Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Spermine synthase engages in macrophages M2 polarization to sabotage antitumor immunity in hepatocellular carcinoma

Cell Death & Differentiation volume 32, pages 573–586 (2025)Cite this article

Subjects

Abstract

Disturbances in tumor cell metabolism reshape the tumor microenvironment (TME) and impair antitumor immunity, but the implicit mechanisms remain elusive. Here, we found that spermine synthase (SMS) was significantly upregulated in tumor cells, which correlated positively with the immunosuppressive microenvironment and predicted poor survival in hepatocellular carcinoma (HCC) patients. Via “subcutaneous” and “orthotopic” HCC syngeneic mouse models and a series of in vitro coculture experiments, we identified elevated SMS levels in HCC cells played a role in immune escape mainly through its metabolic product spermine, which induced M2 polarization of tumor-associated macrophages (TAMs) and subsequently corresponded with a decreased antitumor functionality of CD8+ T cells. Mechanistically, we discovered that spermine reprogrammed TAMs mainly by activating the PI3K-Akt-mTOR-S6K signaling pathway. Spermine inhibition in combination with immune checkpoint blockade effectively diminished tumor burden in vivo. Our results expand the understanding of the critical role of metabolites in regulating cancer progression and antitumor immunity and open new avenues for developing novel therapeutic strategies against HCC.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: HCC progression is enhanced by SMS in dependence of immune microenvironment.
Fig. 2: SMS of tumor cells polarizes macrophages to M2 phenotype.
Fig. 3: Spermine acts as the executor in SMS-driven M2 polarization of macrophages.
Fig. 4: Dysfunction of CD8+ T cells are evoked by SMS at the presence of macrophages.
Fig. 5: SMS modulates M2 polarization via the PI3K-Akt-mTOR-S6K signaling pathway.
Fig. 6: Blockade of spermine strengthens anti-PD-1 therapy efficacy for HCC.
Fig. 7: Elevated SMS expression level positively correlates with CD163 expression in HCC patients.

Similar content being viewed by others

Data availability

All data are available in the main text or supplementary information (RNA-seq data can be found in GSE277581, GSE277457). The data that supports the findings of current study are available from the corresponding author upon reasonable request.

References

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Ca Cancer J Clin 2021;71:209–49.

    Article  PubMed  Google Scholar 

  2. Vogel A, Meyer T, Sapisochin G, Salem R, Saborowski A. Hepatocellular carcinoma. Lancet. 2022;400:1345–62.

    Article  PubMed  CAS  Google Scholar 

  3. Llovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, et al. Hepatocellular carcinoma. Nat Rev Dis Prim. 2021;7:6.

    Article  PubMed  Google Scholar 

  4. Fang Y, Zhan Y, Xie Y, Du S, Chen Y, Zeng Z, et al. Integration of glucose and cardiolipin anabolism confers radiation resistance of HCC. Hepatology. 2022;75:1386–401.

    Article  PubMed  CAS  Google Scholar 

  5. Yang C, Zhang H, Zhang L, Zhu AX, Bernards R, Qin W, et al. Evolving therapeutic landscape of advanced hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2023;20:203–22.

    Article  PubMed  Google Scholar 

  6. Cheng AL, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, et al. Updated efficacy and safety data from IMbrave150: atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma. J Hepatol 2022;76:862–73.

    Article  PubMed  CAS  Google Scholar 

  7. Rimassa L, Finn RS, Sangro B. Combination immunotherapy for hepatocellular carcinoma. J Hepatol. 2023;79:506–15.

    Article  PubMed  CAS  Google Scholar 

  8. Dai E, Wang W, Li Y, Ye D, Li Y. Lactate and lactylation: behind the development of tumors. Cancer Lett. 2024;591:216896.

    Article  PubMed  CAS  Google Scholar 

  9. Xiao S, Ma S, Sun B, Pu W, Duan S, Han J, et al. The tumor-intrinsic role of the m6A reader YTHDF2 in regulating immune evasion. Sci Immunol. 2024;9:eadl2171.

