Abstract Senescent cell-derived extracellular vesicles (senEVs) serve as crucial signaling mediators in senescence. To elucidate the role of senEVs in inflammatory responses to senescence, we established and validated an engraftment-based senescence model in wild-type mice, enabling genetic blockade of senEV release in vivo . Our findings reveal that senEVs play a pivotal role in orchestrating the rapid clearance of senescent cells and suppressing tumor recurrence. In the absence of senEVs, recruitment of MHC-II+ antigen presenting cells into the senescence microenvironment was significantly impaired. Additionally, inhibition of senEV release redirected the primary target of senescent cell signaling from antigen presenting cells to neutrophils. Furthermore, antigen presenting cells recruited and activated CCR2+ T H17 cells, resulting in the inhibition of B cell activation. Through multimodal transcriptional and proteomic analyses, we identified six ligands specific to senEVs, implicating their involvement in promoting cell adhesion. Collectively, our findings suggest that senEVs complement the activity of secreted inflammatory mediators by recruiting and activating distinct immune cell subsets, thus facilitating the efficient clearance of senescent cells.

Senescent cell-derived extracellular vesicles recruit antigen presenting cells and limit squamous carcinoma recurrence