ABSTRACT Kidney transplant recipients (KTRs) are at increased risk of developing cutaneous squamous cell carcinoma (cSCC), particularly when treated with calcineurin inhibitors (CNI), which are strongly associated with tumorigenesis. In contrast, mTOR inhibitors such as sirolimus have demonstrated antitumor activity, but their role in secondary prevention of cSCC remains unclear. We conducted a systematic review and meta‐analysis of randomized controlled trials (RCTs) to evaluate the impact of switching from a CNI‐based to an mTOR inhibitor‐based immunosuppressive regimen on the incidence of cSCC in KTRs with prior cSCC. MEDLINE, EMBASE, CENTRAL, and trial registries were searched through June 2025. Incidence rate ratios (IRRs) for cSCC and risk ratios (RRs) for adverse events (AEs) were pooled using a random‐effects model. Risk of bias was assessed with Cochrane RoB2. The study was registered in PROSPERO prior to data extraction (CRD42024583966). The study was unfunded. Four RCTs (393 patients) were included. Sirolimus significantly reduced 2‐year cSCC incidence (IRR 0.51, 95% CI 0.39–0.67). However, discontinuation was more frequent (RR 8.60, 95% CI 1.95–37.93) due to AEs. No significant differences in mortality or graft rejection were found. Certainty of evidence was high for cSCC incidence and low for adverse events due to heterogeneity and selective reporting. In conclusion, sirolimus reduces secondary cSCC risk but increases AEs; patient selection and monitoring are essential. Trial Registration: PROSPERO number: CRD42024583966
Foerster et al. (Sat,) studied this question.