Which cell death modality wins the contest for photodynamic therapy of cancer?

Abstract

Photodynamic therapy (PDT) was discovered more than 100 years ago. Since then, many protocols and agents for PDT have been proposed for the treatment of several types of cancer. Traditionally, cell death induced by PDT was categorized into three types: apoptosis, cell death associated with autophagy, and necrosis. However, with the discovery of several other regulated cell death modalities in recent years, it has become clear that this is a rather simple understanding of the mechanisms of action of PDT. New observations revealed that cancer cells exposed to PDT can pass through various non-conventional cell death pathways, such as paraptosis, parthanatos, mitotic catastrophe, pyroptosis, necroptosis, and ferroptosis. Nowadays, immunogenic cell death (ICD) has become one of the most promising ways to eradicate tumor cells by activation of the T-cell adaptive immune response and induction of long-term immunological memory. ICD can be triggered by many anti-cancer treatment methods, including PDT. In this review, we critically discuss recent findings on the non-conventional cell death mechanisms triggered by PDT. Next, we emphasize the role and contribution of ICD in these PDT-induced non-conventional cell death modalities. Finally, we discuss the obstacles and propose several areas of research that will help to overcome these challenges and lead to the development of highly effective anti-cancer therapy based on PDT.

Fig. 1. Mechanisms of photodynamic reactions and biological effects induced by photodynamic therapy.

The photosensitizer (PS) accumulates in cancer cells, absorbs photons (hv) from a light source of appropriate wavelength, and is transformed to the short-lived excited singlet state (¹PS•) [1] [11]. ¹PS• can lose its energy by internal conversion into heat [2] or by emitting light (fluorescence) [3]. ¹PS• could also be transformed into a long-lived excited triplet state (³PS•) via an intersystem crossing process [4]. Besides the ability of reversion to a singlet state (¹PS) by emission of light (phosphorescence) [5], ³PS• can launch two kinds of reactions with adjacent molecules [6, 7]. The result of type I photochemical reaction [6] lies in ³PS• transferring an electron or a proton and formation of organic radicals. These radicals can interact with cellular oxygen to generate cytotoxic reactive oxygen species (ROS) (e.g., superoxide anion (O₂^–•)), hydroperoxide radical (HOO•), peroxides (H₂O₂, ROOH) and hydroxyl radical (HO•); this starts free radical chain reactions. The type II photochemical reaction [7] initiates triplet−triplet energy transfer of ³PS• to molecular oxygen, resulting in the formation of singlet oxygen (¹O₂), which is a powerful oxidizing agent [11]. Type I and type II photochemical reactions can occur simultaneously, and the ratio between them depends mainly on the photochemical and photophysical characteristics of the PS, and the concentrations of the substrate and cellular oxygen [11]. Type I and type II photochemical reactions can trigger different cell death mechanisms that are directly cytotoxic to the cancer cells. Traditionally, cell death induced by PDT was categorized into type I (apoptosis), type II (cell death associated with autophagy), and type III (necrosis) [8]. PDT also activates the recruitment and activation of immune cells and causes vascular damage [9]. However, in recent decades, several alternative cell death modalities that can be triggered by PDT have been identified [10]. These findings show that our knowledge of PDT of cancer has expanded.

Fig. 2

A timeline of cell death modalities and PDT.

Fig. 3. An “ideal” protocol for PDT.

An ideal protocol for PDT should comply with the following requirements. [1] Tumor profiling and analysis of predictive markers for evaluation of the degree of tumor sensitivity to PDT. [2] The PS should have a constant chemical composition and photochemical characteristics that enable it to rapidly and selectively accumulate in tumor cells and to gain a strong cytotoxic effect during its photoinduction. [3] The approach should provide at least a sufficient oxygen supply to the tumor microenvironment for successful generation of photodynamic reactions. [4] The concentration of the PS and the irradiation dose should be tailored to the tumor’s origin and have minimal toxic side effects on normal tissue, even in the absence of photoinduction. [5] The PDT protocol should include a light dosimetry control procedure for timely optimization of PDT treatment modes for each patient. [6] Cancer cells exposed to PDT can proceed through several cell death pathways with either immunogenic or non-immunogenic properties that determine the therapeutic outcome of PDT according to the different scenarios. In an ideal protocol, the PS and treatment modes should lead to the simultaneous induction of several regulated forms of immunogenic cell death. We suggest that PDT-induced ferroptosis could be combined with other cell death modalities to boost PDT efficacy. Finally, PDT should activate immunogenic cell death pathways [7] accompanied by the release of damage-associated molecular patterns (DAMPs) such as ATP, HMGB1 and HSP, and by CRT exposure on the outer cell surface in order to trigger the recruitment and maturation of antigen-presenting cells (e.g., DCs). [8] This will result in optimal antigen presentation to CD8⁺ T cells [9], induction of antitumor immunity, and generation of long-lasting immunological memory [10]. The immune system response is successfully engaged in the suppression of tumor growth [11] and will help to deal with any remaining tumor cells, including distant metastatic cells [12]. Therefore, activation of immunogenic cell death modalities plays a crucial role in the therapeutic success of PDT and hence the overall survival and life quality of patients [13].