WWP2 in immune surveillance and antigen presentation: context-dependent roles in B cells, T cells, and tumor immune escape

Abstract

WWP2 is a NEDD4-family HECT E3 ubiquitin ligase with emerging relevance to immune regulation and cancer immunity. Although WWP2 has been widely studied in tumor growth, fibrosis, and cell signaling, its immune functions are less consistently integrated into current models of cancer immune surveillance. This review summarizes the structural and regulatory features of WWP2 and examines how its substrate- and adaptor-dependent activities influence B cell tolerance, helper T cell responses, innate immune signaling, and tumor immune escape. Particular attention is given to the SUSD6/TMEM127/WWP2 axis, which promotes MHC-I ubiquitination and lysosomal degradation, thereby reducing cell-surface antigen presentation and potentially weakening cytotoxic T cell recognition. By separating immune, tumor-intrinsic, and context-specific mechanisms, we highlight WWP2 as a conditional regulator of antigen presentation rather than a uniformly oncogenic ligase. A more precise understanding of WWP2-dependent immune pathways may support biomarker development and guide therapeutic strategies that restore antigen presentation or selectively disrupt pathogenic adaptor-ligase interactions.