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.

三阴性乳腺癌（Triple-negative breast cancer, TNBC）细胞迄今尚未得到有效分型，且目前尚无可用的靶向治疗方案，导致其复发率高且具备转移潜能。本研究中，CD24高表达细胞（CD24high）占三阴性乳腺癌细胞的绝大多数，此类细胞对紫杉醇（Taxol）不敏感，但对铁死亡（ferroptosis）激动剂敏感，且能有效逃脱肿瘤相关巨噬细胞的吞噬作用。此外，NF2-YAP信号轴可调控CD24高表达细胞中铁死亡抑制蛋白1（FSP1）与CD24的表达，进而调控铁死亡过程及巨噬细胞吞噬功能。另外，本研究基于pH环境与谷胱甘肽响应设计了一款精准靶向治疗系统，该系统可有效靶向CD24高表达细胞，通过二氧化碳生成诱导溶酶体逃逸与药物突释，进而通过NF2-YAP信号轴介导的FSP1与CD24抑制，增强铁死亡过程与巨噬细胞吞噬作用。该系统可实现双重抗肿瘤效应，最终促进肿瘤细胞死亡，从而抑制三阴性乳腺癌的生长，部分肿瘤甚至完全消退。本文报道的复合型纳米精准治疗系统，有望成为未来三阴性乳腺癌治疗的潜在策略工具。