Abstract
Tumor-associated macrophages (TAMs) play an essential role in tumor therapeutic resistance. Although the lethal effect of ferroptosis on tumor cells is well reported, how TAMs inhibit the effect of ferroptosis in tumors has not been clearly defined. In this study, it is demonstrated that TAM-secreted taurine suppresses ferroptosis in prostate cancer (PCa) by activating the Liver X receptor alpha/Stearoyl-Coenzyme A desaturase 1 (LXRα/SCD1) pathway. Blocking taurine intake via inhibition of taurine transporter TauT restores the sensitivity to ferroptosis in tumors. Furthermore, LXRα activates the transcription of both miR-181a-5p and its binding protein FUS to increase the recruitment of miR-181a-5p in tumor-derived extracellular vesicles (EVs). It is observed that macrophages appear to be recipient cells of the miR-181a-5p-enriched EVs. Intake of miR-181a-5p in macrophages promotes their M2 polarization and enhances the taurine export by inhibiting expression of its target gene lats1, which in turn inactivates the hippo pathway and results in a Yes-associated protein (YAP) nuclear translocation for transcriptional activation of both M2 polarization-related genes such as ARG1 and CD163 and the taurine transport gene TauT. Taken together, the findings indicate a reciprocal interaction between PCa cells and TAMs as a positive feedback-loop to repress ferroptosis in PCa, mediated by TAM-secreted taurine and tumor EV-delivered miR-181a-5p.