Polyamines are small, positively charged molecules that play crucial roles in cellular functions such as chromatin remodeling, immune cell modulation, and cellular survival. Cancer cells elevate their polyamine levels through increased metabolism and uptake, which supports their survival and promotes an immunosuppressive tumor microenvironment (TME). The TME is characterized by a high concentration of polyamines, which are essential for the growth and function of various cell types, including tumor cells, immune cells, and stromal cells. This review discusses the roles of polyamines in the TME, the impact of polyamine competition on cellular landscapes, and the potential of polyamine depletion as a therapeutic strategy. Polyamine metabolism involves biosynthesis, catabolism, and transport. Key enzymes include ornithine decarboxylase (ODC), spermidine synthase (SRM), and spermine synthase (SMS). Polyamines are also linked to arginine, glutamine, and methionine metabolism, with arginine being a semi-essential amino acid that supports both tumor-suppressive and tumor-permissive functions. Glutamine can serve as an alternative precursor to ornithine, and proline and citrulline are other important metabolites. In the TME, polyamines are required for the development and activation of T-cells, but tumor cells and immunosuppressive cells deplete polyamine availability, dampening T-cell function. Polyamines support the survival and function of myeloid cells, such as tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), and cancer-associated fibroblasts (CAFs), which promote tumor progression and angiogenesis. Endothelial cells, which are crucial for angiogenesis, also rely on polyamines for proliferation. Depletion of polyamines can reprogram the TME into a more immune-permissive phenotype by recruiting pro-inflammatory cells, reducing immunosuppressive cells, and enhancing T-cell function. Difluoromethylornithine (DFMO), an irreversible ODC inhibitor, has shown promise in clinical trials for cancer treatment and immunomodulation. DFMO treatment can reduce polyamine levels, increase T-cell activity, and enhance the efficacy of immunotherapy. Additionally, polyamine metabolism gene expression profiles can serve as prognostic markers for response to immunotherapy, and polyamines themselves can be used as biomarkers for cancer diagnosis. In conclusion, polyamines are pivotal in influencing the tumor microenvironment, and pharmacological modulation of polyamine metabolism offers a promising therapeutic strategy to enhance the immune response and improve cancer treatment outcomes.Polyamines are small, positively charged molecules that play crucial roles in cellular functions such as chromatin remodeling, immune cell modulation, and cellular survival. Cancer cells elevate their polyamine levels through increased metabolism and uptake, which supports their survival and promotes an immunosuppressive tumor microenvironment (TME). The TME is characterized by a high concentration of polyamines, which are essential for the growth and function of various cell types, including tumor cells, immune cells, and stromal cells. This review discusses the roles of polyamines in the TME, the impact of polyamine competition on cellular landscapes, and the potential of polyamine depletion as a therapeutic strategy. Polyamine metabolism involves biosynthesis, catabolism, and transport. Key enzymes include ornithine decarboxylase (ODC), spermidine synthase (SRM), and spermine synthase (SMS). Polyamines are also linked to arginine, glutamine, and methionine metabolism, with arginine being a semi-essential amino acid that supports both tumor-suppressive and tumor-permissive functions. Glutamine can serve as an alternative precursor to ornithine, and proline and citrulline are other important metabolites. In the TME, polyamines are required for the development and activation of T-cells, but tumor cells and immunosuppressive cells deplete polyamine availability, dampening T-cell function. Polyamines support the survival and function of myeloid cells, such as tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), and cancer-associated fibroblasts (CAFs), which promote tumor progression and angiogenesis. Endothelial cells, which are crucial for angiogenesis, also rely on polyamines for proliferation. Depletion of polyamines can reprogram the TME into a more immune-permissive phenotype by recruiting pro-inflammatory cells, reducing immunosuppressive cells, and enhancing T-cell function. Difluoromethylornithine (DFMO), an irreversible ODC inhibitor, has shown promise in clinical trials for cancer treatment and immunomodulation. DFMO treatment can reduce polyamine levels, increase T-cell activity, and enhance the efficacy of immunotherapy. Additionally, polyamine metabolism gene expression profiles can serve as prognostic markers for response to immunotherapy, and polyamines themselves can be used as biomarkers for cancer diagnosis. In conclusion, polyamines are pivotal in influencing the tumor microenvironment, and pharmacological modulation of polyamine metabolism offers a promising therapeutic strategy to enhance the immune response and improve cancer treatment outcomes.