    Article  PubMed  CAS  Google Scholar 

  10. Martínez-Reyes I, Chandel NS. Cancer metabolism: looking forward. Nat Rev Cancer. 2021;21:669–80.

    Article  PubMed  Google Scholar 

  11. Vitale I, Manic G, Coussens LM, Kroemer G, Galluzzi L. Macrophages and metabolism in the tumor microenvironment. Cell Metab. 2019;30:36–50.

    Article  PubMed  CAS  Google Scholar 

  12. Kao KC, Vilbois S, Tsai CH, Ho PC. Metabolic communication in the tumour-immune microenvironment. Nat Cell Biol. 2022;24:1574–83.

    Article  PubMed  CAS  Google Scholar 

  13. Wu JY, Huang TW, Hsieh YT, Wang YF, Yen CC, Lee GL, et al. Cancer-derived succinate promotes macrophage polarization and cancer metastasis via succinate receptor. Mol Cell. 2020;77:213–27.e5.

    Article  PubMed  CAS  Google Scholar 

  14. Ruffell B, Chang-Strachan D, Chan V, Rosenbusch A, Ho CM, Pryer N, et al. Macrophage IL-10 blocks CD8+ T cell-dependent responses to chemotherapy by suppressing IL-12 expression in intratumoral dendritic cells. Cancer Cell. 2014;26:623–37.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Wang J, Wang Y, Chu Y, Li Z, Yu X, Huang Z, et al. Tumor-derived adenosine promotes macrophage proliferation in human hepatocellular carcinoma. J Hepatol. 2021;74:627–37.

    Article  PubMed  CAS  Google Scholar 

  16. Devalaraja S, To TKJ, Folkert IW, Natesan R, Alam MZ, Li M, et al. Tumor-derived retinoic acid regulates intratumoral monocyte differentiation to promote immune suppression. Cell. 2020;180:098–1114.e16.

    Article  Google Scholar 

  17. Xia L, Oyang L, Lin J, Tan S, Han Y, Wu N, et al. The cancer metabolic reprogramming and immune response. Mol Cancer. 2021;20:28.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Liu Y, Xun Z, Ma K, Liang S, Li X, Zhou S, et al. Identification of a tumour immune barrier in the HCC microenvironment that determines the efficacy of immunotherapy. J Hepatol. 2023;78:770–782.

    Article  PubMed  CAS  Google Scholar 

  19. Pegg AE. Functions of polyamines in mammals. J Biol Chem 2016;291:14904–12.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Bachmann AS, Geerts D. Polyamine synthesis as a target of MYC oncogenes. J Biol Chem. 2018;293:18757–69.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Holbert CE, Cullen MT, Casero RA Jr, Stewart TM. Polyamines in cancer: integrating organismal metabolism and antitumour immunity. Nat Rev Cancer. 2022;22:467–80.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Gobert AP, Wilson KT. Editorial: orchestration of macrophage polarization by polyamines. J Leukoc Biol. 2012;91:677–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Puleston DJ, Baixauli F, Sanin DE, Edwards-Hicks J, Villa M, Kabat AM, et al. Polyamine metabolism is a central determinant of helper T cell lineage fidelity. Cell. 2021;184:4186–202.e20.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Wawrzyniak M, Groeger D, Frei R, Ferstl R, Wawrzyniak P, Krawczyk K, et al. Spermidine and spermine exert protective effects within the lung. Pharm Res Perspect. 2021;9:e00837.

    Article  CAS  Google Scholar 

  25. Soda K, Uemura T, Sanayama H, Igarashi K, Fukui T. Polyamine-rich diet elevates blood spermine levels and inhibits pro-inflammatory status: an interventional study. Med Sci 2021;9:22.

    CAS  Google Scholar 

  26. He H, Song Z, Lin S, Wang Y, Wang G. Exploring the effect of polyamines on NK cell function in colorectal cancer process based on glycolysis. Int Immunopharmacol. 2023;117:109944.

