Photodynamic Therapy and Tumor Microenvironment-Targeting Strategies: A Novel Synergy at the Frontier of Cancer Treatment

Despite intensive worldwide research efforts and multiple available therapeutic schemes for cancer treatment, cancer still remains a challenge, rendering the need for the discovery of new therapeutic approaches imperative. Photodynamic therapy (PDT) is a novel, non-invasive anti-cancer treatment that relies on the generation of reactive oxygen species (ROS) that are cytotoxic to cancer cells. ROS are generated by the interaction between a photosensitizer (PS) drug, a light source (primarily a laser), and oxygen. Although PDT offers the advantage of using non-ionizing radiation and bears great therapeutic potential, it has not yet been widely adopted in clinical practice. This review summarizes the new developments in the use of PDT in combination with chemotherapy, immunotherapy, and radiotherapy, giving emphasis to the combination of PDT with a novel type of therapy that also takes into account the tumor microenvironment (TME) to enhance treatment efficacy. TME-targeting therapies include strategies like hypoxia modulation, vascular normalization, and immune cell reprogramming. Interestingly, when combined with PDT, these therapies can improve therapeutic outcomes while reducing side effects, and nanoparticle-based delivery systems have demonstrated the potential to enhance PDT selectivity and efficiency. This review highlights PDT’s enormous potential in treating various cancer types and underscores the need for continued exploration of combination therapies to maximize its clinical impact.