Deubiquitinases at the crossroads of T-cell immunity and tumor immune evasion

Abstract The T-cell-mediated antitumor immune response has emerged as a key axis for controlling cancer growth and progression, as shown by the widespread success of immune checkpoint blockade (ICB). Unfortunately, ICB therapy still fails in a large percentage of patients, and there is a growing need to identify novel targets to increase anticancer immunity and enhance existing treatments. Among emerging therapeutic targets, deubiquitinases (DUBs) have attracted increasing attention because of their central role in regulating ubiquitin signaling. As key components of the ubiquitin system, DUBs catalyze the removal of ubiquitin from substrate proteins, thereby dynamically reversing ubiquitination and fine-tuning protein stability, localization, activity, and protein‒protein interactions. Accumulating evidence indicates that DUBs regulate not only tumor-intrinsic pathways that promote immune evasion but also T-cell activation, differentiation, and effector function, positioning them as promising therapeutic targets at the interface between cancer and immunity. However, DUBs are rarely considered holistically involved in both T-cell immunity and tumor-intrinsic immune evasion, despite the growing appreciation that individual DUBs often act in both compartments. In this review, we comprehensively examine the roles of DUBs in T-cell immunity and tumor-intrinsic immune evasion and discuss perspectives on therapeutic strategies targeting DUBs along this axis.