Targeting deubiquitinating enzymes in cancer: navigating context-dependence for precision medicine

Abstract The ubiquitin-proteasome system (UPS) is a master regulator of protein homeostasis, and its dysregulation is a well-established driver of oncogenesis, metastasis, and therapeutic resistance. Deubiquitinating enzymes (DUBs), which stabilize proteins by counteracting ubiquitination, have emerged as critical nodal points in cancer signaling networks. This review systematically synthesizes evidence from seminal and recent literature to provide a comprehensive analysis of the UPS, focusing on the classification, structural diversity, and multifaceted roles of DUBs in tumor biology. We examine in detail the intricate interplay between DUBs and key oncogenic pathways, including DNA damage response, apoptosis, and epithelial-to-mesenchymal transition. Our synthesis highlights the profound context-dependent functions of DUBs, which can be either oncogenic or tumor-suppressive depending on their specific substrates and the cellular milieu. Mounting evidence underscores the therapeutic potential of targeting DUBs, with advances in small-molecule inhibitors and emerging DUB-targeting chimeras (DUBTACs) showing promise in restoring proteostatic balance. However, clinical translation faces significant hurdles, primarily the need for high selectivity to minimize off-target effects and manage toxicity, as underscored by the termination of VLX1570s clinical trials. We argue that the successful clinical translation of DUB inhibitors hinges on a precision medicine framework, relying on biomarker-driven patient selection to define therapeutic context and minimize toxicity. By synthesizing these intricate regulatory mechanisms, this review aims to catalyze the development of novel, targeted intervention strategies, ultimately improving cancer treatment outcomes and patient survival.