Signalling pathway activation by photodynamic therapy: NF-κB at the crossroad between oncology and immunology

The response of tumors to photodynamic therapy (PDT) largely varies depending upon the intensity of the stress created in the cancer cells and also in the local environment. Singlet oxygen has been demonstrated, in many instances, to be the primary reactive oxygen species generated by PDT and responsible for most of the cellular effects. Cancer cells have developed various sensors which activate signalling pathways in response to PDT, and the nature of the activated pathway varies with the PDT stress intensity. At low doses of PDT, signalling pathways allow cancer cells to both proliferate and switch on pro-survival responses such as autophagy. Above a certain level of PDT stress intensity, cancer cells cannot cope with the heavy damage, and signalling pathways leading to cell death are activated. Two types of regulated cell death have been shown to be induced by PDT: apoptosis and necrosis. Signalling pathways activating NF-κB transcription factors have the peculiar characteristic of being activated both at low and high doses of PDT. These pathways coordinate the cross-talk between the immune system via the release of cytokines and chemokines and an anti-cell death response via the control of apoptosis and necrosis. Therefore, NF-κB induced by PDT appears to play a positive role in educating the immune system to fight tumors but also a negative role in helping cancer cells to survive the stress generated by singlet oxygen. This is why NF-κB cannot easily be considered as a pharmacological target whose inhibition will favor tumor cell eradication by PDT.