Polyamine Metabolism in Cancer: Drivers of Immune Evasion, Ferroptosis, and Therapy Resistance

Polyamines putrescine, spermidine and spermine are small, positively charged metabolites indispensable for DNA stabilization, chromatin remodelling, RNA translation and redox balance, with dynamic distribution across the nucleus, mitochondria and endoplasmic reticulum. In cancer, polyamine homeostasis becomes profoundly dysregulated through altered biosynthesis, degradation and transport, driving malignant phenotypes and therapy resistance. Therefore, there is an urgent need to develop precision techniques that combine polyamine metabolism with immunotherapeutic and redox-based therapies, identify biomarkers to predict therapy response and create logical combination regimens to overcome resistance. The existing literature lacks in providing a holistic view of how polyamine dynamics intersect with diverse cancer hallmarks. Thus, this review consolidates emerging evidence on the multifaceted roles of polyamines in cancer hallmarks, with a particular focus on their impact on efferocytosis, ferroptosis and the dynamics of polyploid giant cancer cells (PGCCs). Furthermore, a comprehensive evaluation of contemporary treatment approaches that focus on polyamine metabolism, including transport blockers, biosynthesis inhibitors and various polyamine analogues, was discussed. While addressing context-dependent effects of polyamines that impede therapeutic progress, our discussion also incorporates important findings from pre-clinical and clinical investigations. Going forward, this review aims to enlighten and direct future translational research by situating polyamine biology within the broader context of cancer evolution and treatment adaptation.