Many types of malignant tumors exhibit dysregulation of polyamine metabolism, characterized by the accumulation of elevated polyamine levels in cancerous tissues.

Altered polyamine metabolism affects epigenetic modifications in tumor cells, contributing to their phenotypic transformation. In cells where polyamine synthesis is inhibited, the activity of AMD1 is elevated, leading to a reduced concentration of SAM, the major donor of DNA methyl groups, and an increased concentration of decarboxylated SAM (dcSAM), a potent inhibitor of DNA methyltransferase (DNMT) (as shown in Figures 1 , 3 ). While polyamine deprivation does not alter the protein levels of DNMT, it regulates methylation levels by activating DNMT1, 3A, and 3B, resulting in a genome-wide aberrant methylation state (39), where methylation is promoted in certain regions and suppressed in others (40). Changes in methylation status can modulate chromatin accessibility, triggering aberrant gene transcriptional activity and genomic instability, which may drive tumorigenesis. Additionally, oncogenes can influence epigenetic modifications by regulating key metabolic pathway enzymes. Hongde Li et al. revealed the YAP/TAZ-polyamine-eIF5A-Hyp-LSD1 axis, linking polyamine-mediated eIF5A hypusination to oncogenic signaling and epigenetic remodeling (41).

There is evidence that polyamines play a vital part in epigenetic modification of normal tissues, but the mechanism in cancer tissues needs to be explored.

Polyamine levels are elevated in many human cancers (42), serving as metabolites that regulate numerous cellular processes (43). Polyamines are recognized as overexpressed tumor biomarkers in several cancer types, including breast and prostate cancers, Polyamines are recognized as overexpressed tumor biomarkers in several cancer types, including breast and prostate cancers, and their levels tend to increase with the grade of malignancy (44). Under hypoxia conditions, ODC induces and stimulates the uptake of exogenous polyamines and the biosynthesis of intracellular polyamines, resulting in elevated levels of putrescine and spermidine. After HT-29 colon cancer cells were exposed to spermine, hypoxia-induced CD44 cell adhesion protein expression was further reduced, and tumor cell migration, invasion and metastasis were promoted. Consumption of polyamines with DFMO during hypoxia increases apoptosis in multiple cancer cell lines, suggesting that hypoxic tumor cells have increased demand for polyamines (24). Furthermore, it has been shown that antizyme inhibitors (AZIN1), which promote production of polyamines, increase IL-8 by postponing c-Myc degradation via the OAZ2-mediated ubiquitin independent proteasome pathway (45), thus promoting tumor angiogenesis. The increased rates of RNA-edited AZIN1 in human malignancies are associated with increased tumor angiogenesis, improved cancer cell stemness, and increased cancer cell proliferation (46). Additionally, putrescine, spermidine, and spermine are critical metabolites in mammalian tissues, playing significant roles in cell cycle regulation, with brain tumor growth often relying entirely on exogenous spermidine supply (47). Increased polyamine levels in brain tumors correlate with heightened ODC activity. Upregulation of ODC is evident in all astrocytomas, ventricular meningiomas, and meningiomas compared to non-tumorigenic brain tissues, increasing with malignancy grade (48).

To summarize, polyamine-mediated hypoxia, angiogenesis, and cancer cell stemness and cell cycle dynamics all result in cancer cells development and metastasis, implying a potential target for anticancer therapies.

Drug resistance in certain tumors complicates treatment strategies. Recent studies suggest a positive association between polyamines and drug resistance in tumors. For instance, Byung-Sun Park et al. demonstrated that AMD1, a key enzyme in A375 melanoma responsible for vemurafenib resistance, upregulates polyamine synthesis, thereby increasing mitochondrial activity and promoting resistance (49) Vemurafenib is commonly used to treat melanoma with BRAF V600E mutations, but tumor resistance diminishes its therapeutic efficacy. Inhibiting polyamine synthesis has been shown to help overcome vemurafenib resistance in melanoma (49).

