Skip to main content

Advertisement

Log in

The role of lipid metabolism in cancer radioresistance

  • REVIEW ARTICLE
  • Published:
Clinical and Translational Oncology Aims and scope Submit manuscript

Abstract

Radiotherapy is one of the main therapies for cancer. The process leading to radioresistance is still not fully understood. Cancer radiosensitivity is related to the DNA reparation of cancer cells and the tumor microenvironment (TME), which supports cancer cell survival. Factors that affect DNA reparation and the TME can directly or indirectly affect the radiosensitivity of cancer. Recent studies have shown that lipid metabolism in cancer cells, which is involved in the stability of cell membrane structure, energy supply and signal transduction of cancer cells, can also affect the phenotype and function of immune cells and stromal cells in the TME. In this review, we discussed the effects of lipid metabolism on the radiobiological characteristics of cancer cells and the TME. We also summarized recent advances in targeted lipid metabolism as a radiosensitizer and discussed how these scientific findings could be translated into clinical practice to improve the radiosensitivity of cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

Data availability

Not Applicable.

References

  1. Jaffray DA. Image-guided radiotherapy: from current concept to future perspectives. Nat Rev Clin Oncol. 2012;9:688–99. https://doi.org/10.1038/nrclinonc.2012.194.

    Article  CAS  PubMed  Google Scholar 

  2. Kim W, Lee S, Seo D, Kim D, Kim K, Kim E, et al. Cellular stress responses in radiotherapy. Cells. 2019. https://doi.org/10.3390/cells8091105.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Morgan MA, Lawrence TS. Molecular pathways: overcoming radiation resistance by targeting DNA damage response pathways. Clin Cancer Res. 2015;21:2898–904. https://doi.org/10.1158/1078-0432.CCR-13-3229.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Darragh LB, Oweida AJ, Karam SD. Overcoming resistance to combination radiation-immunotherapy: a focus on contributing pathways within the tumor microenvironment. Front Immunol. 2018;9:3154. https://doi.org/10.3389/fimmu.2018.03154.

    Article  CAS  PubMed  Google Scholar 

  5. Stone HB, Peters LJ, Milas L. Effect of host immune capability on radiocurability and subsequent transplantability of a murine fibrosarcoma. J Natl Cancer Inst. 1979;63:1229–35.

    CAS  PubMed  Google Scholar 

  6. Chen D, Menon H, Verma V, Guo C, Ramapriyan R, Barsoumian H, et al. Response and outcomes after anti-CTLA4 versus anti-PD1 combined with stereotactic body radiation therapy for metastatic non-small cell lung cancer: retrospective analysis of two single-institution prospective trials. J Immunother Cancer. 2020. https://doi.org/10.1136/jitc-2019-000492.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Luke JJ, Lemons JM, Karrison TG, Pitroda SP, Melotek JM, Zha Y, et al. Safety and clinical activity of pembrolizumab and multisite stereotactic body radiotherapy in patients with advanced solid tumors. J Clin Oncol. 2018;36:1611–8. https://doi.org/10.1200/JCO.2017.76.2229.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med. 2018;379:2342–50. https://doi.org/10.1056/NEJMoa1809697.

    Article  CAS  PubMed  Google Scholar 

  9. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74. https://doi.org/10.1016/j.cell.2011.02.013.

    Article  CAS  PubMed  Google Scholar 

  10. Boroughs LK, DeBerardinis RJ. Metabolic pathways promoting cancer cell survival and growth. Nat Cell Biol. 2015;17:351–9. https://doi.org/10.1038/ncb3124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. 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. https://doi.org/10.1186/s12943-021-01316-8.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Martinez-Reyes I, Chandel NS. Cancer metabolism: looking forward. Nat Rev Cancer. 2021;21:669–80. https://doi.org/10.1038/s41568-021-00378-6.

    Article  CAS  PubMed  Google Scholar 

  13. Piper M, Mueller AC, Karam SD. The interplay between cancer associated fibroblasts and immune cells in the context of radiation therapy. Mol Carcinog. 2020;59:754–65. https://doi.org/10.1002/mc.23205.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Snaebjornsson MT, Janaki-Raman S, Schulze A. Greasing the wheels of the cancer machine: the role of lipid metabolism in cancer. Cell Metab. 2020;31:62–76. https://doi.org/10.1016/j.cmet.2019.11.010.

    Article  CAS  PubMed  Google Scholar 

  15. Currie E, Schulze A, Zechner R, Walther TC, Farese RV. Cellular fatty acid metabolism and cancer. Cell Metab. 2013;18:153–61. https://doi.org/10.1016/j.cmet.2013.05.017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Grabner GF, Xie H, Schweiger M, Zechner R. Lipolysis: cellular mechanisms for lipid mobilization from fat stores. Nat Metab. 2021;3:1445–65. https://doi.org/10.1038/s42255-021-00493-6.

    Article  CAS  PubMed  Google Scholar 

  17. Yoon S, Lee MY, Park SW, Moon JS, Koh YK, Ahn YH, et al. Up-regulation of acetyl-CoA carboxylase alpha and fatty acid synthase by human epidermal growth factor receptor 2 at the translational level in breast cancer cells. J Biol Chem. 2007;282:26122–31. https://doi.org/10.1074/jbc.M702854200.

    Article  CAS  PubMed  Google Scholar 

  18. Madak-Erdogan Z, Band S, Zhao YC, Smith BP, Kulkoyluoglu-Cotul E, Zuo Q, et al. Free fatty acids rewire cancer metabolism in obesity-associated breast cancer via estrogen receptor and mTOR signaling. Cancer Res. 2019;79:2494–510. https://doi.org/10.1158/0008-5472.CAN-18-2849.

    Article  CAS  PubMed  Google Scholar 

  19. Calvisi DF, Wang C, Ho C, Ladu S, Lee SA, Mattu S, et al. Increased lipogenesis, induced by AKT-mTORC1-RPS6 signaling, promotes development of human hepatocellular carcinoma. Gastroenterology. 2011;140:1071–83. https://doi.org/10.1053/j.gastro.2010.12.006.

    Article  CAS  PubMed  Google Scholar 

  20. Brusselmans K, De Schrijver E, Verhoeven G, Swinnen JV. RNA interference-mediated silencing of the acetyl-CoA-carboxylase-alpha gene induces growth inhibition and apoptosis of prostate cancer cells. Cancer Res. 2005;65:6719–25. https://doi.org/10.1158/0008-5472.CAN-05-0571.

    Article  CAS  PubMed  Google Scholar 

  21. Chajes V, Cambot M, Moreau K, Lenoir GM, Joulin V. Acetyl-CoA carboxylase alpha is essential to breast cancer cell survival. Cancer Res. 2006;66:5287–94. https://doi.org/10.1158/0008-5472.CAN-05-1489.

    Article  CAS  PubMed  Google Scholar 

  22. De Schrijver E, Brusselmans K, Heyns W, Verhoeven G, Swinnen JV. RNA interference-mediated silencing of the fatty acid synthase gene attenuates growth and induces morphological changes and apoptosis of LNCaP prostate cancer cells. Cancer Res. 2003;63:3799–804.

