Extracellular vesicles shape tumourigenesis: from signalling networks to systemic progression.

Extracellular vesicles (EVs) are established mediators of long-range intercellular communication in cancer, transferring oncogenic and regulatory cargo that reshapes recipient cells across tissues. Recent integrative multi-omics analyses of small EVs (sEVs) from healthy human donors consistently identify TSAP6/STEAP3 among the most abundant and reproducible sEV components, providing a physiological context for its role in sEV biology. Rather than acting solely as a downstream effector of p53, TSAP6 functions within a broader regulatory network by associating with TPT1/TCTP, which engages DDX3 and promotes the incorporation of RNAs, including microRNAs, into sEVs. The resulting p53-TSAP6-TCTP-DDX3 axis constitutes a wide-reaching regulatory system with non-cell-autonomous impact on cellular communication. Notably, TCTP sustains sEV-mediated signalling even in p53-mutant contexts. We suggest that these findings are consistent with other advances in cancer linking oncogenic transformation with EV biology. Together, these observations support regulated EV-mediated information transfer as a mechanism contributing to cancer progression and systemic cellular reprogramming. Conversely, reduction in EV abundance, altered cargo content, or signalling capacity may contribute to the activation of the tumour reversion programme in TCTP-dependent experimental models.