Ailioaie, L.M.; Ailioaie, C.; Litscher, G. Fighting Cancer with Photodynamic Therapy and Nanotechnologies: Current Challenges and Future Directions. Int. J. Mol. Sci. 2025, 26, 2969. https://doi.org/10.3390/ijms26072969
Abstract
Photodynamic therapy (PDT) is an innovative treatment that has recently been approved for clinical use and holds promise for cancer patients. It offers several benefits, such as low systemic toxicity, minimal invasiveness, and the ability to stimulate antitumor immune responses. For certain types of cancer, it has shown positive results with few side effects. However, PDT still faces some challenges, including limited light penetration into deeper tumor tissues, uneven distribution of the photosensitizer (PS) that can also affect healthy cells, and the difficulties posed by the hypoxic tumor microenvironment (TME). In hypoxic conditions, PDT’s effectiveness is reduced due to insufficient production of reactive oxygen species, which limits tumor destruction and can lead to relapse. This review highlights recent advances in photosensitizers and nanotechnologies that are being developed to improve PDT. It focuses on multifunctional nanoplatforms and nanoshuttles that have shown promise in preclinical studies, especially for treating solid tumors. One of the key areas of focus is the development of PSs that specifically target mitochondria to treat deep-seated malignant tumors. New mitochondria-targeting nano-PSs are designed with better water solubility and extended wavelength ranges, allowing them to target tumors more effectively, even in challenging, hypoxic environments. These advancements in PDT are opening new doors for cancer treatment, especially when combined with other therapeutic strategies. Moving forward, research should focus on optimizing PDT, creating more efficient drug delivery systems, and developing smarter PDT platforms. Ultimately, these efforts aim to make PDT a first-choice treatment option for cancer patients.
Keywords: cancer treatment; mitochondria; multifunctional theranostics platforms; nanoparticles; nanoscale delivery vehicles; nanoshuttles; neoplasms; PDT; photosensitizers; tumor hypoxia; TME
Future Perspectives
Looking ahead, future advancements should focus on overcoming these limitations by developing novel PSs, including mitochondrial-targeted nano-photosensitizers. These new PSs, designed for increased solubility and targeted delivery, offer the potential for improved outcomes, particularly in challenging environments like hypoxic tumors. Additionally, combining PDT with other cancer therapies, such as chemotherapy, immunotherapy, and targeted molecular therapies, could provide synergistic effects that enhance therapeutic efficacy, reduce resistance, and improve patient survival.
The integration of PDT with combination therapies is a promising avenue for future research. By leveraging the strengths of each therapeutic modality, these approaches can help address the multifaceted nature of cancer, including tumor heterogeneity, resistance mechanisms, and the complex tumor microenvironment. For example, the use of PDT in conjunction with immunotherapies could stimulate immune responses while also directly killing cancer cells. Furthermore, nanotechnology offers the potential to design smart delivery systems that can selectively target tumors, reduce systemic toxicity, and maximize the effects of PDT.
Ultimately, continued innovation and interdisciplinary collaboration are essential to refine PDT protocols and develop novel combination strategies that will make PDT a cornerstone in modern cancer treatment regimens. With these efforts, PDT has the potential to become a first-choice treatment, providing patients with more effective, personalized, and less invasive options in the fight against cancer.