Harnessing the TNF-TNFR pathway for graft tolerance: Selective immunomodulation in islet transplantation

Islet transplantation represents a promising treatment for patients with insulin-dependent diabetes or unstable glycemic control. However, its widespread application faces two major challenges: a severe shortage of donor organs and persistent immune rejection. Recent studies consistently indicate that broad blockade of the TNFR signaling pathway is insufficient for controlling autoimmune inflammation. Instead, selectively attenuating the pro-inflammatory TNFR1 pathway while enhancing the anti-inflammatory TNFR2 pathway may offer a more effective strategy. This review is the first to explore, from an islet transplantation perspective, the potential of selective TNFR pathway targeting to promote graft tolerance. We specifically highlight the emerging role of regulatory B cells (Bregs) as key mediators in this process, and propose that targeted enhancement of their immunosuppressive function—particularly through the TNF-TNFR2 signaling axis—represents a promising therapeutic strategy to promote the induction of regulatory T cells (Tregs) and achieve durable transplant tolerance.