    PubMed  Google Scholar 

  23. Mashima T, Oh-hara T, Sato S, Mochizuki M, Sugimoto Y, Yamazaki K, et al. p53-defective tumors with a functional apoptosome-mediated pathway: a new therapeutic target. J Natl Cancer Inst. 2005;97:765–77. https://doi.org/10.1093/jnci/dji133.

    Article  CAS  PubMed  Google Scholar 

  24. Wang J, Li Y. CD36 tango in cancer: signaling pathways and functions. Theranostics. 2019;9:4893–908. https://doi.org/10.7150/thno.36037.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Watt MJ, Clark AK, Selth LA, Haynes VR, Lister N, Rebello R, et al. Suppressing fatty acid uptake has therapeutic effects in preclinical models of prostate cancer. Sci Transl Med. 2019. https://doi.org/10.1126/scitranslmed.aau5758.

    Article  PubMed  Google Scholar 

  26. Pascual G, Avgustinova A, Mejetta S, Martin M, Castellanos A, Attolini CS, et al. Targeting metastasis-initiating cells through the fatty acid receptor CD36. Nature. 2017;541:41–5. https://doi.org/10.1038/nature20791.

    Article  CAS  PubMed  Google Scholar 

  27. Nath A, Li I, Roberts LR, Chan C. Elevated free fatty acid uptake via CD36 promotes epithelial-mesenchymal transition in hepatocellular carcinoma. Sci Rep. 2015;5:14752. https://doi.org/10.1038/srep14752.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Nieman KM, Kenny HA, Penicka CV, Ladanyi A, Buell-Gutbrod R, Zillhardt MR, et al. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat Med. 2011;17:1498–503. https://doi.org/10.1038/nm.2492.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Incio J, Liu H, Suboj P, Chin SM, Chen IX, Pinter M, et al. Obesity-induced inflammation and desmoplasia promote pancreatic cancer progression and resistance to chemotherapy. Cancer Discov. 2016;6:852–69. https://doi.org/10.1158/2159-8290.CD-15-1177.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wen YA, Xing X, Harris JW, Zaytseva YY, Mitov MI, Napier DL, et al. Adipocytes activate mitochondrial fatty acid oxidation and autophagy to promote tumor growth in colon cancer. Cell Death Dis. 2017;8:e2593. https://doi.org/10.1038/cddis.2017.21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Panaroni C, Fulzele K, Mori T, Siu KT, Onyewadume C, Maebius A, et al. Multiple myeloma cells induce lipolysis in adipocytes and uptake fatty acids through fatty acid transporter proteins. Blood. 2022;139:876–88. https://doi.org/10.1182/blood.2021013832.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Tucci J, Chen T, Margulis K, Orgel E, Paszkiewicz RL, Cohen MD, et al. Adipocytes provide fatty acids to acute lymphoblastic leukemia cells. Front Oncol. 2021;11:665763. https://doi.org/10.3389/fonc.2021.665763.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Pham DV, Park PH. Adiponectin triggers breast cancer cell death via fatty acid metabolic reprogramming. J Exp Clin Cancer Res. 2022;41:9. https://doi.org/10.1186/s13046-021-02223-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Cheng X, Geng F, Pan M, Wu X, Zhong Y, Wang C, et al. Targeting DGAT1 ameliorates glioblastoma by increasing fat catabolism and oxidative stress. Cell Metab. 2020;32:229-242 e8. https://doi.org/10.1016/j.cmet.2020.06.002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Xu Y, Qian SY. Anti-cancer activities of omega-6 polyunsaturated fatty acids. Biomed J. 2014;37:112–9. https://doi.org/10.4103/2319-4170.131378.

    Article  PubMed  Google Scholar 

  36. Tanaka A, Yamamoto A, Murota K, Tsujiuchi T, Iwamori M, Fukushima N. Polyunsaturated fatty acids induce ovarian cancer cell death through ROS-dependent MAP kinase activation. Biochem Biophys Res Commun. 2017;493:468–73. https://doi.org/10.1016/j.bbrc.2017.08.168.

    Article  CAS  PubMed  Google Scholar 

  37. Liu Z, Hopkins MM, Zhang Z, Quisenberry CB, Fix LC, Galvan BM, et al. Omega-3 fatty acids and other FFA4 agonists inhibit growth factor signaling in human prostate cancer cells. J Pharmacol Exp Ther. 2015;352:380–94. https://doi.org/10.1124/jpet.114.218974.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Hopkins MM, Meier KE. Free fatty acid receptor (FFAR) agonists inhibit proliferation of human ovarian cancer cells. Prostaglandins Leukot Essent Fatty Acids. 2017;122:24–9. https://doi.org/10.1016/j.plefa.2017.06.013.

    Article  CAS  PubMed  Google Scholar 

  39. Rysman E, Brusselmans K, Scheys K, Timmermans L, Derua R, Munck S, et al. De novo lipogenesis protects cancer cells from free radicals and chemotherapeutics by promoting membrane lipid saturation. Cancer Res. 2010;70:8117–26. https://doi.org/10.1158/0008-5472.CAN-09-3871.

    Article  CAS  PubMed  Google Scholar 

  40. Wenk MR. The emerging field of lipidomics. Nat Rev Drug Discov. 2005;4:594–610. https://doi.org/10.1038/nrd1776.

    Article  CAS  PubMed  Google Scholar 

  41. Bandu R, Mok HJ, Kim KP. Phospholipids as cancer biomarkers: mass spectrometry-based analysis. Mass Spectrom Rev. 2018;37:107–38. https://doi.org/10.1002/mas.21510.

    Article  CAS  PubMed  Google Scholar 

  42. Shafiee MN, Ortori CA, Barrett DA, Mongan NP, Abu J, Atiomo W. Lipidomic biomarkers in polycystic ovary syndrome and endometrial cancer. Int J Mol Sci. 2020. https://doi.org/10.3390/ijms21134753.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Ramirez de Molina A, Rodriguez-Gonzalez A, Gutierrez R, Martinez-Pineiro L, Sanchez JJ, Bonilla F, et al. Overexpression of choline kinase is a frequent feature in human tumor-derived cell lines and in lung, prostate, and colorectal human cancers. Biochem Biophys Res Commun. 2002;296:580–3. https://doi.org/10.1016/s0006-291x(02)00920-8.

    Article  CAS  PubMed  Google Scholar 

  44. Mika A, Pakiet A, Czumaj A, Kaczynski Z, Liakh I, Kobiela J, et al. Decreased triacylglycerol content and elevated contents of cell membrane lipids in colorectal cancer tissue: a lipidomic study. J Clin Med. 2020. https://doi.org/10.3390/jcm9041095.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Chang W, Fa H, Xiao D, Wang J. Targeting phosphatidylserine for cancer therapy: prospects and challenges. Theranostics. 2020;10:9214–29. https://doi.org/10.7150/thno.45125.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Ogretmen B. Sphingolipid metabolism in cancer signalling and therapy. Nat Rev Cancer. 2018;18:33–50. https://doi.org/10.1038/nrc.2017.96.

