Copper-Bacteriochlorin Nanosheet as a Specific Pyroptosis Inducer for Robust Tumor Immunotherapy

Abstract

Pyroptosis is increasingly considered a new weathervane in cancer immune therapy. However, triggering specific pyroptotic tumor cell death while preserving normal cells still remains a major challenge. Herein, a brand-new pyroptosis inducer, copper-bacteriochlorin nanosheet (Cu-TBB), is designed. The synthesized Cu-TBB can be activated to an "on" state in the tumor microenvironment with glutathione (GSH) overexpression, leading to the release of Cu⁺ and TBB, respectively. Intriguingly, the released Cu⁺ can drive cascade reactions to produce O₂ ^-• and highly toxic ·OH in cells. Additionally, the released TBB can also generate O₂ ^-• and ¹ O₂ upon 750 nm laser irradiation. Encouragingly, both Cu⁺ -driven cascade reactions and photodynamic therapy pathways result in potent pyroptosis along with dendritic cell maturation and T cell priming, thus simultaneously eliminating the primary tumors and inhibiting the distant tumor growth and metastases. Conclusively, the well-designed Cu-TBB nanosheet is shown to trigger specific pyroptosis in vitro and in vivo, leading to enhanced tumor immunogenicity and antitumor efficacy while minimizing systemic side effects.

Keywords: Cu-bacteriochlorin; immunogenicity pyroptosis; reactive oxygen species; tumor microenvironment.