Additionally, therapies targeting SAT1 can help overcome chemotherapy resistance in patients with PDAC (31). Aberrant expression or stimulation of SAT1 can restore cisplatin sensitivity in cell culture systems (50). α-Difluoromethylornithine (DFMO) has been shown to reduce resistance to poly(ADP-ribose) polymerase (PARP) inhibitors in ovarian cancer, acting as an effective adjuvant chemotherapy (51). In TNBC, known for its resistance to chemotherapy and poor prognosis, existing studies indicate that inhibiting polyamine synthesis improves chemotherapy sensitivity (52). Collectively, these studies suggest that inhibiting polyamine synthesis and metabolism may help address therapeutic challenges in drug-resistant tumors, providing new hope for treatment. Furthermore, certain polyamine-related drugs can also mitigate tumor drug resistance; for example, the combination of a novel arylmethyl-polyamine (AP) with the BRAF inhibitor (PLX4720) significantly delays recurrence in PLX4720-resistant melanoma (53). Additionally, homospermidineplatin (4a) effectively inhibits in situ tumor growth and reverses cisplatin resistance (54).

There is a unique post-translational modification called hypusination, which occurs on a specific lysine residues of a known protein eIF5a and the hypusinated effects of polyamine-dependent eIF5a have been shown to be important in controlling T cell metabolism and function. Spermidine has been demonstrated to activate autophagy in cardiomyocytes, neurons, satellite cells, CD8⁺ T cells, and B cells (55). eIF5a hypusination declines as the body ages (56), nevertheless, it can augment the anti-tumor efficacy of CD8⁺ T cells lymphocytes by directly targeting mitochondrial trifunctional protein (MTP) (57), and can be reinstated with dietary supplementation with spermidine (58). Numerous results indicate that spermidine prolongs lifespan across species in an autophagy-dependent manner and mitigates cancer and age-related illnesses, such as cardiovascular disease and dementia (55, 59, 60). Spermidine, however, is notable for its regulation of CD4⁺ T cell development in vitro, preferring directing early T cells towards a regulatory phenotype. Following spermidine treatment, activated T cells deficient in the autophagy gene Atg5 exhibited a diminished capacity to upregulate Foxp3 compared to wild-type cells. The findings indicate that the polarizing impact of spermidine necessitates a functional autophagic system (61). Furthermore, tumor cells generated endogenous spermidine, which reduced plasma membrane cholesterol levels, consequently reducing CD8⁺ T cell antigen receptor aggregation and obstructing T cell activation (62). Furthermore, putrescine obstructs the development of cytolytic T lymphocytes (CTLs), thereby undermining anti-tumor immunity (59).

In summary, the hypusinated effects of polyamine-dependent eIF5A can enhance the anti-tumor effects of CD8⁺ cells directly via MTP and can be restored by dietary supplementation. In addition, tumor cells can release endogenous spermidine, which blocks T cell activation and thus suppresses anti-tumor immunity. Whether these mechanisms are consistent in different requires more research to verify.

The SREBP-cMyc axis is essential for the de novo production of polyamines, which subsequently facilitates NK cell metabolism and functionality (63). SREBP and cMyc are two significant metabolic regulators of NK cells.

Myc is a crucial regulator of immune cell activity and function (27), the rate-limiting enzyme in polyamine production. During the progression of colon cancer, compromised energy production in tumor cells facilitates the consumption of NK cell polyamines by these cells, which inhibits cMyc in NK cells and disrupts their glycolysis, ultimately diminishing their cytotoxic ability (64). The findings indicated that NK cells may counteract the inhibitory effects of cMyc and the disruption of glycolytic energy supply, thereby reinstating the cytotoxic activity of NK cells following the administration of a specific amount of spermidine. The findings indicate that cMyc-regulated polyamine levels and glycolytic availability are essential for the immunological function of NK cells (64). In colon cancer, the administration of exogenous polyamines can enhance tumor proliferation and glycolysis, fulfill the tumor’s requirements, and prevent the invasion of the intestinal mucosa by tumor consumption of polyamines (64). In RPMI-8402 cells, DMSO prompted a cMyc-dependent reduction in ODC activity and consequent depletion of intracellular polyamine levels, correlating with programmed cell death and cell growth arrest (65).

