Photodynamic therapy (
PDT) has emerged as a promising alternative to conventional
cancer therapies such as surgery,
chemotherapy, and
radiotherapy.
PDT comprises the administration of a
photosensitizer, its accumulation in
tumor tissue, and subsequent irradiation of the
photosensitizer-loaded
tumor, leading to the localized photoproduction of
reactive oxygen species (ROS). The resulting oxidative damage ultimately culminates in
tumor cell death, vascular shutdown, induction of an antitumor immune response, and the consequent destruction of the
tumor. However, the ROS produced by
PDT also triggers a stress response that, as part of a cell survival mechanism, helps
cancer cells to cope with the
PDT-induced oxidative stress and cell damage. These survival pathways are mediated by the
transcription factors activator protein 1 (AP-1),
nuclear factor E2-related factor 2 (NRF2),
hypoxia-inducible factor 1 (HIF-1), nuclear factor κB (NF-κB), and those that mediate the proteotoxic stress response. The survival pathways are believed to render some types of
cancer recalcitrant to
PDT and alter the tumor microenvironment in favor of
tumor survival. In this review, the molecular mechanisms are elucidated that occur post-
PDT to mediate
cancer cell survival, on the basis of which pharmacological interventions are proposed. Specifically, pharmaceutical inhibitors of the molecular regulators of each survival pathway are addressed. The ultimate aim is to facilitate the development of adjuvant intervention strategies to improve
PDT efficacy in recalcitrant solid
tumors.