    Article  CAS  PubMed  Google Scholar 

  47. Vaena S, Chakraborty P, Lee HG, Janneh AH, Kassir MF, Beeson G, et al. Aging-dependent mitochondrial dysfunction mediated by ceramide signaling inhibits antitumor T cell response. Cell Rep. 2021;35: 109076. https://doi.org/10.1016/j.celrep.2021.109076.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Boedtkjer E, Pedersen SF. The acidic tumor microenvironment as a driver of cancer. Annu Rev Physiol. 2020;82(82):103–26. https://doi.org/10.1146/annurev-physiol-021119-034627.

    Article  CAS  PubMed  Google Scholar 

  49. Urbanelli L, Buratta S, Logozzi M, Mitro N, Sagini K, Di Raimo RD, et al. Lipidomic analysis of cancer cells cultivated at acidic pH reveals phospholipid fatty acids remodelling associated with transcriptional reprogramming. J Enzyme Inhib Med Chem. 2020;35:963–73. https://doi.org/10.1080/14756366.2020.1748025.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Li YJ, Fahrmann JF, Aftabizadeh M, Zhao Q, Tripathi SC, Zhang C, et al. Fatty acid oxidation protects cancer cells from apoptosis by increasing mitochondrial membrane lipids. Cell Rep. 2022;39: 111044. https://doi.org/10.1016/j.celrep.2022.111044.

    Article  CAS  PubMed  Google Scholar 

  51. Boyd NF, McGuire V. Evidence of association between plasma high-density lipoprotein cholesterol and risk factors for breast cancer. J Natl Cancer Inst. 1990;82:460–8. https://doi.org/10.1093/jnci/82.6.460.

    Article  CAS  PubMed  Google Scholar 

  52. Mayengbam SS, Singh A, Pillai AD, Bhat MK. Influence of cholesterol on cancer progression and therapy. Transl Oncol. 2021;14: 101043. https://doi.org/10.1016/j.tranon.2021.101043.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Wang XX, Xu WJ, Zhan P, Xu TX, Jin JJ, Miu YY, et al. Overexpression of geranylgeranyl diphosphate synthase contributes to tumour metastasis and correlates with poor prognosis of lung adenocarcinoma. J Cell Mol Med. 2018;22:2177–89. https://doi.org/10.1111/jcmm.13493.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Todenhofer T, Hennenlotter J, Kuhs U, Gerber V, Gakis G, Vogel U, et al. Altered expression of farnesyl pyrophosphate synthase in prostate cancer: evidence for a role of the mevalonate pathway in disease progression? World J Urol. 2013;31:345–50. https://doi.org/10.1007/s00345-012-0844-y.

    Article  CAS  PubMed  Google Scholar 

  55. Baek AE, Nelson ER. The contribution of cholesterol and its metabolites to the pathophysiology of breast cancer. Horm Cancer. 2016;7:219–28. https://doi.org/10.1007/s12672-016-0262-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Zhang GM, Chen W, Yao Y, Luo L, Sun LJ. LDLR promotes growth and invasion in renal cell carcinoma and activates the EGFR pathway. Neoplasma. 2022;69:113–22. https://doi.org/10.4149/neo_2021_210607N762.

    Article  CAS  PubMed  Google Scholar 

  57. Gallagher EJ, Zelenko Z, Neel BA, Antoniou IM, Rajan L, Kase N, et al. Elevated tumor LDLR expression accelerates LDL cholesterol-mediated breast cancer growth in mouse models of hyperlipidemia. Oncogene. 2017;36:6462–71. https://doi.org/10.1038/onc.2017.247.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. de Gonzalo-Calvo D, Lopez-Vilaro L, Nasarre L, Perez-Olabarria M, Vazquez T, Escuin D, et al. Intratumor cholesteryl ester accumulation is associated with human breast cancer proliferation and aggressive potential: a molecular and clinicopathological study. BMC Cancer. 2015;15:460. https://doi.org/10.1186/s12885-015-1469-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Smith B, Land H. Anticancer activity of the cholesterol exporter ABCA1 gene. Cell Rep. 2012;2:580–90. https://doi.org/10.1016/j.celrep.2012.08.011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Bovenga F, Sabba C, Moschetta A. Uncoupling nuclear receptor LXR and cholesterol metabolism in cancer. Cell Metab. 2015;21:517–26. https://doi.org/10.1016/j.cmet.2015.03.002.

    Article  CAS  PubMed  Google Scholar 

  61. Wang B, Tontonoz P. Liver X receptors in lipid signalling and membrane homeostasis. Nat Rev Endocrinol. 2018;14:452–63. https://doi.org/10.1038/s41574-018-0037-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Boudreau DM, Gardner JS, Malone KE, Heckbert SR, Blough DK, Daling JR. The association between 3-hydroxy-3-methylglutaryl conenzyme A inhibitor use and breast carcinoma risk among postmenopausal women: a case–control study. Cancer. 2004;100:2308–16. https://doi.org/10.1002/cncr.20271.

    Article  CAS  PubMed  Google Scholar 

  63. Nayan M, Punjani N, Juurlink DN, Finelli A, Austin PC, Kulkarni GS, et al. Statin use and kidney cancer survival outcomes: a systematic review and meta-analysis. Cancer Treat Rev. 2017;52:105–16. https://doi.org/10.1016/j.ctrv.2016.11.009.

    Article  CAS  PubMed  Google Scholar 

  64. Alfaqih MA, Allott EH, Hamilton RJ, Freeman MR, Freedland SJ. The current evidence on statin use and prostate cancer prevention: are we there yet? Nat Rev Urol. 2017;14:107–19. https://doi.org/10.1038/nrurol.2016.199.

    Article  CAS  PubMed  Google Scholar 

  65. Wu Y, Si R, Tang H, He Z, Zhu H, Wang L, et al. Cholesterol reduces the sensitivity to platinum-based chemotherapy via upregulating ABCG2 in lung adenocarcinoma. Biochem Biophys Res Commun. 2015;457:614–20. https://doi.org/10.1016/j.bbrc.2015.01.035.

    Article  CAS  PubMed  Google Scholar 

  66. Mok EHK, Leung CON, Zhou L, Lei MML, Leung HW, Tong M, et al. Caspase-3-induced activation of SREBP2 drives drug resistance via promotion of cholesterol biosynthesis in hepatocellular carcinoma. Cancer Res. 2022;82:3102–15. https://doi.org/10.1158/0008-5472.CAN-21-2934.

    Article  CAS  PubMed  Google Scholar 

  67. Wang X, Sun B, Wei L, Jian X, Shan K, He Q, et al. Cholesterol and saturated fatty acids synergistically promote the malignant progression of prostate cancer. Neoplasia. 2022;24:86–97. https://doi.org/10.1016/j.neo.2021.11.004.

    Article  CAS  PubMed  Google Scholar 

  68. Tanaka A, Sakaguchi S. Regulatory T cells in cancer immunotherapy. Cell Res. 2017;27:109–18. https://doi.org/10.1038/cr.2016.151.

