Overcoming Tumor Hypoxia and Acidic Microenvironment to Convert Photodynamic Therapy into a Systemic Antitumor Immune Response

Photodynamic therapy (PDT) has become an interesting minimally invasive method of cancer treatment, which employs the use of photosensitizers to produce reactive oxygen species (ROS) that cause tumor cells to die. Nevertheless, PDT is highly inefficient in hypoxic and acidic tumor microenvironment (TME) that inhibits the production of ROS and the development of antitumor immune response. The new recent developments in nanomedicine and tumor microenvironment modulation have demonstrated an ability to overcome these barriers. Nanomaterials that generate oxygen, photoswitchable hypoxia-sensitive nanomaterials and pH-responsive nanoplatforms are some of the strategies that increase the efficacy of local PDT, at the same time overcoming immunosuppression. Besides, localized phototoxicity may be translated into a systemic antitumor immune response with combination strategies targeting immune checkpoint inhibitors and immunomodulatory nanocarriers, which potentially induces lasting tumor regression and avoids recurrence. This review critically discusses how hypoxia and acidity inhibit PDT, the nanotechnology-based approaches to address such drawbacks, and how PDT can be used to complement immunotherapy. Knowledge and control of the TME provides an avenue through which PDT can be employed to become a systemic method of anticancer therapy rather than a local treatment system.