Pancreatic cancer remains at a stagnant 5-year survival of <13% attributed to the high heterogeneity and plasticity of these tumors. To circumvent this, we focus on the abundant nuclear protein HMGB2. HMGB2 depletion is key for establishing replicative senescence in normal cells, but it is significantly overexpressed across multiple cancer types. Here, we combine single-cell and spatial genomics with patient-derived organoids and tumor samples to show how increased HMGB2 availability represents a transcriptional addiction fueling cell cycle progression and growth. We repurpose a small molecule inhibitor targeting HMGB2 to interfere with its binding to DNA, restrict chromatin accessibility at promoters, and constrain tumor growth both in vitro and in vivo. 3D chromatin interactions involving HMGB2-bound enhancers and promoters also collapse upon drug treatment. Thus, pharmacological HMGB2 targeting represents a universal strategy for managing cancer progression irrespective of its genetic or molecular characteristics.