Abstract
Ubiquitin-conjugating enzymes (E2s) are emerging as critical regulators of oncogenic signaling networks by modulating protein stability, localization, and interactome dynamics. Distinct E2s orchestrate ubiquitin chain topology to drive cancer hallmarks including proliferation, immune evasion, metastasis, and metabolic reprogramming. Despite their central role in the ubiquitin-proteasome system, E2s remain underexploited as therapeutic targets. This review systematically maps E2-mediated signaling mechanisms across cancer types and proposes translational strategies for E2-targeted intervention.