Regulation of undruggable c-MYC with controlled photothermal therapy for efficient cancer immunotherapy

Cancer immunotherapies have revolutionized the treatment of metastatic cancers however most patients cannot benefit from current immunotherapies due to a suppressive tumor immune microenvironment (TIME). Photothermal therapy (PTT) with nanoparticles (NPs) as photothermal conversion agents has shown potential to induce immunogenic cell death (ICD) by remodeling TIME. PTT with different temperatures have been applied and mild temperature-PTT was recently claimed as the most promising approach. However, the optimal PTT temperature and related mechanisms in activation of immunotherapy have remained unclear. In the present study, black porous silicon (BPSi) NPs coated with polyethylene glycol and cancer cell membranes were utilized as photothermal agents. These NPs have good biocompatibility, high photothermal conversion efficacy, and homotypic tumor targeting ability. It was found that the PTT with the BPSi NPs could efficiently induce ICD, which was largely affected by the applied temperature in PTT. As compared to the mild temperature (46°C) and high temperature (54 °C) PTT, medium temperature PTT at 50 °C was the optimal treatment to induce effective ICD in vitro and inhibit tumor growth in vivo. Furthermore, it was unveiled that PTT could efficiently regulate undruggable c-MYC by tuning temperatures. c-MYC was upregulated by PTT at 46°C while downregulated by PTT at 50 °C. The activities of MYC-induced pathways such as p53 were also significantly enhanced. These findings not only discover the mechanisms in activating immunotherapy with NPs-based PTT but also suggest new directions for developing more potent therapy regimens to treat metastatic tumors. RNA-seq of MDA-MB-231 breast cancer cells incubated with photothermal therapy nanoparticles at different treatment temperatures.