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The combination of nivolumab and ipilimumab has demonstrated durable responses and survival benefits; however, approximately 20%\u201325% of patients exhibit primary resistance and derive limited clinical benefit. This review provides a comprehensive overview of current evidence regarding the incidence, clinical predictors, and biological mechanisms of primary resistance to nivolumab plus ipilimumab in mRCC. Key contributing factors include an immunosuppressive tumor microenvironment, metabolic reprogramming, interferon signaling abnormalities, and T\u2010cell exhaustion. Potential strategies to overcome resistance, such as vascular endothelial growth factor receptor\u2013targeted combinations, biomarker\u2010driven treatment selection, and novel immune checkpoint targets, are also discussed. A deeper understanding of primary resistance will be essential for the development of mechanism\u2010based therapeutic strategies and for achieving durable clinical benefit in patients with mRCC.<\/jats:p>","DOI":"10.1111\/iju.70597","type":"journal-article","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T06:08:05Z","timestamp":1789020485000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Primary Resistance to Immune Checkpoint Inhibitor Combination Therapy in Metastatic Renal Cell Carcinoma: Focus on Nivolumab Plus Ipilimumab"],"prefix":"10.1111","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5899-1738","authenticated-orcid":false,"given":"Kazuyuki","family":"Numakura","sequence":"first","affiliation":[{"name":"Department of Renal and Urologic Surgery Asahikawa Medical University  Asahikawa 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