Intercellular Horizontal Transfer of TXNDC5 mRNA via Extracellular Vesicles Contributes to Tumor‐Associated Macrophage‐Mediated Prostate Cancer Metastasis

ABSTRACT As one of the predominant male malignancies globally, prostate cancer (PCa) transitions to a treatment‐refractory phase upon metastasis, for which no curative modalities currently exist. Tumor‐associated macrophages (TAMs), a crucial component of the tumor microenvironment (TME), primarily adopt a metastasis‐promoting M2 phenotype. However, the mechanisms underlying the TAM‐cancer cell crosstalk and resultant PCa metastasis remain elusive. In this study, primary lesions of metastatic PCa (mPCa) exhibit both greater infiltration of M2 macrophages and a higher proportion of M2 macrophage‐derived extracellular vesicles (M2 EVs) compared to those of non‐metastatic PCa (nmPCa). Furthermore, M2 EVs can be internalized by PCa cells, promoting a mesenchymal‐like state (MLS) in PCa and affecting tumor metastasis. Mechanistically, thioredoxin domain‐containing 5 ( TXNDC5 ) mRNA encapsulated in M2 EVs contributes to MLS of DU145 and PC3 cells, enhancing migration and invasion. Single‐vesicle particle analysis confirms that TXNDC5 mRNA encapsulated within M2 EVs can be horizontally transferred to target cells, where it is translated to produce functional proteins. In conclusion, our study demonstrates that M2 macrophages can promote MLS and metastasis of PCa through EV‐mediated horizontal mRNA transfer. A novel role of EVs in the communication between the TME and tumor cells is discovered, offering new insights into tumor metastasis.