    Article  CAS  PubMed  Google Scholar 

  69. Gardner A, Ruffell B. Dendritic cells and cancer immunity. Trends Immunol. 2016;37:855–65. https://doi.org/10.1016/j.it.2016.09.006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Thommen DS, Schumacher TN. T cell dysfunction in cancer. Cancer Cell. 2018;33:547–62. https://doi.org/10.1016/j.ccell.2018.03.012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Patsoukis N, Bardhan K, Chatterjee P, Sari D, Liu B, Bell LN, et al. PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation. Nat Commun. 2015;6:6692. https://doi.org/10.1038/ncomms7692.

    Article  CAS  PubMed  Google Scholar 

  72. Lim SA, Wei J, Nguyen TM, Shi H, Su W, Palacios G, et al. Lipid signalling enforces functional specialization of T(reg) cells in tumours. Nature. 2021;591:306–11. https://doi.org/10.1038/s41586-021-03235-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. King RJ, Singh PK, Mehla K. The cholesterol pathway: impact on immunity and cancer. Trends Immunol. 2022;43:78–92. https://doi.org/10.1016/j.it.2021.11.007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Pearce EL, Walsh MC, Cejas PJ, Harms GM, Shen H, Wang LS, et al. Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature. 2009;460:103–7. https://doi.org/10.1038/nature08097.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Zhang Y, Kurupati R, Liu L, Zhou XY, Zhang G, Hudaihed A, et al. Enhancing CD8(+) T cell fatty acid catabolism within a metabolically challenging tumor microenvironment increases the efficacy of melanoma immunotherapy. Cancer Cell. 2017;32:377-391 e9. https://doi.org/10.1016/j.ccell.2017.08.004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Chowdhury PS, Chamoto K, Kumar A, Honjo T. PPAR-induced fatty acid oxidation in T cells increases the number of tumor-reactive CD8(+) T cells and facilitates anti-PD-1 therapy. Cancer Immunol Res. 2018;6:1375–87. https://doi.org/10.1158/2326-6066.CIR-18-0095.

    Article  CAS  PubMed  Google Scholar 

  77. Li W, Guo X, Chen C, Li J. The prognostic value of arachidonic acid metabolism in breast cancer by integrated bioinformatics. Lipids Health Dis. 2022;21:103. https://doi.org/10.1186/s12944-022-01713-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Yang W, Bai Y, Xiong Y, Zhang J, Chen S, Zheng X, et al. Potentiating the antitumour response of CD8(+) T cells by modulating cholesterol metabolism. Nature. 2016;531:651–5. https://doi.org/10.1038/nature17412.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Yu W, Lei Q, Yang L, Qin G, Liu S, Wang D, et al. Contradictory roles of lipid metabolism in immune response within the tumor microenvironment. J Hematol Oncol. 2021;14:187. https://doi.org/10.1186/s13045-021-01200-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Kleinfeld AM, Okada C. Free fatty acid release from human breast cancer tissue inhibits cytotoxic T-lymphocyte-mediated killing. J Lipid Res. 2005;46:1983–90. https://doi.org/10.1194/jlr.M500151-JLR200.

    Article  CAS  PubMed  Google Scholar 

  81. Ma X, Bi E, Lu Y, Su P, Huang C, Liu L, et al. Cholesterol induces CD8(+) T cell exhaustion in the tumor microenvironment. Cell Metab. 2019;30:143-156 e5. https://doi.org/10.1016/j.cmet.2019.04.002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Ma X, Xiao L, Liu L, Ye L, Su P, Bi E, et al. CD36-mediated ferroptosis dampens intratumoral CD8(+) T cell effector function and impairs their antitumor ability. Cell Metab. 2021;33:1001-1012 e5. https://doi.org/10.1016/j.cmet.2021.02.015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Xu S, Chaudhary O, Rodriguez-Morales P, Sun X, Chen D, Zappasodi R, et al. Uptake of oxidized lipids by the scavenger receptor CD36 promotes lipid peroxidation and dysfunction in CD8(+) T cells in tumors. Immunity. 2021;54:1561-1577 e7. https://doi.org/10.1016/j.immuni.2021.05.003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Liu X, Hartman CL, Li L, Albert CJ, Si F, Gao A, et al. Reprogramming lipid metabolism prevents effector T cell senescence and enhances tumor immunotherapy. Sci Transl Med. 2021. https://doi.org/10.1126/scitranslmed.aaz6314.

    Article  PubMed  PubMed Central  Google Scholar 

  85. Odegaard JI, Chawla A. Alternative macrophage activation and metabolism. Annu Rev Pathol. 2011;6:275–97. https://doi.org/10.1146/annurev-pathol-011110-130138.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Huang SC, Everts B, Ivanova Y, O’Sullivan D, Nascimento M, Smith AM, et al. Cell-intrinsic lysosomal lipolysis is essential for alternative activation of macrophages. Nat Immunol. 2014;15:846–55. https://doi.org/10.1038/ni.2956.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Corn KC, Windham MA, Rafat M. Lipids in the tumor microenvironment: from cancer progression to treatment. Prog Lipid Res. 2020;80: 101055. https://doi.org/10.1016/j.plipres.2020.101055.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Yang P, Qin H, Li Y, Xiao A, Zheng E, Zeng H, et al. CD36-mediated metabolic crosstalk between tumor cells and macrophages affects liver metastasis. Nat Commun. 2022;13:5782. https://doi.org/10.1038/s41467-022-33349-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Masetti M, Carriero R, Portale F, Marelli G, Morina N, Pandini M, et al. Lipid-loaded tumor-associated macrophages sustain tumor growth and invasiveness in prostate cancer. J Exp Med. 2022. https://doi.org/10.1084/jem.20210564.

    Article  PubMed  Google Scholar 

  90. Liu Z, Gao Z, Li B, Li J, Ou Y, Yu X, et al. Lipid-associated macrophages in the tumor-adipose microenvironment facilitate breast cancer progression. Oncoimmunology. 2022;11:2085432. https://doi.org/10.1080/2162402X.2022.2085432.

    Article  PubMed  PubMed Central  Google Scholar 

  91. Timperi E, Gueguen P, Molgora M, Magagna I, Kieffer Y, Lopez-Lastra S, et al. Lipid-associated macrophages are induced by cancer-associated fibroblasts and mediate immune suppression in breast cancer. Cancer Res. 2022;82:3291–306. https://doi.org/10.1158/0008-5472.CAN-22-1427.

    Article  CAS  PubMed  Google Scholar 

  92. Su P, Wang Q, Bi E, Ma X, Liu L, Yang M, et al. Enhanced lipid accumulation and metabolism are required for the differentiation and activation of tumor-associated macrophages. Cancer Res. 2020;80:1438–50. https://doi.org/10.1158/0008-5472.CAN-19-2994.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Xu M, Wang X, Li Y, Geng X, Jia X, Zhang L, et al. Arachidonic acid metabolism controls macrophage alternative activation through regulating oxidative phosphorylation in PPARgamma dependent manner. Front Immunol. 2021;12: 618501. https://doi.org/10.3389/fimmu.2021.618501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Sag D, Cekic C, Wu R, Linden J, Hedrick CC. The cholesterol transporter ABCG1 links cholesterol homeostasis and tumour immunity. Nat Commun. 2015;6:6354. https://doi.org/10.1038/ncomms7354.

