A “three musketeers” tactic for inclining interferon-γ as a comrade-in-arm to reinforce the synergistic-tumoricidal therapy

Interferon-γ (IFN-γ), secreted by activated T cells predominantly, plays a crucial performance in the tumoricidal immune response. Unfortunately, a high level of IFN-γ severely ignites the immunosuppressive response, especially by increasing the expression of immune checkpoint programmed death-ligand 1 (PD-L1) and immunoregulatory enzyme indoleamine 2,3-dioxygenase 1 (IDO-1). Herein, we have explored a versatile IFN-γ-nano-integrator (aPD-L1-SH@Ce6@NLG919-PEG, simplified as CNDP) to establish a positive anti-tumor feedback loop to amplify the IFN-γ-mediated tumoricidal effect. In this nano-integrator, photosensitizer chlorin e6 (Ce6) mediates photodynamic therapy (PDT) to re-shape immunogenicity and activate the adaptive immune response, followed by the secretion of high-level IFN-γ to struggle tumor cells. IDO-1 inhibitor (NLG919) afterwards mitigates the immunosuppressive behavior of IFN-γ by neutralizing the function of IDO-1. To turn “waste” into wealth, anti-PD-L1 (aPD-L1) antibodies are technically integrated into the nano-integrator to propel the precise attack of breast cancer through ascending PD-L1 blockade. Together, this “three musketeers” nano-integrator tumoricidal tactic may give a unique insight into the clinical anti-tumor therapy.