Dysfunction of CD58 in tumor immune evasion: from mechanistic regulation to therapeutic resistance

Abstract CD58, the primary ligand of the co-stimulatory receptor CD2, plays a crucial role in the formation of the immunological synapse (IS) and the initiation of antitumor immunity involving T cells and natural killer (NK) cells. Aberrant CD58 expression, resulting from genomic inactivation, epigenetic silencing, transcriptional repression, and post-translational modifications, disrupts the architecture of the IS, impairs T and NK cell activation and effector functions, and promotes an immunosuppressive microenvironment. Consequently, restoring CD58 expression or function has emerged as a promising therapeutic strategy, with approaches such as epigenetic drugs to reverse CD58 silencing, engineered T cells to restore CD2 co-stimulation, and neutralizing agents targeting soluble CD58. In this review, we summarize the current understanding of how CD58 expression is regulated across multiple dimensions and how its dysfunction drives immune evasion and therapy resistance. We also explore the therapeutic potential of targeting the CD58-CD2 axis in cancer treatment, aiming to provide novel theoretical insights and innovative strategies to advance cancer immunotherapy.