    Article  CAS  PubMed  Google Scholar 

  95. Goossens P, Rodriguez-Vita J, Etzerodt A, Masse M, Rastoin O, Gouirand V, et al. Membrane cholesterol efflux drives tumor-associated macrophage reprogramming and tumor progression. Cell Metab. 2019;29:1376-1389 e4. https://doi.org/10.1016/j.cmet.2019.02.016.

    Article  CAS  PubMed  Google Scholar 

  96. Cheng Y, Bai F, Ren X, Sun R, Guo X, Liu W, et al. Phosphoinositide-binding protein TIPE1 promotes alternative activation of macrophages and tumor progression via PIP3/Akt/TGFbeta axis. Cancer Res. 2022;82:1603–16. https://doi.org/10.1158/0008-5472.CAN-21-0003.

    Article  CAS  PubMed  Google Scholar 

  97. Herber DL, Cao W, Nefedova Y, Novitskiy SV, Nagaraj S, Tyurin VA, et al. Lipid accumulation and dendritic cell dysfunction in cancer. Nat Med. 2010;16:880–6. https://doi.org/10.1038/nm.2172.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Oh DS, Lee HK. Autophagy protein ATG5 regulates CD36 expression and anti-tumor MHC class II antigen presentation in dendritic cells. Autophagy. 2019;15:2091–106. https://doi.org/10.1080/15548627.2019.1596493.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Cubillos-Ruiz JR, Silberman PC, Rutkowski MR, Chopra S, Perales-Puchalt A, Song M, et al. ER stress sensor XBP1 controls anti-tumor immunity by disrupting dendritic cell homeostasis. Cell. 2015;161:1527–38. https://doi.org/10.1016/j.cell.2015.05.025.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Zou W. Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol. 2006;6:295–307. https://doi.org/10.1038/nri1806.

    Article  CAS  PubMed  Google Scholar 

  101. Wang H, Franco F, Tsui YC, Xie X, Trefny MP, Zappasodi R, et al. CD36-mediated metabolic adaptation supports regulatory T cell survival and function in tumors. Nat Immunol. 2020;21:298–308. https://doi.org/10.1038/s41590-019-0589-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Angelin A, Gil-de-Gomez L, Dahiya S, Jiao J, Guo L, Levine MH, et al. Foxp3 reprograms T cell metabolism to function in low-glucose, high-lactate environments. Cell Metab. 2017;25:1282-1293 e7. https://doi.org/10.1016/j.cmet.2016.12.018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Sharma S, Yang SC, Zhu L, Reckamp K, Gardner B, Baratelli F, et al. Tumor cyclooxygenase-2/prostaglandin E2-dependent promotion of FOXP3 expression and CD4+ CD25+ T regulatory cell activities in lung cancer. Cancer Res. 2005;65:5211–20. https://doi.org/10.1158/0008-5472.CAN-05-0141.

    Article  CAS  PubMed  Google Scholar 

  104. Kumagai S, Togashi Y, Sakai C, Kawazoe A, Kawazu M, Ueno T, et al. An oncogenic alteration creates a microenvironment that promotes tumor progression by conferring a metabolic advantage to regulatory T cells. Immunity. 2020;53:187-203 e8. https://doi.org/10.1016/j.immuni.2020.06.016.

    Article  CAS  PubMed  Google Scholar 

  105. Liu C, Chikina M, Deshpande R, Menk AV, Wang T, Tabib T, et al. Treg cells promote the SREBP1-dependent metabolic fitness of tumor-promoting macrophages via repression of CD8(+) T cell-derived interferon-gamma. Immunity. 2019;51:381-397 e6. https://doi.org/10.1016/j.immuni.2019.06.017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Liu J, Sun B, Guo K, Yang Z, Zhao Y, Gao M, et al. Lipid-related FABP5 activation of tumor-associated monocytes fosters immune privilege via PD-L1 expression on Treg cells in hepatocellular carcinoma. Cancer Gene Ther. 2022;29:1951–60. https://doi.org/10.1038/s41417-022-00510-0.

    Article  CAS  PubMed  Google Scholar 

  107. Kim MJ, Kim K, Park HJ, Kim GR, Hong KH, Oh JH, et al. Deletion of PD-1 destabilizes the lineage identity and metabolic fitness of tumor-infiltrating regulatory T cells. Nat Immunol. 2023;24:148–61. https://doi.org/10.1038/s41590-022-01373-1.

    Article  CAS  PubMed  Google Scholar 

  108. Hossain F, Al-Khami AA, Wyczechowska D, Hernandez C, Zheng L, Reiss K, et al. Inhibition of fatty acid oxidation modulates immunosuppressive functions of myeloid-derived suppressor cells and enhances cancer therapies. Cancer Immunol Res. 2015;3:1236–47. https://doi.org/10.1158/2326-6066.CIR-15-0036.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Al-Khami AA, Zheng L, Del Valle L, Hossain F, Wyczechowska D, Zabaleta J, et al. Exogenous lipid uptake induces metabolic and functional reprogramming of tumor-associated myeloid-derived suppressor cells. Oncoimmunology. 2017;6: e1344804. https://doi.org/10.1080/2162402X.2017.1344804.

    Article  PubMed  PubMed Central  Google Scholar 

  110. Yang Z, Huo Y, Zhou S, Guo J, Ma X, Li T, et al. Cancer cell-intrinsic XBP1 drives immunosuppressive reprogramming of intratumoral myeloid cells by promoting cholesterol production. Cell Metab. 2022;34:2018-2035 e8. https://doi.org/10.1016/j.cmet.2022.10.010.

    Article  CAS  PubMed  Google Scholar 

  111. Niavarani SR, Lawson C, Bakos O, Boudaud M, Batenchuk C, Rouleau S, et al. Lipid accumulation impairs natural killer cell cytotoxicity and tumor control in the postoperative period. BMC Cancer. 2019;19:823. https://doi.org/10.1186/s12885-019-6045-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Bonavita E, Bromley CP, Jonsson G, Pelly VS, Sahoo S, Walwyn-Brown K, et al. Antagonistic inflammatory phenotypes dictate tumor fate and response to immune checkpoint blockade. Immunity. 2020;53:1215-1229 e8. https://doi.org/10.1016/j.immuni.2020.10.020.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Kobayashi T, Lam PY, Jiang H, Bednarska K, Gloury R, Murigneux V, et al. Increased lipid metabolism impairs NK cell function and mediates adaptation to the lymphoma environment. Blood. 2020;136:3004–17. https://doi.org/10.1182/blood.2020005602.

    Article  CAS  PubMed  Google Scholar 

  114. Tao L, Huang G, Song H, Chen Y, Chen L. Cancer associated fibroblasts: an essential role in the tumor microenvironment. Oncol Lett. 2017;14:2611–20. https://doi.org/10.3892/ol.2017.6497.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Bu L, Baba H, Yoshida N, Miyake K, Yasuda T, Uchihara T, et al. Biological heterogeneity and versatility of cancer-associated fibroblasts in the tumor microenvironment. Oncogene. 2019;38:4887–901. https://doi.org/10.1038/s41388-019-0765-y.

