Abstract
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).