Photodynamic therapy combined with immunotherapy: Recent advances and future research directions

Innovative anticancer therapies based on the activation of the immune system offer promise in the battle against cancers resistant to traditional treatments. Examples of such therapeutic approaches include, along with various types of immunotherapies, photodynamic therapy (PDT). PDT is a photochemistry-based strategy that results not only from its direct effects on cancer cells but also from disruption of tumor vasculature and activation of the host immune system. However, to achieve therapeutic success manifested in the eradication of the primary tumor and distant metastases, it is necessary to design suitable photosensitizers (PSs) with the desired optical and photophysical properties to enable efficient generation of ROS under tumor microenvironmental (TME) conditions, especially hypoxia. Thus, in this review particular attention is paid to the photochemical properties of PSs, notably the sufficiently long-lived triplet states and mechanisms of energy/electron transfer reactions. Photogenerated ROS initiate inflammatory reaction, expression of heat-shock proteins, infiltration of immune cells and long-term immune memory. These unique features of PDT give new possibilities to combine PDT with agents stimulating immune response as well as with immunotherapy, especially based on PD-1/PD-L1 blockade. Most of the systems explored in this aspect so far are either derivatives of naturally occurring metal complexes (Heme, Chlorophyll a, and Bacteiochorophyll a - inspired PSs), synthetic (metallo)porphyrins, and (metallo)phthalocyanines or hybrid materials containing metal nanoparticles. This work also summarizes recent reports on the synthesis of antibody-PS conjugates with desired spectroscopic and photochemical properties along with enhanced selectivity and biological activity. Finally, the most notable drawbacks of PDT are presented, and a scenario is outlined for the development of PDT alone, and combined with immunotherapy to overcome these challenges in the future.