Emerging regulatory model of Ubiquitin-Specific Proteases 14 in cancer: from canonical oncogenesis to TME modulation, therapeutic resistance, and non-canonical activities

BACKGROUND: Ubiquitin-Specific Protease 14 (USP14) is a proteasome-associated deubiquitinase historically viewed as a pro-tumorigenic driver of the ubiquitin-proteasome system (UPS) by stabilizing oncoproteins. Recent evidence expands this view, positioning USP14 as a central regulator that integrates tumor cell-intrinsic malignancy, tumor microenvironment (TME) remodeling, and resistance to multiple therapies. Importantly, USP14 exerts functions beyond canonical deubiquitination, including non-catalytic and scaffolding activities, and is subject to complex allosteric regulation. MAIN BODY: This review synthesizes emerging regulatory crosstalks that broaden the functional landscape of USP14 in cancer. We first outline the dynamic allosteric regulatory network of USP14 and its activation modes, emphasizing post-translational modifications (PTMs)-notably phosphorylation and lactylation-that modulate USP14 activity and connectivity beyond traditional links to cell cycle control and metabolism. We then consolidate the signaling frameworks through which USP14 contributes to resistance across therapeutic modalities, including targeted therapies, chemotherapy, radiotherapy, and immunotherapy, highlighting both shared and treatment-specific mechanisms. In parallel, we discuss context-dependent tumor-suppressive roles of USP14 and detail its non-catalytic scaffolding functions that reshape signaling outputs independent of enzymatic activity. Collectively, these classical and non-classical mechanisms depict USP14 as a systems-level coordinator of oncogenic signaling, adaptive stress responses, and microenvironmental interactions. CONCLUSIONS: By integrating catalytic and non-catalytic functions with PTM-driven allosteric regulation, we propose a unified regulatory model in which USP14 operates as a master node connecting malignancy, TME dynamics, and therapeutic resistance. This framework provides strategic guidance for developing next-generation allosteric inhibitors and combination strategies aimed at overcoming clinical drug resistance and exploiting context-specific vulnerabilities in USP14-regulated networks.