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The acellular fraction of this ascitic fluid contains tumor-promoting soluble factors, bioactive lipids, cytokines, and extracellular vesicles, all of which communicate with the tumor cells within this peritoneal fluid. Metabolomic profiling of ovarian cancer ascites has revealed significant differences in the pathways of fatty acids, cholesterol, glucose, and insulin. The proteins involved in these pathways promote tumor growth, resistance to chemotherapy, and immune evasion. Unveiling the key role of this liquid tumor microenvironment is crucial for discovering more efficient treatment options. This review focuses on the cholesterol and insulin pathways in ovarian cancer, identifying statins and metformin as viable treatment options when combined with standard chemotherapy. These findings are supported by clinical trials showing improved overall survival with these combinations. Additionally, statins and metformin are associated with the reversal of T-cell exhaustion, positioning these drugs as potential combinatory strategies to improve immunotherapy outcomes in ovarian cancer patients.<\/jats:p>","DOI":"10.3390\/ijms25010323","type":"journal-article","created":{"date-parts":[[2023,12,25]],"date-time":"2023-12-25T23:00:12Z","timestamp":1703545212000},"page":"323","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Enhancing Immunotherapy in Ovarian Cancer: The Emerging Role of Metformin and Statins"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4270-7701","authenticated-orcid":false,"given":"Diana Lu\u00edsa","family":"Almeida-Nunes","sequence":"first","affiliation":[{"name":"Differentiation and Cancer Group, Institute for Research and Innovation in Health (i3S) of the University of Porto, 4200-135 Porto, Portugal"},{"name":"1H-TOXRUN\u2014One Health Toxicology Research Unit, University Institute of Health Sciences, CESPU, CRL, 4585-116 Gandra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9270-2717","authenticated-orcid":false,"given":"Ricardo","family":"Silvestre","sequence":"additional","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal"},{"name":"ICVS\/3B\u2019s\u2014PT Government Associate Laboratory, 4710-057 Braga, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7430-6297","authenticated-orcid":false,"given":"Ricardo Jorge","family":"Dinis-Oliveira","sequence":"additional","affiliation":[{"name":"1H-TOXRUN\u2014One Health Toxicology Research Unit, University Institute of Health Sciences, CESPU, CRL, 4585-116 Gandra, Portugal"},{"name":"UCIBIO-REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4169-007 Porto, Portugal"},{"name":"Department of Public Health and Forensic Sciences, and Medical Education, Faculty of Medicine, University of Porto, 4169-007 Porto, Portugal"},{"name":"FOREN\u2014Forensic Science Experts, 1400-136 Lisboa, Portugal"}]},{"given":"Sara","family":"Ricardo","sequence":"additional","affiliation":[{"name":"Differentiation and Cancer Group, Institute for Research and Innovation in Health (i3S) of the University of Porto, 4200-135 Porto, Portugal"},{"name":"1H-TOXRUN\u2014One Health Toxicology Research Unit, University Institute of Health Sciences, CESPU, CRL, 4585-116 Gandra, Portugal"},{"name":"Faculty of Medicine, University of Porto, 4169-007 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1016\/j.semcancer.2022.03.004","article-title":"Emerging Perspectives on Growth Factor Metabolic Relationships in the Ovarian Cancer Ascites Environment","volume":"86","author":"Monavarian","year":"2022","journal-title":"Semin. 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