{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:36:37Z","timestamp":1785411397207,"version":"3.56.0"},"reference-count":195,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T00:00:00Z","timestamp":1777507200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000780","name":"European Union","doi-asserted-by":"publisher","award":["uniri-mzi-25-19"],"award-info":[{"award-number":["uniri-mzi-25-19"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]},{"award":["uniri-mzi-25-19"],"award-info":[{"award-number":["uniri-mzi-25-19"]}],"id":[{"id":"https:\/\/ror.org\/019w4f821","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Renal cell carcinoma (RCC) is acknowledged as a heterogeneous malignancy underlined by complex genetic, metabolic, and immune dysregulation. In particular, molecular studies have revealed distinct oncogenic mechanisms that have been exploited and studied as therapeutic intervention targets. These include hypoxia-driven signaling, chromosomal translocations, and gene fusion events that affect tumor progression. This review provides a comprehensive overview of these targets and rethinks RCC management. Therapeutic concepts include the targeting of genomic fusion biology with emerging cell-based immunotherapies or targeted molecular inhibition, and orthomolecular therapeutic strategies are presented. Two clinical and pathological features are highlighted\u2014namely, the TFE3 fusion proteins in translocation RCC and the growing role of hypoxia-inducible factor-2\u03b1 (HIF-2\u03b1) inhibitors in clear-cell RCC. We also present recent data on novel immunotherapeutic approaches, including autologous hematopoietic stem and progenitor cell-based interferon-\u03b1 gene therapy, as well as chimeric antigen receptor T-cell therapy. These therapies are discussed in light of their mechanistic rationale, translational potential, and existing clinical challenges due to unwanted side effects. At last, orthomolecular and natural product-based therapies are reviewed for their potential as adjunctive therapies that might be used for oxidative stress management, the targeting of tumor metabolism and immune effects, and to increase standard treatment tolerance. This review points to a multidimensional framework that might support further research and studies in precision-guided RCC management, as integrative approaches may enhance therapeutic efficacy, reduce toxicity, and support the development of personalized interventions for advanced or treatment-resistant RCC.<\/jats:p>","DOI":"10.3390\/cancers18091435","type":"journal-article","created":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T10:47:28Z","timestamp":1777546048000},"page":"1435","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Rethinking Advanced Renal Cell Carcinoma: Integrative Genomics, Immunotherapy, and Molecular\u2013Orthomolecular Strategies"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-1621-8802","authenticated-orcid":false,"given":"Marijana","family":"Tur\u010di\u0107","sequence":"first","affiliation":[{"name":"Teaching Institute of Public Health of Primorsko-Goranska County, Kre\u0161imirova 52a, 51000 Rijeka, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristian","family":"Krpina","sequence":"additional","affiliation":[{"name":"Department of Urology, Clinical Hospital Center Rijeka, Tome Stri\u017ei\u0107a 3, 51000 Rijeka, Croatia"},{"name":"Department of Urology, Faculty of Medicine, University of Rijeka, Bra\u0107e Branchetta 20, 51000 Rijeka, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dragan","family":"Trivanovi\u0107","sequence":"additional","affiliation":[{"name":"Department of Oncology and Hematology, General Hospital Pula, Santorijeva 24a, 52200 Pula, Croatia"},{"name":"Faculty of Medicine, Juraj Dobrila University of Pula, Zagreba\u010dka 30, 52100 Pula, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7706-6858","authenticated-orcid":false,"given":"Kre\u0161imir","family":"Paveli\u0107","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Juraj Dobrila University of Pula, Zagreba\u010dka 30, 52100 Pula, Croatia"},{"name":"International Academy of Science and Arts in Bosnia and Herzegovina, Radni\u010dka cesta, 71000 Sarajevo, Bosnia and Herzegovina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0491-673X","authenticated-orcid":false,"given":"Sandra","family":"Kraljevi\u0107 Paveli\u0107","sequence":"additional","affiliation":[{"name":"Department of Basic Medical Sciences, Faculty of Health Studies, University of Rijeka, Viktora Cara Emina 5, 51000 Rijeka, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.cancergen.2024.06.002","article-title":"Cancer treatments: Past, present, and future","volume":"286\u2013287","author":"Sonkin","year":"2024","journal-title":"Cancer Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"383","DOI":"10.4132\/jptm.2022.08.16","article-title":"What\u2019s new in kidney tumor pathology 2022: WHO 5th edition updates","volume":"56","author":"Tretiakova","year":"2022","journal-title":"J. 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