Fig. 3: An “ideal” protocol for PDT.
From: Which cell death modality wins the contest for photodynamic therapy of cancer?
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].
