Polyamine homeostasis is tightly coupled to tumor-cell proliferation, metabolic reprogramming, stress adaptation, and immune escape. Ornithine decarboxylase antizyme 1 (OAZ1) is a central negative regulator of this network. When intracellular polyamine levels increase, the ribosome shifts one nucleotide downstream and switches to a new reading frame during translation of OAZ1 mRNA, thereby enabling the production of the full-length active OAZ1 protein. OAZ1 then restrains polyamine accumulation through two complementary mechanisms. It binds ornithine decarboxylase (ODC), inhibits enzyme activity, promotes dissociation of the active ODC homodimer, and facilitates ubiquitin-independent proteasomal degradation of ODC, thereby reducing endogenous putrescine synthesis. In parallel, OAZ1 suppresses the polyamine transport system (PTS), limiting the uptake of extracellular polyamines that may compensate for reduced biosynthesis. Recent studies have reshaped the concept of the mammalian PTS. Rather than a single plasma-membrane transporter, it is now viewed as a multicomponent and compartmentalized network involving cell-surface enrichment by heparan sulfate proteoglycans, caveolin-associated endocytosis in selected cellular contexts, endosomal or lysosomal escape mediated by P5B-type ATPases such as ATP13A3 and ATP13A2, vesicular storage mediated by SLC18B1, and acetylation-coupled export mediated by spermidine/spermine N1-acetyltransferase 1 (SAT1) and the SLC3A2-associated diamine exporter pathway. These findings provide a broader framework for understanding how tumor cells maintain high polyamine availability even when synthesis is pharmacologically inhibited. However, several fundamental questions remain unresolved. The direct PTS targets recognized by OAZ1 have not been identified, the structural basis by which polyamine-induced OAZ1 dimerization contributes to transport inhibition is still unclear, and the relationship between dysregulation of the OAZ1-PTS axis and therapeutic responses varies among tumor types. In this review, we summarize the molecular mechanisms of OAZ1 polyamine sensing, programmed frameshift translation, ODC inhibition and degradation, and feedback control of polyamine uptake. We also integrate recent advances on ATP13A2, ATP13A3, ATP13A4, SLC3A2, SLC18B1, SAT1, and related transport or export modules, and compare their alterations in neuroblastoma, lung cancer, prostate cancer, colorectal cancer, hepatocellular carcinoma, breast cancer, pancreatic cancer, leukemia, glioma, and oral squamous cell carcinoma. Particular attention is given to tumor-type specificity. MYCN-driven neuroblastoma appears to depend on both enhanced biosynthesis and compensatory uptake, lung and prostate cancer models provide functional evidence for OAZ1-dependent feedback repression of uptake, hepatocellular carcinoma highlights the immunological role of acetylated-polyamine efflux, and breast and pancreatic cancer studies suggest nonredundant contributions of ATP13 family members. Finally, we discuss translational strategies that aim to mimic or restore the dual negative-feedback function of OAZ1, including difluoromethylornithine (DFMO), AMXT1501-based polyamine blockade therapy, ATP13A3-directed intervention, targeting of AZIN1-OAZ1 antagonism, and modulation of SAT1-SLC3A2-associated acetylated-polyamine export. Future work should combine transport assays, interaction mapping, spatial omics, metabolomics, and immune profiling to define actionable biomarkers, such as OAZ1, AZIN1, ODC, ATP13A3, SLC3A2, SAT1, and tumor polyamine signatures. Such biomarkers will be important for selecting patients, monitoring target engagement, and designing combinations with chemotherapy, targeted therapy, or immune checkpoint blockade. A better understanding of the OAZ1-PTS axis may support biomarker-guided patient stratification and rational combination therapies targeting polyamine dependence and the immunometabolic tumor microenvironment.