The sterol regulatory element binding protein (SREBP) is another regulator that modulates cMyc expression via cytokines IL-2 and IL-12, therefore facilitating the de novo synthesis of polyamines (63). The induction of SREBP target genes relies on the mammalian target of rapamycin complex 1 (mTORC1), and SREBP activation is heightened in cytokine-stimulated NK cells. Furthermore, it has been demonstrated that mTORC1 inhibition does not influence cMyc expression in NK cells activated by IL-2 and IL-12 (66). Experimental data indicated that supplementing NK cells with impaired SREBP activity with exogenous polyamines only partially restored NK cell function, implying that additional SREBP-regulated processes or endogenously synthesized polyamines are crucial for enhancing NK cell effector function (63).

Spermine catalyzes the substrate for eIF5a via the sequential actions of the enzymes deoxyhydroxylase (DHPS) and deoxyhydroxylase (DOHH), with all proteins in this pathway expressed in cytokine-activated NK cells, which regulate the de novo synthesis of polyamines to supply substrates for catalepsy.

As mentioned above, SREBP and cMyc are two significant metabolic regulators of NK cells. The induction of SREBP is dependent on mTORC1, and SREBP activation is increased under cytokine stimulation, and cMyc expression is inhibited, but inhibition of mTOR1 does not affect cMyc expression in NK cells. In addition, the depredation of polyamines inhibited cMyc, thus reducing the killing activity of NK cells, and supplementing exogenous polyamines could restore its function to a certain extent.

Polyamines are significant immunomodulators that influence macrophage polarization and are crucial in tumorigenesis. Recent studies indicate that polyamines can facilitate the alternative activation of OXPHOS-dependent macrophages, suppress the classical activation of aerobic glycolysis-dependent macrophages, and polarize macrophages towards the M2 phenotype via polyamine (4). Spermidine serves as a substrate for the production of conserved lysine residues in polyamine-eIF5A-hypusine axis. The hypusinated form of eIF5A (eIF5A^H) enhances the effective production of specific mitochondrial proteins associated with the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) (67). Furthermore, it has been shown that spermine-induced M2 polarization is facilitated by mitochondrial reactive oxygen species (mtROS). mtROS activates AMP-activated protein kinase (AMPK), which induces the upregulation of HIF-1α and autophagy, essential for the production of M2-associated genes such as Arg1 and Chil3 (68). Nakamura et al. discovered that exogenous putrescine prompted metabolic reprogramming similar to IL-4 activation (69).

Polyamines can potentially influence macrophage functions, including pro-inflammatory and anti-inflammatory actions. Spermine efficiently enhances interleukin-10 (IL-10) production in macrophages while suppressing the synthesis of pro-inflammatory cytokines such as tumor necrosis factor (TNF), IL-1, IL-12, IL-6, IFN-γ, and MIP-1β (70). Similarly, spermidine selectively inhibits the secretion of TNF-α, IL-1β, IL-12, and chemokine monocyte chemoattractant protein-1(MCP-1) by macrophages, directly downregulates NOD-like receptor protein 3 (NLRP3) inflammasome activation in these cells, and lowers the co-stimulatory molecules CD80 and CD86 to suppress M1-type macrophages (71). Furthermore, the impact of polyamines on cytokines is intricately associated with the concentration and classification of polyamines (72). Putrescine inhibited macrophage polarization to the M1 phenotype by down-regulating IL-8 (73).

Taken together, polyamines participate in regulating the differentiation process of macrophages and thereby facilitate the establishment of an immunosuppressive tumor microenvironment.

MDSC-induced L-arginine depletion decreased CD 3⁺ expression in activated T cells and suppressed antigen-specific proliferation of OT-1 and OT-2 cells (74). Numerous investigations have shown that polyamines activate myeloid-derived suppressor cells in an inhibitory manner and facilitate their metabolism. The V-domain suppressor of T cell activation (VISTA)/STAT3/polyamine axis recently regulates the development of myeloid cells into MDSC.VISTA triggers STAT3, which facilitates MDSC development through the initiation of a transcriptional and metabolic pathway (75).