    Article  CAS  PubMed  Google Scholar 

  116. Li Z, Sun C, Qin Z. Metabolic reprogramming of cancer-associated fibroblasts and its effect on cancer cell reprogramming. Theranostics. 2021;11:8322–36. https://doi.org/10.7150/thno.62378.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Gong J, Lin Y, Zhang H, Liu C, Cheng Z, Yang X, et al. Reprogramming of lipid metabolism in cancer-associated fibroblasts potentiates migration of colorectal cancer cells. Cell Death Dis. 2020;11:267. https://doi.org/10.1038/s41419-020-2434-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Jung JG, Le A. Targeting metabolic cross talk between cancer cells and cancer-associated fibroblasts. Adv Exp Med Biol. 2021;1311:205–14. https://doi.org/10.1007/978-3-030-65768-0_15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Auciello FR, Bulusu V, Oon C, Tait-Mulder J, Berry M, Bhattacharyya S, et al. A stromal lysolipid-autotaxin signaling axis promotes pancreatic tumor progression. Cancer Discov. 2019;9:617–27. https://doi.org/10.1158/2159-8290.CD-18-1212.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Nambiar M, Raghavan SC. How does DNA break during chromosomal translocations? Nucleic Acids Res. 2011;39:5813–25. https://doi.org/10.1093/nar/gkr223.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Chuang HY, Lee YP, Lin WC, Lin YH, Hwang JJ. Fatty acid inhibition sensitizes androgen-dependent and -independent prostate cancer to radiotherapy via FASN/NF-kappaB pathway. Sci Rep. 2019;9:13284. https://doi.org/10.1038/s41598-019-49486-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Chen J, Zhang F, Ren X, Wang Y, Huang W, Zhang J, et al. Targeting fatty acid synthase sensitizes human nasopharyngeal carcinoma cells to radiation via downregulating frizzled class receptor 10. Cancer Biol Med. 2020;17:740–52. https://doi.org/10.20892/j.issn.2095-3941.2020.0219.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Jin Y, Chen Z, Dong J, Wang B, Fan S, Yang X, et al. SREBP1/FASN/cholesterol axis facilitates radioresistance in colorectal cancer. FEBS Open Bio. 2021;11:1343–52. https://doi.org/10.1002/2211-5463.13137.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Joshi PR, Zierz S. Muscle carnitine palmitoyltransferase II (CPT II) deficiency: a conceptual approach. Molecules. 2020. https://doi.org/10.3390/molecules25081784.

    Article  PubMed  PubMed Central  Google Scholar 

  125. Tan Z, Xiao L, Tang M, Bai F, Li J, Li L, et al. Targeting CPT1A-mediated fatty acid oxidation sensitizes nasopharyngeal carcinoma to radiation therapy. Theranostics. 2018;8:2329–47. https://doi.org/10.7150/thno.21451.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Han S, Wei R, Zhang X, Jiang N, Fan M, Huang JH, et al. CPT1A/2-mediated FAO enhancement—a metabolic target in radioresistant breast cancer. Front Oncol. 2019;9:1201. https://doi.org/10.3389/fonc.2019.01201.

    Article  PubMed  PubMed Central  Google Scholar 

  127. Jiang N, Xie B, Xiao W, Fan M, Xu S, Duan Y, et al. Fatty acid oxidation fuels glioblastoma radioresistance with CD47-mediated immune evasion. Nat Commun. 2022;13:1511. https://doi.org/10.1038/s41467-022-29137-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Nix P, Lind M, Greenman J, Stafford N, Cawkwell L. Expression of Cox-2 protein in radioresistant laryngeal cancer. Ann Oncol. 2004;15:797–801. https://doi.org/10.1093/annonc/mdh185.

    Article  CAS  PubMed  Google Scholar 

  129. Cook PJ, Thomas R, Kingsley PJ, Shimizu F, Montrose DC, Marnett LJ, et al. Cox-2-derived PGE2 induces Id1-dependent radiation resistance and self-renewal in experimental glioblastoma. Neuro Oncol. 2016;18:1379–89. https://doi.org/10.1093/neuonc/now049.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Brocard E, Oizel K, Lalier L, Pecqueur C, Paris F, Vallette FM, et al. Radiation-induced PGE2 sustains human glioma cells growth and survival through EGF signaling. Oncotarget. 2015;6:6840–9. https://doi.org/10.18632/oncotarget.3160.

    Article  PubMed  PubMed Central  Google Scholar 

  131. Zhang P, Song E, Jiang M, Song Y. Celecoxib and afatinib synergistic enhance radiotherapy sensitivity on human non-small cell lung cancer A549 cells. Int J Radiat Biol. 2021;97:170–8. https://doi.org/10.1080/09553002.2021.1846817.

    Article  CAS  PubMed  Google Scholar 

  132. Cai F, Sorg O, Granci V, Lecumberri E, Miralbell R, Dupertuis YM, et al. Interaction of omega-3 polyunsaturated fatty acids with radiation therapy in two different colorectal cancer cell lines. Clin Nutr. 2014;33:164–70. https://doi.org/10.1016/j.clnu.2013.04.005.

    Article  CAS  PubMed  Google Scholar 

  133. Antal O, Hackler L Jr, Shen J, Man I, Hideghety K, Kitajka K, et al. Combination of unsaturated fatty acids and ionizing radiation on human glioma cells: cellular, biochemical and gene expression analysis. Lipids Health Dis. 2014;13:142. https://doi.org/10.1186/1476-511X-13-142.

    Article  PubMed  PubMed Central  Google Scholar 

  134. Zand H, Rahimipour A, Salimi S, Shafiee SM. Docosahexaenoic acid sensitizes Ramos cells to gamma-irradiation-induced apoptosis through involvement of PPAR-gamma activation and NF-kappaB suppression. Mol Cell Biochem. 2008;317:113–20. https://doi.org/10.1007/s11010-008-9838-x.

    Article  CAS  PubMed  Google Scholar 

  135. Lee H, To NB, Kim M, Nguyen YT, Cho SK, Choi HK. Metabolic and lipidomic characterization of radioresistant MDA-MB-231 human breast cancer cells to investigate potential therapeutic targets. J Pharm Biomed Anal. 2022;208: 114449. https://doi.org/10.1016/j.jpba.2021.114449.

    Article  CAS  PubMed  Google Scholar 

  136. 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. https://doi.org/10.1002/hep.32177.

    Article  CAS  PubMed  Google Scholar 

  137. Chmura SJ, Nodzenski E, Beckett MA, Kufe DW, Quintans J, Weichselbaum RR. Loss of ceramide production confers resistance to radiation-induced apoptosis. Cancer Res. 1997;57:1270–5.

    CAS  PubMed  Google Scholar 

  138. Doan NB, Nguyen HS, Al-Gizawiy MM, Mueller WM, Sabbadini RA, Rand SD, et al. Acid ceramidase confers radioresistance to glioblastoma cells. Oncol Rep. 2017;38:1932–40. https://doi.org/10.3892/or.2017.5855.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Kumar A, Oskouian B, Fyrst H, Zhang M, Paris F, Saba JD. S1P lyase regulates DNA damage responses through a novel sphingolipid feedback mechanism. Cell Death Dis. 2011;2: e119. https://doi.org/10.1038/cddis.2011.3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Michael JM, Lavin MF, Watters DJ. Resistance to radiation-induced apoptosis in Burkitt’s lymphoma cells is associated with defective ceramide signaling. Cancer Res. 1997;57:3600–5.

