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Cortisol-secreting ACCs are characterized by a worse prognosis, and in these patients, the normalization of hypercortisolism is mandatory and requires an urgent approach to avoid complications related to glucocorticoid excess. Clinical and biochemical parameters, including hormonal values, can be used to define cortisol normalization. However, in patients on concomitant mitotane treatment, serum cortisol and ACTH levels may be falsely altered and thus unreliable for defining cortisol normalization. Adrenal steroidogenesis inhibitors, alone or in combination, are the first-line treatment for severe hypercortisolism in ACC due to their rapid action, efficacy, and safety profile. Mitotane is the cornerstone of ACC treatment in both adjuvant and advanced settings. Similarly, glucocorticoid receptor antagonists also have a rapid onset of action, but their use is limited by challenges in monitoring efficacy and safety. This review aims to address the critical aspects of managing cortisol-secreting ACC, including the definition of hypercortisolism control, current therapeutic approaches and future perspectives for ACC, with a focus to the potential role of immune checkpoint inhibitors.<\/jats:p>","DOI":"10.1007\/s11154-025-09989-y","type":"journal-article","created":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T06:07:07Z","timestamp":1753855627000},"page":"1023-1035","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Management of cushing\u2019s syndrome in patients with adrenocortical cancer: state of the art and future perspectives"],"prefix":"10.1007","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8088-4947","authenticated-orcid":false,"given":"Valentina","family":"Guarnotta","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7143-0775","authenticated-orcid":false,"given":"Antonio","family":"Stigliano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4171-2851","authenticated-orcid":false,"given":"Massimo","family":"Terzolo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6204-3423","authenticated-orcid":false,"given":"Giorgio","family":"Arnaldi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,30]]},"reference":[{"key":"9989_CR1","first-page":"100759","volume":"37","author":"R Lib\u00e9","year":"2023","unstructured":"Lib\u00e9 R, Huillard O. 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