Targeted Intervention of NF2–YAP Signaling Axis in CD24-Overexpressing Cells Contributes to Encouraging Therapeutic Effects in TNBC

Triple-negative breast cancer (TNBC) cells have not been usefully classified, and no targeted therapeutic plans are currently available, resulting in a high recurrence rate and metastasis potential. In this research, CD24^high cells accounted for the vast majority of TNBC cells, and they were insensitive to Taxol but sensitive to ferroptosis agonists and effectively escaped phagocytosis by tumor-associated macrophages. Furthermore, the NF2-YAP signaling axis modulated the expression of ferroptosis suppressor protein 1 (FSP1) and CD24 in CD24^high cells, with subsequent ferroptotic regulation and macrophage phagocytosis. In addition, a precision targeted therapy system was designed based on the pH level and glutathione response, and it can be effectively used to target CD24^high cells to induce lysosomal escape and drug burst release through CO₂ production, resulting in enhanced ferroptosis and macrophage phagocytosis through FSP1 and CD24 inhibition mediated by the NF2-YAP signaling axis. This system achieved dual antitumor effects, ultimately promoting cell death and thus inhibiting TNBC tumor growth, with some tumors even disappearing. The composite nanoprecision treatment system reported in this paper is a potential strategic tool for future use in the treatment of TNBC.