Abstract
Photodynamic immunotherapy, which combines photodynamic therapy (PDT) with immunotherapy, has become an important and effective treatment for cancer. However, most photodynamic immunotherapy systems for cancer do not allow for the precise release of immunomodulators, leading to systemic side effects and poor patient prognosis. This study reports a dual-activatable nanoimmunomodulator (CPPM), whose photodynamic effect and agonist release are both activated in response to specific stimuli, which can be used for precise photodynamic immunotherapy of cancer. CPPM has a half-life of 119 min in circulation and accumulates in tumor tissue 4 h after injection (23.8%). In addition, CPPM is able to achieve tumor localization of nanomedicines through PD-L1-targeting peptides, blocking the specific binding of PD-L1 to PD-1, exposing tumor surface antigens, and reinvigorating the activity of T cells in combination with macitentan to promote T-cell proliferation. Meanwhile, under laser irradiation, CPPM was able to increase intracellular oxidative stress, inhibit cell proliferation through PDT, and trigger immunogenic cell death, further enhancing tumor immunogenicity through synergistic treatment. Ultimately, CPPM enhanced the immunotherapeutic efficiency against tumors by improving the tumor immunosuppressive microenvironment, synergistically inhibiting the growth of primary and distant tumors while activating systemic antitumor immunity to eliminate lung metastases without obvious side effects. This study presents an uncomplicated and multifunctional strategy for the precise modulation of tumor photodynamic immunotherapy with a dual-activatable smart nanoimmunomodulator that can improve the efficacy of PDT, enhance systemic antitumor immunity, and potentially extend it to a wide range of cancers.