    CAS  PubMed  Google Scholar 

  141. Sautin Y, Takamura N, Shklyaev S, Nagayama Y, Ohtsuru A, Namba H, et al. Ceramide-induced apoptosis of human thyroid cancer cells resistant to apoptosis by irradiation. Thyroid. 2000;10:733–40. https://doi.org/10.1089/thy.2000.10.733.

    Article  CAS  PubMed  Google Scholar 

  142. Cheng JC, Bai A, Beckham TH, Marrison ST, Yount CL, Young K, et al. Radiation-induced acid ceramidase confers prostate cancer resistance and tumor relapse. J Clin Invest. 2013;123:4344–58. https://doi.org/10.1172/JCI64791.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Yura Y, Masui A, Hamada M. Inhibitors of ceramide- and sphingosine-metabolizing enzymes as sensitizers in radiotherapy and chemotherapy for head and neck squamous cell carcinoma. Cancers (Basel). 2020. https://doi.org/10.3390/cancers12082062.

    Article  PubMed  Google Scholar 

  144. Souchek JJ, Baine MJ, Lin C, Rachagani S, Gupta S, Kaur S, et al. Unbiased analysis of pancreatic cancer radiation resistance reveals cholesterol biosynthesis as a novel target for radiosensitisation. Br J Cancer. 2014;111:1139–49. https://doi.org/10.1038/bjc.2014.385.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Lingwood D, Kaiser HJ, Levental I, Simons K. Lipid rafts as functional heterogeneity in cell membranes. Biochem Soc Trans. 2009;37:955–60. https://doi.org/10.1042/Bst0370955.

    Article  CAS  PubMed  Google Scholar 

  146. Simons K, Toomre D. Lipid rafts and signal transduction. Nat Rev Mol Cell Biol. 2000;1:31–9. https://doi.org/10.1038/35036052.

    Article  CAS  PubMed  Google Scholar 

  147. Bionda C, Athias A, Poncet D, Alphonse G, Guezguez A, Gambert P, et al. Differential regulation of cell death in head and neck cell carcinoma through alteration of cholesterol levels in lipid rafts microdomains. Biochem Pharmacol. 2008;75:761–72. https://doi.org/10.1016/j.bcp.2007.10.004.

    Article  CAS  PubMed  Google Scholar 

  148. Tavori H, Rashid S, Fazio S. On the function and homeostasis of PCSK9: reciprocal interaction with LDLR and additional lipid effects. Atherosclerosis. 2015;238:264–70. https://doi.org/10.1016/j.atherosclerosis.2014.12.017.

    Article  CAS  PubMed  Google Scholar 

  149. Gan SS, Ye JQ, Wang L, Qu FJ, Chu CM, Tian YJ, et al. Inhibition of PCSK9 protects against radiation-induced damage of prostate cancer cells. Onco Targets Therapy. 2017;10:2139–46. https://doi.org/10.2147/OTT.S129413.

    Article  CAS  Google Scholar 

  150. Efimova EV, Ricco N, Labay E, Mauceri HJ, Flor AC, Ramamurthy A, et al. HMG-CoA reductase inhibition delays DNA repair and promotes senescence after tumor irradiation. Mol Cancer Ther. 2018;17:407–18. https://doi.org/10.1158/1535-7163.Mct-17-0288.

    Article  CAS  PubMed  Google Scholar 

  151. Mohapatra D, Das B, Suresh V, Parida D, Minz AP, Nayak U, et al. Fluvastatin sensitizes pancreatic cancer cells toward radiation therapy and suppresses radiation- and/or TGF-beta-induced tumor-associated fibrosis. Lab Invest. 2022;102:298–311. https://doi.org/10.1038/s41374-021-00690-7.

    Article  CAS  PubMed  Google Scholar 

  152. He Z, Yuan J, Shen F, Zeng F, Qi P, Wang Z, et al. Atorvastatin enhances effects of radiotherapy on prostate cancer cells and xenograft tumor mice through triggering interaction between Bcl-2 and MSH2. Med Sci Monit. 2020;26: e923560. https://doi.org/10.12659/MSM.923560.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149:1060–72. https://doi.org/10.1016/j.cell.2012.03.042.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Yuan H, Li XM, Zhang XY, Kang R, Tang DL. Identification of ACSL4 as a biomarker and contributor of ferroptosis. Biochem Biophys Res Commun. 2016;478:1338–43. https://doi.org/10.1016/j.bbrc.2016.08.124.

    Article  CAS  PubMed  Google Scholar 

  155. Lei G, Zhang YL, Koppula P, Liu XG, Zhang J, Lin SH, et al. The role of ferroptosis in ionizing radiation-induced cell death and tumor suppression. Cell Res. 2020;30:146–62. https://doi.org/10.1038/s41422-019-0263-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Xie L, Song XR, Yu JM, Guo W, Wei L, Liu YL, et al. Solute carrier protein family may involve in radiation-induced radioresistance of non-small cell lung cancer. J Cancer Res Clin Oncol. 2011;137:1739–47. https://doi.org/10.1007/s00432-011-1050-9.

    Article  CAS  PubMed  Google Scholar 

  157. Angeli JPF, Schneider M, Proneth B, Tyurina YY, Tyurin VA, Hammond VJ, et al. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat Cell Biol. 2014;16:1180-U120. https://doi.org/10.1038/ncb3064.

    Article  CAS  PubMed Central  Google Scholar 

  158. Lang XT, Green MD, Wang WM, Yu JL, Choi JE, Jiang L, et al. Radiotherapy and Immunotherapy promote tumoral lipid oxidation and ferroptosis via synergistic repression of SLC7A11. Cancer Discov. 2019;9:1673–85. https://doi.org/10.1158/2159-8290.Cd-19-0338.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Nagane M, Kanai E, Shibata Y, Shimizu T, Yoshioka C, Maruo T, et al. Sulfasalazine, an inhibitor of the cystine-glutamate antiporter, reduces DNA damage repair and enhances radiosensitivity in murine B16F10 melanoma. PLoS ONE. 2018;13: e0195151. https://doi.org/10.1371/journal.pone.0195151.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Cobler L, Zhang H, Suri P, Park C, Timmerman LA. xCT inhibition sensitizes tumors to gamma-radiation via glutathione reduction. Oncotarget. 2018;9:32280–97. https://doi.org/10.18632/oncotarget.25794.

    Article  PubMed  PubMed Central  Google Scholar 

  161. Lei G, Zhang YL, Hong T, Zhang XD, Liu XG, Mao C, et al. Ferroptosis as a mechanism to mediate p53 function in tumor radiosensitivity. Oncogene. 2021;40:3533–47. https://doi.org/10.1038/s41388-021-01790-w.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Shen D, Luo J, Chen L, Ma W, Mao X, Zhang Y, et al. PARPi treatment enhances radiotherapy-induced ferroptosis and antitumor immune responses via the cGAS signaling pathway in colorectal cancer. Cancer Lett. 2022;550: 215919. https://doi.org/10.1016/j.canlet.2022.215919.

