Quaternary Nanobomb Triggered Ferroptosis and Pyroptosis Enhance Immunogenicity and Immunotherapy of Triple Negative Breast Cancer

Abstract

Reversing immunosuppressive "cold" tumor into immunoresponsive "hot" tumor is the principle for immunotherapy of immunosuppressive tumors, such as triple-negative breast cancer (TNBC). In this study, the "Quaternary Nanobomb" of MnO₂-shelled Chlorin e6 (Ce6), Polydopamine (PDA), Arginine (Arg), and CO₂ is prepared, namely BCPA-CO₂@MnO₂. In the weakly acidic tumor microenvironment (TME) or the lysosome of TNBC cells (4T1 cell line), MnO₂ is rapidly degraded to Mn²⁺, while CO₂ and the large number of guanidine-mediated proton sponge effects (PSE) accelerate the "explosive release" of Ce6 and PDA. The result demonstrates that the BCPA-CO₂@MnO₂ disrupts intracellular ion homeostasis and exerts glutathione oxidase (GSH-Ox), catalase (CAT), and peroxidase-like activities, thereby accelerating the process of ferroptosis in 4T1 cells. Under dual near-infrared (NIR) irradiation (660 and 808 nm), the pyroptosis and immunogenic cell death (ICD) are effectively triggered by the nascent reactive oxygen species (ROS), reactive nitrogen species (RNS), and thermal effects. Ferroptosis, pyroptosis, Mn²⁺, and ICD-mediated damage-associated molecular patterns (DAMPs) release synergistically activate the cGAS-STING pathway, innate/adaptive immunity, thereby boosting TNBC immunogenicity and immune memory to enhance immunotherapy efficacy.

Keywords: cGAS‐STING pathway; ferroptosis; immunogenicity; proton sponge effect (PSE); pyroptosis.