    Article  PubMed  CAS  Google Scholar 

  27. Gavin IM, Glesne D, Zhao Y, Kubera C, Huberman E. Spermine acts as a negative regulator of macrophage differentiation in human myeloid leukemia cells. Cancer Res. 2004;64:7432–8.

    Article  PubMed  CAS  Google Scholar 

  28. Li Y, Shen Z, Chai Z, Zhan Y, Zhang Y, Liu Z, et al. Targeting MS4A4A on tumour-associated macrophages restores CD8+ T-cell-mediated antitumour immunity. Gut. 2023;72:2307–20.

    Article  PubMed  CAS  Google Scholar 

  29. Guo Y, Ye Q, Deng P, Cao Y, He D, Zhou Z, et al. Spermine synthase and MYC cooperate to maintain colorectal cancer cell survival by repressing Bim expression. Nat Commun. 2020;11:3243.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Fahrmann JF, Vykoukal J, Fleury A, Tripathi S, Dennison JB, Murage E, et al. Association between plasma diacetylspermine and tumor spermine synthase with outcome in triple-negative breast cancer. J Natl Cancer Inst. 2020;112:607–16.

    Article  PubMed  Google Scholar 

  31. Origanti S, Shantz LM. Ras transformation of RIE-1 cells activates cap-independent translation of ornithine decarboxylase: regulation by the Raf/MEK/ERK and phosphatidylinositol 3-kinase pathways. Cancer Res. 2007;67:4834–42.

    Article  PubMed  CAS  Google Scholar 

  32. Nakkina SP, Gitto SB, Pandey V, Parikh JG, Geerts D, Maurer HC, et al. Differential expression of polyamine pathways in human pancreatic tumor progression and effects of polyamine blockade on tumor microenvironment. Cancers 2021;13:6391.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Yang H, Zhang Q, Xu M, Wang L, Chen X, Feng Y, et al. CCL2-CCR2 axis recruits tumor associated macrophages to induce immune evasion through PD-1 signaling in esophageal carcinogenesis. Mol Cancer. 2020;19:41.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Larrubia JR, Calvino M, Benito S, Sanz-de-Villalobos E, Perna C, Pérez-Hornedo J, et al. The role of CCR5/CXCR3 expressing CD8+ cells in liver damage and viral control during persistent hepatitis C virus infection. J Hepatol. 2007;47:632–41.

    Article  PubMed  CAS  Google Scholar 

  35. Karaki S, Blanc C, Tran T, Galy-Fauroux I, Mougel A, Dransart E, et al. CXCR6 deficiency impairs cancer vaccine efficacy and CD8+ resident memory T-cell recruitment in head and neck and lung tumors. J Immunother Cancer. 2021;9:e001948.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Harlin H, Meng Y, Peterson AC, Zha Y, Tretiakova M, Slingluff C, et al. Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment. Cancer Res. 2009;69:3077–85.

    Article  PubMed  CAS  Google Scholar 

  37. Zhou S, Gu J, Liu R, Wei S, Wang Q, Shen H, et al. Spermine alleviates acute liver injury by inhibiting liver-resident macrophage pro-inflammatory response through ATG5-dependent autophagy. Front Immunol. 2018;9:948.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Latour YL, Gobert AP, Wilson KT. The role of polyamines in the regulation of macrophage polarization and function. Amino Acids. 2020;52:151–60.

