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, CD24high 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 CD24high 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 CD24high 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.