDT. Particular emphasis is given to the mechanisms that can be exploited to establish PDT as a systemic treatment of solid tumours and metastatic disease.

Introduction to PDT 2 Adaptive mechanisms to photooxidative stress 2.1 Integrated stress response 2.2 Antioxidant stress response: The Nrf2 pathway 3 Cell death pathways in PDT 3.1 Accidental Necrosis 3.2 Regulated forms of necrosis 3.3 Apoptosis: intrinsic vs. extrinsic pathways 3.4 Autophagy 4 PDT and immunogenic cell death 4.1 Danger/damage-associated molecular patterns (DAMPs) 4.2 PDT-based vaccines 5 Anti-tumor immunity mediated by PDT 6 Concluding remarks

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