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Late diagnosis, low drug selectivity, high toxicity, and treatment resistance are challenges associated with pharmacological interventions. The commonly used therapies include surgery, radiotherapy, hormonal therapy, immunotherapy, and chemotherapy. Recently, Cu complexes have been studied owing to their biological functions and effects on tumor angiogenesis. In this review, we examined 23 types of cancer and revealed the use of cell lines. The synthesis of Cu complexes with ligands such as phenanthroline and thiosemicarbazones has also been reported. Such co-ligation is promising because of its high cytotoxicity and selectivity. Compared with cisplatin, Cu complexes, especially mixed complexes, showed better interactions with DNA, generating reactive oxygen species and inducing apoptosis. Nanoformulations have also been adopted to improve the pharmacological activity of compounds. They enhance the efficacy of complexes by targeting them to the tumor tissue, thereby improving their safety. Studies have also explored Cu complexes with clinically relevant pharmacophores, suggesting a \u201chybrid chemotherapy\u201d against resistant tumors. Overall, Cu complexes have demonstrated therapeutic versatility, antitumor efficacy, and reduced adverse effects, showing great potential as alternatives to conventional chemotherapy and justifying future clinical investigations to validate their use.<\/jats:p>","DOI":"10.3390\/molecules30102104","type":"journal-article","created":{"date-parts":[[2025,5,9]],"date-time":"2025-05-09T06:18:51Z","timestamp":1746771531000},"page":"2104","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Innovative Approaches in the Synthesis and Optimization of Copper Complexes for Antitumor Therapies: A Comprehensive Review"],"prefix":"10.3390","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3300-5073","authenticated-orcid":false,"given":"Clara Maria Faria","family":"Silva","sequence":"first","affiliation":[{"name":"Laboratory of Cytogenetics, Institute of Biotechnology, Federal University of Uberl\u00e2ndia, Campus Umuarama, St. Piaui s\/n, Uberl\u00e2ndia 38405-320, MG, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7667-0671","authenticated-orcid":false,"given":"Ricardo Campos","family":"Lino","sequence":"additional","affiliation":[{"name":"Laboratory of Cytogenetics, Institute of Biotechnology, Federal University of Uberl\u00e2ndia, Campus Umuarama, St. Piaui s\/n, Uberl\u00e2ndia 38405-320, MG, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariana Cristina Teixeira","family":"de Moura","sequence":"additional","affiliation":[{"name":"Laboratory of Cytogenetics, Institute of Biotechnology, Federal University of Uberl\u00e2ndia, Campus Umuarama, St. Piaui s\/n, Uberl\u00e2ndia 38405-320, MG, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Paula","family":"de S\u00e1 Borges","sequence":"additional","affiliation":[{"name":"Academic Institute of health and biological Sciencies, State University of Goi\u00e1s, UnU Itumbiara, Av. Modesto de Carvalho, s\/n, District Agro. Industrial, Itumbiara 75536-100, GO, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8453-3194","authenticated-orcid":false,"given":"Robson Jos\u00e9","family":"de Oliveira J\u00fanior","sequence":"additional","affiliation":[{"name":"Laboratory of Cytogenetics, Institute of Biotechnology, Federal University of Uberl\u00e2ndia, Campus Umuarama, St. Piaui s\/n, Uberl\u00e2ndia 38405-320, MG, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. 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