Background <p>Epithelial ovarian cancer (EOC) has the worst prognosis in all of gynecologic malignant tumors because of its high recurrence. Cellular senescence is widely involved in cancer tumor relapse and metastasis. Hypoxia has a profound impact on malignant progression and participates in modulating senescence; however, the mechanism of inducing senescence by hypoxia in EOC is unclear.</p> Methods <p>Tissue microarrays and immunohistochemistry were used to assess the expression of CSN8 and CD47 in EOC tissues. Tissue microarrays and multiplex fluorescent immunohistochemistry were used to analyze the expression of CSN8, p16, CD68 and CD206 in EOC tissues. The regulatory effects of CSN8 on the senescence of EOC cells were evaluated by EdU, CCK-8, SA-β-gal staining, transwell, ELISA and flow cytometry assays. To investigate the underlying mechanism in regulating senescence by CSN8 in EOC cells, real-time PCR, immunoprecipitation and Western blot assays were utilized. Transplanted tumor models of mice were used to study the antitumor effects of targeting CSN8 combined anti-CD47 therapy.</p> Results <p>CSN8 expression is upregulated in EOC tissues, and CSN8-overexpressed EOC cells exhibit senescence-like features (increased SA-β-gal activity, p16 expression, and SASP production) and robust tumor-promoting properties. An increase in CSN8 + p16+EOC cells in primary tumor tissues correlates with EOC stage, invasion depth, distant metastasis, poor overall survival, and relapse. Furthermore, CSN8-mediated senescence-like EOC cells display unique features, including low ROS production; low p21 expression; low DDR activation; low CD47 expression; and high resistance to senolytic drugs. CSN8 promotes senescence-like EOC cell survival and induces reversible growth arrest by eliminating excessive ROS. These cells shape the immunosuppressive tumor microenvironment by promoting macrophage recruitment and M2-like polarization. CSN8 silencing enhanced sensitivity to chemotherapy and senolytic drugs, and improved the therapeutic effects of anti-CD47 antibody. CSN8 enhanced HIF-1α protein expression and suppressed Skp2 and p21 expression through inhibiting HIF-1α ubiquitination, and promoting Skp2 and p21 ubiquitination, thereby mediating a hypoxia-induced senescence-like state.</p> Conclusions <p>Our studies demonstrated a novel mechanism of inducing a senescence-like state in EOC cells mediated by CSN8 under hypoxia, which correlates with EOC relapse and metastasis. CSN8 + p16+ EOC cells could be exploited as a novel prognostic biomarker for EOC. CSN8 would be an ideal target to eliminate senescence-like tumor cells for treating EOC relapse and metastasis.</p>