In addition, research has shown that polyamines can be synthesized by dendritic cells or by Arg1⁺ myeloid-derived suppressor cells. They govern the conversion of dendritic cells into an indoleamine 2,3-dioxygenase 1(IDO1)-dependent immunosuppressive state by activating Src kinases that possess IDO1 phosphorylation activity (76). Gervais et al. discovered that the incorporation of putrescine into the milieu of dendritic cells inhibited their capacity to effectively cross-present exogenous antigens, leading to diminished immunological functionality of dendritic cells (77).

Cytokine regulation is influenced by polyamine metabolism. Spermine has been demonstrated to act as a metabolic inhibitor of Janus kinase (JAK) signaling. Spermine directly engages with the N-terminal structural domain of JAK1, disrupting the interaction between JAK1 and cytokine receptors, which consequently inhibits JAK1 phosphorylation induced by cytokines IFN-I, IFN-II, IL-2, and IL-6 (78). Additionally, it does not influence the membrane localization or mRNA expression of interferon α/β receptor (IFNAR)1 and IFNAR2 in target cells.

Moreover, polyamines participate in the inflammatory response via SMOX, functioning as either a positive or negative regulator of inflammatory variables contingent upon the unique tissue environment and the method of polyamine replenishment (79). Polyamines can enhance the expression of inflammatory factors under specific conditions. Following infection with Citrobacter rodentium, levels of the chemokines CCL 2, CCL 3, CCL 4, CXCL 1, CXCL 2, and CXCL 10, together with the cytokines IL 6, TNF α, CSF 3, IFN γ, and IL 17, were significantly raised in the colon. All of these factors were down-regulated in mice deficient in Smox. Conversely, in the dextran sodium sulfate(DSS)-induced colitis paradigm, the concentrations of IL-6, CSF-3, and IL-17 were significantly increased in mice deficient in Smox (80). In a colitis-associated cancer (CAC) model treated with oxidized azomethine (AOM)-DSS, SMOX deficiency correlated with exacerbation of CAC, heightened production of α-defensins, and supplementation with spermidine ameliorated these phenotypes, functioning as a preventive agent in CAC (81). Inflammatory factors are chemotactic and facilitate the function of immune cells in suppressing the growth and migration of cancer cells (82). A significant characteristic of the tumor microenvironment is persistent inflammation, and research on polyamines and inflammation may elucidate a survival strategy for tumor cells to circumvent the immune response.

Polyamines are crucial for cellular proliferation, and neoplasms necessitate elevated levels of polyamines, which promote angiogenesis, augment biomass through enhanced protein translation, facilitate the survival and metastasis of epithelial tumor cells, influence the production, viability, and functionality of tumor-infiltrating immune cell subsets, and suppress organismal immunity, thereby aiding tumors in evading immune responses. Consequently, polyamine metabolism, transport, and catabolism are often dysregulated in cancer (83). Stringent regulation of enzymes implicated in polyamine production, transport, and catabolism can impede tumor proliferation. Inhibitors of nearly all enzymes involved in polyamine synthesis, transport, and catabolism have been identified to date (as illustrated in Table 1 ).

Ornithine decarboxylase is the principal rate-limiting enzyme in polyamine production, and DFMO is the most prevalent irreversible inhibitor of ODC. Numerous experimental studies have demonstrated that DFMO possesses oncostatic properties. DFMO can reduce neuroblastoma at clinically significant levels by targeting cells critical for neuroblastoma carcinogenesis (84). DFMO can inhibit PDAC via suppressing MYC (85). DFMO is presently FDA-approved for the treatment of African sleeping sickness; nevertheless, it has not yet achieved widespread recognition for cancer therapy. DFMO is associated with toxicity; for instance, it may induce hearing loss even at low dosages (86). Moreover, DFMO diminishes intracellular polyamines and suppresses tumor cell proliferation across several model systems, yet it does not demonstrate substantial anticancer efficacy (87). Furthermore, many innovative polyamine synthesis inhibitors, like clofazimine (CLF), also impede multiple myeloma through the aryl hydrocarbon receptor/polyamine biosynthesis axis (88). Drugs such as AMXT1501 and Trimer44NMe inhibit tumor growth and diffusion by inhibiting polyamine transport. In conclusion, as an effective polyamine synthesis blocker, DFMO shows certain potential for cancer treatment, but the accompanying toxicity and the body’s compensatory mechanisms limit its effectiveness in tumor treatment.