    Article  PubMed  CAS  Google Scholar 

  39. Bi G, Liang J, Bian Y, Shan G, Huang Y, Lu T, et al. Polyamine-mediated ferroptosis amplification acts as a targetable vulnerability in cancer. Nat Commun. 2024;15:2461.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Ma S, Sun B, Duan S, Han J, Barr T, Zhang J, et al. YTHDF2 orchestrates tumor-associated macrophage reprogramming and controls antitumor immunity through CD8+ T cells. Nat Immunol. 2023;24:255–66.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Kersten K, Hu KH, Combes AJ, Samad B, Harwin T, Ray A, et al. Spatiotemporal co-dependency between macrophages and exhausted CD8+ T cells in cancer. Cancer Cell. 2022;40:624–38.e9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Glaviano A, Foo ASC, Lam HY, Yap KCH, Jacot W, Jones RH, et al. PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer. Mol Cancer. 2023;22:138.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Riviere-Cazaux C, Neth BJ, Hoplin MD, Wessel B, Miska J, Kizilbash SH, et al. Glioma metabolic feedback in situ: a first-in-human pharmacodynamic trial of difluoromethylornithine + AMXT-1501 through high-molecular weight microdialysis. Neurosurgery. 2023;93:932–8.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Lian J, Liang Y, Zhang H, Lan M, Ye Z, Lin B, et al. The role of polyamine metabolism in remodeling immune responses and blocking therapy within the tumor immune microenvironment. Front Immunol. 2022;13:912279.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Zabransky DJ, Danilova L, Leatherman JM, Lopez-Vidal TY, Sanchez J, Charmsaz S, et al. Profiling of syngeneic mouse HCC tumor models as a framework to understand anti-PD-1 sensitive tumor microenvironments. Hepatology. 2023;77:1566–79.

    Article  PubMed  Google Scholar 

  46. Bai Y, Chen D, Cheng C, Li Z, Chi H, Zhang Y, et al. Immunosuppressive landscape in hepatocellular carcinoma revealed by single-cell sequencing. Front Immunol. 2022;13:950536.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Al-Habsi M, Chamoto K, Matsumoto K, Nomura N, Zhang B, Sugiura Y, et al. Spermidine activates mitochondrial trifunctional protein and improves antitumor immunity in mice. Science. 2022;378:eabj3510.

    Article  PubMed  CAS  Google Scholar 

  48. Geiger R, Rieckmann JC, Wolf T, Basso C, Feng Y, Fuhrer T, et al. L-arginine modulates T cell metabolism and enhances survival and anti-tumor activity. Cell. 2016;167:829–42.e13.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Xiang L, Piao L, Wang D, Qi LF. Overexpression of SMS in the tumor microenvironment is associated with immunosuppression in hepatocellular carcinoma. Front Immunol. 2022;13:974241.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Shi HX, Liang C, Yao CY, Gao ZX, Qin J, Cao JL, et al. Elevation of spermine remodels immunosuppressive microenvironment through driving the modification of PD-L1 in hepatocellular carcinoma. Cell Commun Signal. 2022;20:175.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Mantovani A, Allavena P, Marchesi F, Garlanda C. Macrophages as tools and targets in cancer therapy. Nat Rev Drug Discov. 2022;21:799–820.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Reschke R, Gajewski TF. CXCL9 and CXCL10 bring the heat to tumors. Sci Immunol. 2022;7:eabq6509.

    Article  PubMed  CAS  Google Scholar 

  53. Dangaj D, Bruand M, Grimm AJ, Ronet C, Barras D, Duttagupta PA, et al. Cooperation between constitutive and inducible chemokines enables T cell engraftment and immune attack in solid tumors. Cancer Cell. 2019;35:885–900.e10.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Reschke R, Yu J, Flood B, Higgs EF, Hatogai K, Gajewski TF. Immune cell and tumor cell-derived CXCL10 is indicative of immunotherapy response in metastatic melanoma. J Immunother Cancer. 2021;9:e003521.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Kennedy PG. Human African trypanosomiasis-neurological aspects. J Neurol. 2006;253:411–6.

    Article  PubMed  Google Scholar 

  56. Wallace HM, Fraser AV, Hughes A. A perspective of polyamine metabolism. Biochem J. 2003;376:1–14.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Gamble LD, Purgato S, Murray J, Xiao L, Yu DMT, Hanssen KM, et al. Inhibition of polyamine synthesis and uptake reduces tumor progression and prolongs survival in mouse models of neuroblastoma. Sci Transl Med. 2019;11:eaau1099.

