Targeted enhancement of antigen cross-presentation capability of M2-like tumor-associated macrophages to boost glioblastoma immunotherapy.

Macrophage antigen cross-presentation plays a vital role in activating CD8 T cells for tumor immunotherapy. However, as the most abundant immune cells in glioblastoma (GBM), M2-like tumor-associated macrophages (TAMs) impede CD8 T cell activation due to their insufficient antigen cross-presentation capability. Herein, we report a strategy of enhancing the antigen cross-presentation capability of M2-like TAMs, by precisely modulating their cysteine protease activity through the photo-controllable nanotherapeutic agent to boost the GBM immunotherapy. The therapeutic nanoprobes (i.e. NPs-RuIn-M) are rationally designed and fabricated from lanthanide nanoparticles (NPs), M2-like macrophage targeting peptide (M) coupled with ovalbumin (OVA), and Ru-caged cysteine protease inhibitor (RuIn). They can be efficiently delivered into the orthotopic GBM after temporary opening of blood-brain barrier with focused ultrasound to accurately locate M2-like TAMs by the second near-infrared-IIb (NIR IIb, 1500-1700 nm) imaging. Subsequently, under the guidance of highly sensitive NIR IIb imaging, the up-conversion emission of NPs-RuIn-M under 808 nm laser irradiation can precisely trigger the release of cysteine protease inhibitor to effectively inhibit cysteine protease activity of M2-like TAMs, thereby enhancing their antigen cross-presentation ability. The abundant M2-like TAMs in GBM can directly cross-present the OVA antigen carried by NPs-RuIn-M to effectively promote the activation and proliferation of CD8 T cells, thereby inhibiting the growth of GBM. More importantly, in combination with anti-PD-L1 antibody and granulocyte colony-stimulating factor (G-CSF), photo-controllable NPs-RuIn-M can significantly improve the survival rate of GL261-OVA-bearing mice after irradiation with 808 nm laser. This study provides a precise and efficient photo-controllable strategy to improve the antigen cross-presentation capability of M2-like TAMs for suppressing GBM growth, which shows great potential in immunotherapy of other solid tumors with abundant M2-like TAMs.