Targeting TYRO3 attenuates apoptotic cell–driven cancer stemness in triple negative breast cancer

Apoptosis is a prevalent feature of the tumor microenvironment, driven not only by the rapid cellular turnover of high-grade cancers but also by chemotherapeutic agents. Although accumulating apoptotic cells can paradoxically support cancer cell survival and contribute to tumor recurrence, the roles of apoptotic cells in triple-negative breast cancer (TNBC) have not been elucidated. TYRO3, a receptor tyrosine kinase frequently overexpressed in cancers, plays a pivotal role in malignant progression. Here, we demonstrate that aggressive breast cancer cells exploit TYRO3 as a phosphatidylserine (PS)–sensing receptor to interact with apoptotic cells. We investigated whether apoptotic cell–induced TYRO3 activation promotes cancer stemness. Expression of stemness markers NANOG and OCT4 was evaluated by immunoblottings and quantitative polymerase-chain-reaction, and spheroid formation assays were performed to functionally validate stemness. YAP nuclear translocation upon TYRO3 activation was assessed by nuclear fractionation, confocal microscopy, and dual-luciferase reporter assay. To validate the functional role of the TYRO3/YAP signaling axis, TYRO3 and YAP knockdown models were established by CRISPR/Cas9 or retroviral system. The anti-tumor efficacy of KRCT87, a selective TYRO3 inhibitor, was assessed in mouse models of tumor recurrence and tumor formation. Apoptotic cells activated TYRO3 in aggressive breast cancer cells, enhancing stem-like properties and promoting tumor recurrence. Co-culture with apoptotic cells enhanced spheroid formation and upregulated stemness markers in TNBC cells, which were abolished by TYRO3 knockdown. Mechanistically, TYRO3 activation led to YAP nuclear translocation, which was responsible for stemness induction, as YAP knockdown suppressed this effect. In vivo xenograft studies demonstrated that TYRO3 inhibition suppressed tumor recurrence and apoptotic cells-induced tumor formation. Our findings indicate that apoptotic cells in the tumor microenvironment enhance cancer cell stemness and facilitate recurrence through TYRO3 activation. Neoadjuvant treatment with a TYRO3 inhibitor may represent a promising strategy to prevent breast cancer relapse.