Cisplatin Promotes Immunosuppression in Ovarian Cancer by Enhancing miR‐181a‐5p‐Enriched Extracellular Vesicles to Drive Regulatory T Cell Differentiation

ABSTRACT

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.