Single DFMO agents exhibit restricted therapeutic efficacy in clinical tumors, and DFMO-mediated inhibition of ODC induces a compensatory mechanism whereby tumor cells augment the uptake of exogenous polyamines, including those present in the tumor microenvironment, dietary metabolites, microbiota, and particularly from decidualized or damaged cells in the intestinal lumen (24). Tracy Murray Stewart et al. established that the suppression of cell proliferation due to DFMO-induced polyamine depletion was mitigated by exogenous N8-acetylspermidine (at physiological concentrations), which was metabolized to spermine exclusively in cell lines exhibiting histone deacetylase-10 (HDAC10) activity (89). Combination medicines have demonstrated superior efficacy relative to monotherapy. For example, DFMO increases the anti-tumor activity of PARP inhibitors in the treatment of ovarian cancer⁴.

The inhibition of polyamine synthesis activates a compensatory mechanism in the body, rendering direct inhibition of polyamine synthase minimally effective in treating advanced cancers. In contrast, polyamine analogs can effectively disrupt this compensatory mechanism by promoting the catabolism of polyamines without substituting the growth support function of natural polyamines. Intracellular accumulation of polyamine analogs selectively enhances the activities of SSAT and SMOX, hence promoting polyamine catabolism and reducing their production (42). Numerous symmetrically substituted polyamine analogs demonstrate regulation of polyamine metabolism in vitro and show efficacy in preclinical and clinical cancer studies. The chemicals consist of diethylenedihydroxyhomospermine (SBP-101), N1,N12-bis(ethyl)-cis-dehydrogenated spermine (PG-11047), and N1,N11-bis(ethyl)nordemethylspermine (BENSpm). The outcomes of BENSpm Phase I and Phase II clinical trials were unsatisfactory (99), exhibiting neurotoxicity, but PG-11047 is altered by the configuration of the central cis-double bond and demonstrates a reduced incidence of adverse clinical effects (100). PG-11047 is a second-generation unsaturated analog of the polyamine spermine, exhibiting antitumor activity against prostatic, pulmonary, colorectal, and breast malignancies (100–102). Certain clinical trials have demonstrated that the amalgamation of PG-11047 with cytotoxic and anti-angiogenic chemotherapeutic agents (gemcitabine, docetaxel, bevacizumab, erlotinib, cisplatin, 5-fluorouracil) in patients with advanced, refractory metastatic solid tumors or lymphomas sustains stable disease (103).

SBP-101 decreased cell viability in lung, pancreatic, and ovarian cancers in vitro, demonstrated efficacy in decelerating the growth of pancreatic tumors both in vitro and in vivo, and is presently undergoing clinical evaluation for pancreatic cancer (104). Recent advancements in nanomedicine have led to the development of nanostructures featuring polyamine analog backbones, termed nanopolyamines. Comparable nanostructures including non-polyamine backbones have demonstrated transport through endocytosis, potentially serving as a mechanism for delivering polyamine analogs that circumvents polyamine transport (105). Self-consuming prodrug nanoparticles can also be utilized for the delivery of therapeutic nucleic acids and other drug payloads (42). For instance, Nano11047, derived from PG11047, is a biodegradable prodrug nanocarrier designed to target polyamine metabolism, serving both an innovative drug formulation and a potential vehicle for nucleic acid delivery (106). Ao Yu et al. successfully synthesized bioactive polycationic prodrugs (FPaP) derived from BENSpm, partially modified with perfluoroalkyl groups. FPaP F-PaP/siRNA nanoparticles were encapsulated in hyaluronic acid (HA) to create the ternary nanoparticles HA@F-PaP/siRNA.RNA interference (RNAi) is a novel approach to cancer therapy that necessitates the use of delivery vehicles. RNA interference (RNAi) represents a novel therapeutic strategy for cancer treatment, necessitating the use of delivery vectors, whereas HA@F-PaP/siRNA improves the delivery of siRNA within tumor cells (107). Polyamine analogs are another option for cancer treatment as an alternative to polyamine synthase inhibitors. Polyamine analogs not only play a role in inhibiting polyamine synthesis, but also serve as delivery vectors to carry nucleic acids and other substances.