Susceptibility and Resistance Mechanisms During Photodynamic Therapy of Melanoma

Abstract

Melanoma is the most aggressive malignant skin tumor and arises from melanocytes. The resistance of melanoma cells to various treatments results in rapid tumor growth and high mortality. As a local therapeutic modality, photodynamic therapy has been successfully applied for clinical treatment of skin diseases. Photodynamic therapy is a relatively new treatment method for various types of malignant tumors in humans and, compared to conventional treatment methods, has fewer side effects, and is more accurate and non-invasive. Although several in vivo and in vitro studies have shown encouraging results regarding the potential benefits of photodynamic therapy as an adjuvant treatment for melanoma, its clinical application remains limited owing to its relative inefficiency. This review article discusses the use of photodynamic therapy in melanoma treatment as well as the latest progress made in deciphering the mechanism of tolerance. Lastly, potential targets are identified that may improve photodynamic therapy against melanoma cells.

Keywords: apoptosis; autophagy; melanoma; photodynamic therapy; tumor immunity.

Figure 1

Effector mechanisms during photodynamic therapy of melanoma. The ground state photosensitizer (PS) is activated by irradiation with appropriate wavelength light to produce singlet state. Reactive oxygen species (ROS), the main cytotoxic components, can cause death of tumor cells by apoptosis (①) and induce the damage of the tumor vascular system (②). In addition, photodynamic therapy may also activate immune responses against tumors by affecting the secretion of inflammatory factor (IL-6, IL-1, and TNF-α), HSPs (heat shock proteins) and DAMPs (damage associated molecular patterns) (③), and exosomes (④). Moreover, exosomes induced by photodynamic therapy (PDT) might play an important role in inhibitory regulation of EMT (epithelial-mesenchymal transition) in melanoma cells (⑤).

Figure 2

Effector mechanisms leading to necrosis after photodynamic therapy of melanoma. PDT may induce DNA damage and swelling of organelles, leading to necrosis of melanoma cells. PDT may also activate the RIPK1 pathway to promote the phosphorylation of downstream RIPK3, make the phosphorylation of RIPK3 merge with MLKL, and form RIPK1-RIPK3-MLKL complex, namely necrotizing corpuscles.

Figure 3

Resistance mechanisms during photodynamic therapy of melanoma. Photosensitizers cannot be effectively excited by near-infrared (NIR) in PDT for melanoma, melanin granules and autophagy could be the main contributors to this resistance. First, visible light can be absorbed by melanin in melanoma cell (①), leading to diminishment of photothermal effect induced by PS and decrease in production of ROS and singlet oxygen, then resulting in the inhibition of immune response in tumor microenvironment (②) and apoptosis blocking (③) of melanoma cell. Only in the near-infrared conditions, PS can play an even greater role in PDT treatment of melanoma. Second, subcellular organelle damage induced by ROS in PDT treatment can enhance autophagy to maintain cell homeostasis against apoptosis, which ultimately leads to the resistance to PDT treatment in melanoma (④).