Cytoreductive nephrectomy in the era of immune-checkpoint inhibitors: back to the future?

To investigate the role of cytoreductive nephrectomy (CN) in metastatic renal cell carcinoma (mRCC) treated with immune-checkpoint inhibitors (ICIs).

A narrative review was carried out using PubMed and searching for English articles published from January 2015 to May 2025.

After the screening process, 12 retrospective studies comparing outcomes in patients with mRCC treated with ICI-based regimens, with or without CN (either upfront or deferred) were deemed eligible. Of those, six indicated a survival benefit for patients undergoing CN in combination with ICIs with hazards ratios ranging from 0.19 to 0.63, a finding that remains consistent within the upfront CN subgroup. However, the included studies' retrospective nature, inherent selection, and immortal time biases limit definitive conclusions. Ongoing phase III randomised trials, NORDIC-SUN (ClinicalTrials.gov identifier: NCT03977571) and Southwest Oncology Group (SWOG)-1931 (also known as PROBE; NCT04510597), are evaluating the role of deferred CN after initial ICI therapy, while the role of upfront CN in the ICI era will be likely elucidated by SEVURO-CN (NCT05753839) trial.

Our findings highlight reconsidering the importance of CN in the ICI era, potentially driven by the influence of tumour burden on anti-cancer immunity and the limited efficacy of ICIs against primary tumours. Future research, ideally through randomised trials involving patients suitable for safe surgery, should aim to clarify the optimal timing of CN in the context of ICI therapy.