pH-gated nanoparticles selectively regulate lysosomal function of tumour-associated macrophages for cancer immunotherapy
Mingmei Tang, Binlong Chen, Heming Xia, Meijie Pan, Ruiyang Zhao, Jiayi Zhou, Qingqing Yin, Fangjie Wan, Yue Yan, Chuanxun Fu, Lijun Zhong, Qiang Zhang, Yiguang Wang
Abstract
Tumour-associated macrophages (TAMs), as one of the most abundant tumour-infiltrating immune cells, play a pivotal role in tumour antigen clearance and immune suppression. M2-like TAMs present a heightened lysosomal acidity and protease activity, limiting an effective antigen cross-presentation. How to selectively reprogram M2-like TAMs to reinvigorate anti-tumour immune responses is challenging. Here, we report a pH-gated nanoadjuvant (PGN) that selectively targets the lysosomes of M2-like TAMs in tumours rather than the corresponding organelles from macrophages in healthy tissues. Enabled by the PGN nanotechnology, M2-like TAMs are specifically switched to a M1-like phenotype with attenuated lysosomal acidity and cathepsin activity for improved antigen cross-presentation, thus eliciting adaptive immune response and sustained tumour regression in tumour-bearing female mice. Our findings provide insights into how to specifically regulate lysosomal function of TAMs for efficient cancer immunotherapy.