Polyamines are essential for cellular proliferation, function, and survival, and are highly elevated in cancer cells due to increased metabolic demands. These molecules support the growth and function of immunosuppressive cells like MDSCs, macrophages, and regulatory T-cells, contributing to a tumor-permissive microenvironment. Modulating polyamine metabolism is a promising therapeutic strategy for cancer treatment. This review discusses the roles of polyamines in various TME cell types, the competition for nutrients like polyamine precursors, and their use as biomarkers. Polyamine depletion can enhance immunogenicity and reprogram tumors to respond better to immunotherapy. Polyamine metabolism involves biosynthesis, catabolism, and transport, with key enzymes like ornithine decarboxylase (ODC) and spermidine synthase (SRM) playing critical roles. ODC is regulated by MYC, leading to increased polyamine production in malignant tumors. Polyamines are also involved in epigenetic regulation, affecting DNA methylation and gene expression. The metabolism of arginine, glutamine, and proline contributes to polyamine synthesis, with arginine being a primary source in adult tissues and glutamine serving as an alternative in some cancers. Polyamines are required for the growth and function of all TME cells, including T-cells, macrophages, and cancer-associated fibroblasts. However, tumor cells and immunosuppressive cells deplete polyamines, impairing T-cell function. Polyamines regulate macrophage polarization, with M1 macrophages being pro-inflammatory and M2 macrophages being immunosuppressive. Polyamines also support the growth and immunosuppressive function of myeloid-derived suppressor cells (MDSCs). Polyamines compete with T-cells for arginine, glutamine, and methionine, limiting the availability of these nutrients for pro-inflammatory cells. This competition contributes to immunosuppression in the TME. Polyamine depletion can reprogram the TME to be more immune-permissive, increasing the efficacy of immunotherapy. Clinical trials have shown that polyamine-depleting agents like DFMO and ivospemin can enhance immune responses and improve survival in cancer models. Polyamine metabolism gene expression profiles can serve as prognostic markers for immunotherapy response, with high expression associated with poor outcomes. Polyamines are also potential biomarkers for cancer diagnosis, particularly in immunologically cold tumors. Clinical trials are investigating polyamine-modulating therapies, including DFMO and ivospemin, in various cancer types. Overall, polyamine modulation holds promise as a therapeutic strategy to enhance immunotherapy in cancer.Polyamines are essential for cellular proliferation, function, and survival, and are highly elevated in cancer cells due to increased metabolic demands. These molecules support the growth and function of immunosuppressive cells like MDSCs, macrophages, and regulatory T-cells, contributing to a tumor-permissive microenvironment. Modulating polyamine metabolism is a promising therapeutic strategy for cancer treatment. This review discusses the roles of polyamines in various TME cell types, the competition for nutrients like polyamine precursors, and their use as biomarkers. Polyamine depletion can enhance immunogenicity and reprogram tumors to respond better to immunotherapy. Polyamine metabolism involves biosynthesis, catabolism, and transport, with key enzymes like ornithine decarboxylase (ODC) and spermidine synthase (SRM) playing critical roles. ODC is regulated by MYC, leading to increased polyamine production in malignant tumors. Polyamines are also involved in epigenetic regulation, affecting DNA methylation and gene expression. The metabolism of arginine, glutamine, and proline contributes to polyamine synthesis, with arginine being a primary source in adult tissues and glutamine serving as an alternative in some cancers. Polyamines are required for the growth and function of all TME cells, including T-cells, macrophages, and cancer-associated fibroblasts. However, tumor cells and immunosuppressive cells deplete polyamines, impairing T-cell function. Polyamines regulate macrophage polarization, with M1 macrophages being pro-inflammatory and M2 macrophages being immunosuppressive. Polyamines also support the growth and immunosuppressive function of myeloid-derived suppressor cells (MDSCs). Polyamines compete with T-cells for arginine, glutamine, and methionine, limiting the availability of these nutrients for pro-inflammatory cells. This competition contributes to immunosuppression in the TME. Polyamine depletion can reprogram the TME to be more immune-permissive, increasing the efficacy of immunotherapy. Clinical trials have shown that polyamine-depleting agents like DFMO and ivospemin can enhance immune responses and improve survival in cancer models. Polyamine metabolism gene expression profiles can serve as prognostic markers for immunotherapy response, with high expression associated with poor outcomes. Polyamines are also potential biomarkers for cancer diagnosis, particularly in immunologically cold tumors. Clinical trials are investigating polyamine-modulating therapies, including DFMO and ivospemin, in various cancer types. Overall, polyamine modulation holds promise as a therapeutic strategy to enhance immunotherapy in cancer.