Belatacept and non-melanoma skin cancer risk in kidney transplant recipients: a narrative review from a mechanistic and clinical perspective.

Non-melanoma skin cancer is a prevalent complication in renal transplant recipients due to long-term immunosuppressive therapy. Calcineurin inhibitors, such as tacrolimus and cyclosporine, are effective in preventing graft rejection; however, they significantly increase the risk of non-melanoma skin cancer through broad immunosuppressive and pro-oncogenic mechanisms. Belatacept, a selective co-stimulation blocker targeting the CD80/CD86-CD28 axis, has emerged as a mechanistically distinct alternative with potential benefits for oncologic and renal outcomes. The primary objective of this review is to examine the impact of belatacept-based immunosuppression on the incidence and progression of non-melanoma skin cancer in renal transplant recipients, compared to conventional Calcineurin inhibitors. Secondary objectives include evaluating the immunologic mechanisms underlying its distinct cancer risk profile, exploring combinatory regimens (particularly with mammalian target of rapamycin inhibitors), assessing metabolic and nephrotoxic implications, and addressing ethical and clinical considerations in switching stable patients from Calcineurin inhibitors to belatacept. Although retrospective studies suggest a lower incidence of non-melanoma skin cancer with belatacept, robust prospective data remain limited, and its use is associated with increased early rejection and post-transplant lymphoproliferative disorder risk, particularly in Epstein-Barr virus seronegative patients. Emerging molecular biomarkers and transcriptomic insights may facilitate the development of personalized immunosuppression strategies. Further randomized controlled trials and longitudinal studies are essential to clarify belatacept's oncologic safety and optimize immunosuppressive protocols in high-risk transplant populations.