2240 nm NIR-IV Photodynamic Therapy Can Reverse Ineffective Anti-OX40 Cancer Immunotherapy to Become Effective.

The discovery of immune checkpoint inhibitor (ICI) therapies was granted the Nobel Prize in 2018. However, ICI immunotherapies were later found working poorly for the large majority (70-80%) of cancer patients. It is an urgent need to develop a strategy to conquer this grand challenge and reverse otherwise ineffective immunotherapies to become effective. Herein, we propose a "Blind T cells" model to well rationalize the course leading to the ineffectiveness of immunotherapies. We demonstrate an effective strategy to conquer the ineffectiveness of immunotherapies via producing a large amount of newly generated tumor-recognizing cytolytic CD8+ T cells before the administration of immunotherapy reagents. We apply a NIR-IV photodynamic therapy, mediated by LaB6-PEG-folate nanoparticles using 2240 nm NIR light excitation, to generate reactive oxygen species, kill cancer cells, in situ produce whole cancer vaccines for priming of CD8+ T cells, and induce immunogenic responses in the presence of immunomodulator anti-OX40. A multifunctional anti-OX40 agonist could co-stimulate naive T cells to proliferate with tumor-recognizing properties, as well as suppress the activities of immunosuppressive Treg, and M2-phenotype macrophages, resulting in the complete disappearance of the primary melanoma tumor (that exposes to NIR light irradiation) as well as the effective suppression of remote/metastatic tumors' growths in the lung (that did not receive photo-irradiation).