Cisplatin Promotes Immunosuppression in Ovarian Cancer by Enhancing miR-181a-5p-Enriched Extracellular Vesicles to...

Although cisplatin (CDDP) is widely employed in combination immunotherapy, no CDDP-based regimen has shown a survival benefit when treating the ovarian cancers. This is mainly because the impact of CDDP on immunotherapy is not fully understood. A critical gap concerns how CDDP reshape the tumour microenvironment, especially through extracellular vesicles (EVs)-mediated communication. In this work, using human and murine ovarian cancer cells as a model, we demonstrate that CDDP boosts the secretion of EVs from cancer cells, while exerting no such effect on non-cancerous cells. These CDDP-induced tumour-derived EVs, in turn, drive the differentiation of CD4⁺ T cells towards immunosuppressive regulatory T cells (T_reg cells), which are known to limit the efficacy of immunotherapy. Based on next-generation sequencing, a significant enrichment of miR-181a-5p was identified in CDDP-induced tumour-derived EVs, and further functional studies confirmed that this microRNA promoted T_reg cell differentiation via suppressing sirtuin 1 (SIRT1), a key regulator of the transcription factor forkhead box protein P3 (FOXP3). Importantly, inhibition of miR-181a-5p abrogated the T_reg-promoting effect of CDDP-induced tumour-derived EVs, a finding further validated in vivo, where blockade of miR-181a-5p not only impaired T_reg differentiation but also restored T-cell-mediated antitumour immunity and restrained tumour growth. Together, these findings uncover a previously unrecognised mechanism by which CDDP exacerbates immunosuppression via miR-181a-5p-enriched EVs and suggest that targeting this pathway could improve the therapeutic efficacy of combination immunotherapy in ovarian cancer.