The CD155-TIGIT Signaling Axis in NK Cell Immune Evasion in Tumors: Mechanisms, Synergy with TGF-β, and Combined Intervention Strategies

Abstract

Although significant progress has been made in cancer immunotherapy, the issue of immune resistance has become an increasingly important issue. NK cell dysfunction is the key factor contributing to poor treatment response. The CD155-TIGIT signaling axis serves as the core pathway mediating tumor cell immune evasion, however, the outcome of clinical trials concerning about T cell immunoreceptor with Ig and ITIM domains (TIGIT) blockade alone in Phase III settings has failed to meet expectations. It suggests the existence of synergistic inhibitory mechanisms. This review systematically integrates and finds that TGF-β not only directly suppresses NK cell function but also upregulates cluster of differentiation 155 (CD155) expression on tumor cells through both classical and non-classical pathways. Therefore, it is able to amplify TIGIT-mediated negative signaling. More notably, a positive feedback loop may exist between CD155 and TGF-β, mutually reinforcing each other to form an immunosuppressive circuit. The clinical challenges of TIGIT inhibitors highlight the need for combination intervention strategies. At present, the precise molecular mechanisms and general relevance of this feedback loop remain to be explored. Based on these gaps, this review discusses four key parts: the inhibitory effects of the CD155-TIGIT axis on NK cells; the dual suppressive mechanisms of TGF-β and their positive feedback loop; current clinical challenges in targeting these pathways; and combined intervention strategies of TIGIT/TGF-β bispecific antibodies. The aim is to provide theoretical guidance for optimizing NK cell-based cancer immunotherapy.