    Article  PubMed  Google Scholar 

  58. Khan A, Gamble LD, Upton DH, Ung C, Yu DMT, Ehteda A, et al. Dual targeting of polyamine synthesis and uptake in diffuse intrinsic pontine gliomas. Nat Commun. 2021;12:971.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgements

We appreciate the generous donation of H22 cell line from Dr. Xiaojun Xia’s lab of Sun Yat-sen University Cancer Center, and we are also grateful for Prof. Dongming Kuang from Sun Yat-sen University for authorizing the use of this cell line.

Funding

This work was supported by Natural Science Foundation of China (Nos. 82073394, 82272737 to DHW, No. 82103595 to YF), Guangdong Provincial Regional Joint Fund-Youth Fund Project (No. 2020A1515110006 to YF, No. 2022A1515111142 to YZZ), The Foundation of President of Nanfang Hospital (No.2020B012 to YF), The Natural Science Foundation of Guangdong Province, China (No. 2023A1515011789 to YF, No. 2022B1515120035 to DHW), and Science and Technology Projects in Guangzhou (No. 2023B03J1237 to DHW).

Author information

Author notes

  1. These authors contributed equally: Yining Sun, Peitao Zhou, Junying Qian, Qin Zeng.

Authors and Affiliations

  1. Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China

    Yining Sun, Peitao Zhou, Junying Qian, Qin Zeng, Yingjie Lai, Dehua Wu & Yuan Fang

  2. Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases, Guangzhou, Guangdong Province, China

    Yining Sun, Peitao Zhou, Dehua Wu & Yuan Fang

  3. Department of Radiation Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China

    Guangyan Wei

  4. Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China

    Yongsheng Li, Yuechen Liu & Yizhi Zhan

Authors
  1. Yining Sun
    View author publications

    Search author on:PubMed Google Scholar

  2. Peitao Zhou
    View author publications

    Search author on:PubMed Google Scholar

  3. Junying Qian
    View author publications

    Search author on:PubMed Google Scholar

  4. Qin Zeng
    View author publications

    Search author on:PubMed Google Scholar

  5. Guangyan Wei
    View author publications

    Search author on:PubMed Google Scholar

  6. Yongsheng Li
    View author publications

    Search author on:PubMed Google Scholar

  7. Yuechen Liu
    View author publications

    Search author on:PubMed Google Scholar

  8. Yingjie Lai
    View author publications

    Search author on:PubMed Google Scholar

  9. Yizhi Zhan
    View author publications

    Search author on:PubMed Google Scholar

  10. Dehua Wu
    View author publications

    Search author on:PubMed Google Scholar

  11. Yuan Fang
    View author publications

    Search author on:PubMed Google Scholar

Contributions

YF conceived the project and generated the original hypothesis. DHW and YZZ supervised and discussed the study. YNS designed and performed most of the cellular and animal experiments, analyzed the data, and wrote the manuscript. PTZ, JYQ, and QZ performed part of the in vivo experiments. GYW, YSL, YCL, and YJL analyzed and discussed the data. All authors have read and approved the article.

Corresponding authors

Correspondence to Yizhi Zhan, Dehua Wu or Yuan Fang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethical approval and consent to participate

HCC patients’ samples were approved by Medical Ethics Committee of Nanfang Hospital, Southern Medical University (NFEC-202301-K3). The informed consent was obtained from all participants. Animal experiments were approved by Nanfang Hospital Animal Ethics Committee (IACUC-LAC-20230914-003).

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sun, Y., Zhou, P., Qian, J. et al. Spermine synthase engages in macrophages M2 polarization to sabotage antitumor immunity in hepatocellular carcinoma. Cell Death Differ 32, 573–586 (2025). https://doi.org/10.1038/s41418-024-01409-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41418-024-01409-z

This article is cited by

Search

Advanced search

Quick links