Dual-modulation of immunosuppressive pathways using sono-activatable semiconducting polymer nanofeedbacks for cancer immunotherapy

Abstract

Although the combinations of immunotherapy with other therapies can offer promising possibility to sensitize tumors to various immunotherapeutic strategies for amplified antitumor immune responses, the up-regulations of immunosuppressive pathways after cancer treatments still greatly compromise the therapeutic outcomes. Herein, we report the dual-modulation of up-regulated immunosuppressive pathways by designing sono-activatable semiconducting polymer nanofeedbacks (SPNSA) for cancer immunotherapy. The SPNSA are constructed to contain semiconducting polymer nanoparticles (SPNs) as the sonosensitizers, adenosine receptor A2A antagonist (SCH58261), programmed death-ligand 1 (PD-L1) antibody (aPD-L1) and singlet oxygen (1O2)-cleavable linkers. Upon ultrasound (US) irradiation, the SPNs produce 1O2 for sonodynamic therapy (SDT) and inducing immunogenic cell death (ICD) with up-regulations of adenosine level and PD-L1 expression. In addition, the produced 1O2 can snip the 1O2-cleavable linkers for on-demand release of SCH58261 and aPD-L1 that act as the feedbacks to modulate the up-regulated immunosuppressive adenosine and PD-L1 pathways simultaneously, resulting in further amplified antitumor immunological effect. In the bilateral tumor-bearing mouse models, the administration of SPNSA and sono-activation can greatly inhibit the tumor growths and metastasis. This study thus provides a sono-activatable nanoplatform for precisely amplifying immunotherapeutic effect via feedback modulating of immunosuppressive pathways post-treatments.