Targeting neddylation in cancer: molecular mechanisms, translational advances, and therapeutic challenges

Neddylation is a ubiquitin-like post-translational modification that regulates cullin–RING ligases and selected non-cullin substrates involved in cell-cycle progression, DNA replication licensing, DNA-damage repair, apoptosis, hypoxic signaling, inflammatory responses, epithelial–mesenchymal transition, metabolic adaptation, and immune regulation. Many tumors rely on aberrant neddylation-dependent protein turnover to sustain proliferation, survival, metastatic plasticity, and therapeutic resistance, making this pathway a compelling anticancer target. This review outlines the molecular architecture of the NEDD8 cascade, encompassing NEDD8 activation, E2-mediated conjugation, E3/co-E3-facilitated ligation, deneddylation, and the central role of cullin–RING ligases as oncogenic effectors. It also examines the principal classes of neddylation-pathway inhibitors, including the first-in-class NEDD8-activating enzyme inhibitor MLN4924, newer NAE inhibitors such as TAS4464, emerging UBE2M- and UBE2F-directed approaches, DCN1/DCUN1-targeted inhibitors, and natural product-derived or other experimental compounds. Preclinical evidence across hematologic malignancies, gastrointestinal and genitourinary cancers, thoracic and head-and-neck tumors, brain tumors, and pediatric cancers indicates that neddylation inhibition can suppress tumor growth and enhance responses to chemotherapy, radiotherapy, apoptosis-targeted agents, proteasome inhibition, autophagy modulation, and immunotherapy. Nevertheless, clinical translation remains constrained by inadequate patient selection, context-dependent substrate accumulation, adaptive resistance, complex immune effects, and limited therapeutic windows. Future development should therefore move beyond empirical pan-pathway inhibition toward biomarker-guided, tumor-context-specific precision strategies integrating selective E1, E2, and E3 inhibitors, rational combination regimens, pharmacodynamic monitoring, resistance profiling, immune-state assessment, and tumor-targeted delivery systems.