Ovarian cancer (OC) represents the most frequent gynecological malignancy, accounting for the seventh most common female tumor and the eighth leading cause of death in the female population worldwide, showing a 5-year survival rate of 49% (Sung et al., 2021). Epithelial OC (EOC) is the most frequent subtype (95%), whereas non-epithelial ovarian tumors, arising from the sex cord, stroma and, rarely, from germ cells, represents only 5%. The most common subtype of EOC is the high-grade serous OC (HGSOC), followed by endometrioid (10%) and clear cell (10%) subtypes, low-grade serous carcinoma (<5%), and the mucinous type (3%) (Lheureux et al., 2019a). These histological subtypes differ for molecular features, prognosis, survival rates, therapy response, risk factors, and type of dissemination (Lheureux et al., 2019b). Age, tumor histology, performance status, volume of residual disease, and presence of tumor-infiltrating lymphocytes (TILs) are considered the main prognostic factors, able to predict the clinical outcome of OC patients. A poor prognosis is favoured by the high tumour heterogeneity and therapy resistance (Rojas et al., 2016). The risk of OC is particularly increased in a small proportion of women (15–20%) harbouring germline pathogenic variants in the BRCA1 and BRCA2 genes and other homologous recombination genes (Incorvaia et al., 2020, Bono et al., 2021).

Among all subtypes, HGSOC shows the highest immunogenic potential, because its tumour microenvironment (TME) is characterized by the abundant presence of tumor-infiltrating immune cells, which are capable to modulating immune response (Fanale et al., 2022a). Recent studies suggested an interesting prognostic role of plasma immune checkpoints, such as PD-L1/PD-1, and other circulating immunomodulatory proteins in HGSOC women (Fanale et al., 2023, Fanale et al., 2022b).

In the last years, specific tumor-derived extracellular vesicles (EVs), called exosomes, have been shown to be potential key players in cross-talk between immune system and TME in several solid tumors, because of their ability to act as natural intercellular shuttles carrying signalling molecules involved in the interplay between cancer cells and neighbouring cells (Giallombardo et al., 2016). Exosomes were initially considered as a vehicle used by cells to eliminate waste material, but then the characterization of their content allowed to better define their role as mediators of intracellular communication. They are nanosize vesicles carrying lipids, proteins, and nucleic acids, such as DNA, RNA, and non-coding RNAs (ncRNAs), able to induce phenotypic reprogramming of target cells (Cammarata et al., 2022a, Fanale et al., 2018). Among the bioactive molecules present within exosomes, those that have attracted the most interest by the scientific community are microRNAs (miRNAs), due to their role as mediators of post-transcriptional gene silencing (Cammarata et al., 2022b, Pucci et al., 2018). The miRNAs are a heterogeneous family of small non-coding RNAs (19–22 nucleotides), which, through the regulation of the gene expression, may control several signalling pathways, including cell cycle, proliferation, apoptosis and DNA damage repair (Bronte et al., 2016). A significant amount of miRNAs may be released by tumor-derived exosomes and disseminated in the extracellular space, where they act on target cells of TME with either tumor suppressor or oncogenic functions (Pucci et al., 2018).

On the basis of this evidence, the aim of this review is to discuss the promising role of miRNAs shuttled by exosomes, called exosomal miRNAs (exo-miRNAs), as potential biomarkers for early detection, tumour progression and metastasis, prognosis, and response to therapy in OC patients, by providing an overview of main exo-miRNAs and their gene targets involved in major cellular signalling pathways.