Citation: Moloudi, K.; Sarbadhikary, P.; Abrahamse, H.; George, B.P. Understanding the Photodynamic Therapy Induced Bystander and Abscopal Effects: A Review. Antioxidants 2023, 12, 1434. https:// doi.org/10.3390/antiox12071434 Academic Editor: Alfeu Zanotto-Filho Received: 30 June 2023 Revised: 12 July 2023 Accepted: 14 July 2023 Published: 16 July 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). antioxidants Review Understanding the Photodynamic Therapy Induced Bystander and Abscopal Effects: A Review Kave Moloudi, Paromita Sarbadhikary, Heidi Abrahamse and Blassan P. George * Laser Research Centre, Faculty of Health Sciences, Doornfontein Campus, University of Johannesburg, Johannesburg 2028, South Africa; 223138872@student.uj.ac.za (K.M.); paromitas@uj.ac.za (P.S.); habrahamse@uj.ac.za (H.A.) * Correspondence: blassang@uj.ac.za; Tel.: +27-11-599-6926 Abstract: Photodynamic therapy (PDT) is a clinically approved minimally/non-invasive treatment modality that has been used to treat various conditions, including cancer. The bystander and abscopal effects are two well-documented significant reactions involved in imparting long-term systemic effects in the field of radiobiology. The PDT-induced generation of reactive oxygen and nitrogen species and immune responses is majorly involved in eliciting the bystander and abscopal effects. However, the results in this regard are unsatisfactory and unpredictable due to several poorly elucidated underlying mechanisms and other factors such as the type of cancer being treated, the irradiation dose applied, the treatment regimen employed, and many others. Therefore, in this review, we attempted to summarize the current knowledge regarding the non-targeted effects of PDT. The review is based on research published in the Web of Science, PubMed, Wiley Online Library, and Google Scholar databases up to June 2023. We have highlighted the current challenges and prospects in relation to obtaining clinically relevant robust, reproducible, and long-lasting antitumor effects, which may offer a clinically viable treatment against tumor recurrence and metastasis. The effectiveness of both targeted and untargeted PDT responses and their outcomes in clinics could be improved with more research in this area. Keywords: abscopal effect; bystander effect; cancer; calcium signaling; immune response; photodynamic therapy; reactive oxygen species; reactive nitrogen species; T cell 1. Introduction Photodynamic therapy (PDT) has been clinically approved as a relatively safe and effective treatment option for certain types of cancer as well as noncancerous skin condi- tions such as psoriasis, acne, and infections. In principle, PDT is a two-stage procedure whereby a (i) photosensitizer (PS), i.e., a drug that is sensitive to light, is excited by light of an appropriate wavelength, resulting in (ii) the production of cytotoxic reactive oxygen species (ROS) that destroy abnormal cells. PDT has drawn more attention as a therapeutic approach, both as an independent antitumor therapy and as an immunogenic cell death (ICD) approach, due to new mechanistic insights. Until recently, it was widely believed that the mechanisms of action of PDT were mediated by the direct intracellular gener- ation of ROS, which induces a plethora of direct cellular effects such as abnormal cell death, tumor vasculature damage, and the activation of both innate and adaptive immune responses against tumor masses [1]. However, several recent observations have shown that non-irradiated cells can occasionally exhibit the same responses as irradiated cells, whether they are close by (the bystander effect) or located far away (the abscopal effect), thereby disproving this assumption. For many years, the bystander and abscopal effects of ionizing radiation therapy have been well documented and well described. With more mechanistic insights and clinical studies, other non-conventional local and nonionizing radiation therapies like PDT have also been shown to induce the bystander and abscopal Antioxidants 2023, 12, 1434. https://doi.org/10.3390/antiox12071434 https://www.mdpi.com/journal/antioxidants