    Article  CAS  PubMed  Google Scholar 

  163. Zhang Z, Lu M, Chen C, Tong X, Li Y, Yang K, et al. Holo-lactoferrin: the link between ferroptosis and radiotherapy in triple-negative breast cancer. Theranostics. 2021;11:3167–82. https://doi.org/10.7150/thno.52028.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Chen Q, Zheng W, Guan J, Liu H, Dan Y, Zhu L, et al. SOCS2-enhanced ubiquitination of SLC7A11 promotes ferroptosis and radiosensitization in hepatocellular carcinoma. Cell Death Differ. 2023;30:137–51. https://doi.org/10.1038/s41418-022-01051-7.

    Article  CAS  PubMed  Google Scholar 

  165. Lin L, Wang S, Deng H, Yang W, Rao L, Tian R, et al. Endogenous labile iron pool-mediated free radical generation for cancer chemodynamic therapy. J Am Chem Soc. 2020;142:15320–30. https://doi.org/10.1021/jacs.0c05604.

    Article  CAS  PubMed  Google Scholar 

  166. Ali MY, Oliva CR, Flor S, Goswami PC, Griguer CE. Cytochrome c oxidase mediates labile iron level and radioresistance in glioblastoma. Free Radic Biol Med. 2022;185:25–35. https://doi.org/10.1016/j.freeradbiomed.2022.04.012.

    Article  CAS  PubMed  Google Scholar 

  167. Rae C, Fragkoulis GI, Chalmers AJ. Cytotoxicity and radiosensitizing activity of the fatty acid synthase inhibitor C75 is enhanced by blocking fatty acid uptake in prostate cancer cells. Adv Radiat Oncol. 2020;5:994–1005. https://doi.org/10.1016/j.adro.2020.06.022.

    Article  PubMed  PubMed Central  Google Scholar 

  168. Lovey J, Nie D, Tovari J, Kenessey I, Timar J, Kandouz M, et al. Radiosensitivity of human prostate cancer cells can be modulated by inhibition of 12-lipoxygenase. Cancer Lett. 2013;335:495–501. https://doi.org/10.1016/j.canlet.2013.03.012.

    Article  CAS  PubMed  Google Scholar 

  169. Ye LF, Chaudhary KR, Zandkarimi F, Harken AD, Kinslow CJ, Upadhyayula PS, et al. Radiation-induced lipid peroxidation triggers ferroptosis and synergizes with ferroptosis inducers. ACS Chem Biol. 2020;15:469–84. https://doi.org/10.1021/acschembio.9b00939.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Sleire L, Skeie BS, Netland IA, Forde HE, Dodoo E, Selheim F, et al. Drug repurposing: sulfasalazine sensitizes gliomas to gamma knife radiosurgery by blocking cystine uptake through system Xc-, leading to glutathione depletion. Oncogene. 2015;34:5951–9. https://doi.org/10.1038/onc.2015.60.

    Article  CAS  PubMed  Google Scholar 

  171. Zhang P, Lo A, Huang Y, Huang G, Liang G, Mott J, et al. Identification of genetic loci that control mammary tumor susceptibility through the host microenvironment. Sci Rep. 2015;5:8919. https://doi.org/10.1038/srep08919.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Ketteler J, Wittka A, Leonetti D, Roy VV, Estephan H, Maier P, et al. Caveolin-1 regulates the ASMase/ceramide-mediated radiation response of endothelial cells in the context of tumor-stroma interactions. Cell Death Dis. 2020;11:228. https://doi.org/10.1038/s41419-020-2418-z.

    Article  PubMed  PubMed Central  Google Scholar 

  173. Dai E, Han L, Liu J, Xie Y, Kroemer G, Klionsky DJ, et al. Autophagy-dependent ferroptosis drives tumor-associated macrophage polarization via release and uptake of oncogenic KRAS protein. Autophagy. 2020;16:2069–83. https://doi.org/10.1080/15548627.2020.1714209.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Wan C, Sun Y, Tian Y, Lu L, Dai X, Meng J, et al. Irradiated tumor cell-derived microparticles mediate tumor eradication via cell killing and immune reprogramming. Sci Adv. 2020;6: eaay9789. https://doi.org/10.1126/sciadv.aay9789.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Tabraue C, Lara PC, De Mirecki-Garrido M, De La Rosa JV, Lopez-Blanco F, Fernandez-Perez L, et al. LXR signaling regulates macrophage survival and inflammation in response to ionizing radiation. Int J Radiat Oncol Biol Phys. 2019;104:913–23. https://doi.org/10.1016/j.ijrobp.2019.03.028.

    Article  CAS  PubMed  Google Scholar 

  176. Teresa Pinto A, Laranjeiro Pinto M, Patricia Cardoso A, Monteiro C, Teixeira Pinto M, Filipe Maia A, et al. Ionizing radiation modulates human macrophages towards a pro-inflammatory phenotype preserving their pro-invasive and pro-angiogenic capacities. Sci Rep. 2016;6:18765. https://doi.org/10.1038/srep18765.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Budhu S, Giese R, Gupta A, Fitzgerald K, Zappasodi R, Schad S, et al. Targeting phosphatidylserine enhances the anti-tumor response to tumor-directed radiation therapy in a preclinical model of melanoma. Cell Rep. 2021;34: 108620. https://doi.org/10.1016/j.celrep.2020.108620.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Gao F, Liu C, Guo J, Sun W, Xian L, Bai D, et al. Radiation-driven lipid accumulation and dendritic cell dysfunction in cancer. Sci Rep. 2015;5:9613. https://doi.org/10.1038/srep09613.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Prima V, Kaliberova LN, Kaliberov S, Curiel DT, Kusmartsev S. COX2/mPGES1/PGE2 pathway regulates PD-L1 expression in tumor-associated macrophages and myeloid-derived suppressor cells. Proc Natl Acad Sci USA. 2017;114:1117–22. https://doi.org/10.1073/pnas.1612920114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Taniguchi K, Karin M. NF-kappaB, inflammation, immunity and cancer: coming of age. Nat Rev Immunol. 2018;18:309–24. https://doi.org/10.1038/nri.2017.142.

    Article  CAS  PubMed  Google Scholar 

  181. Wang W, Green M, Choi JE, Gijon M, Kennedy PD, Johnson JK, et al. CD8(+) T cells regulate tumour ferroptosis during cancer immunotherapy. Nature. 2019;569:270–4. https://doi.org/10.1038/s41586-019-1170-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Wang NH, Lei Z, Yang HN, Tang Z, Yang MQ, Wang Y, et al. Radiation-induced PD-L1 expression in tumor and its microenvironment facilitates cancer-immune escape: a narrative review. Ann Transl Med. 2022;10:1406. https://doi.org/10.21037/atm-22-6049.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Oweida A, Hararah MK, Phan A, Binder D, Bhatia S, Lennon S, et al. Resistance to radiotherapy and PD-L1 blockade is mediated by TIM-3 upregulation and regulatory T-cell infiltration. Clin Cancer Res. 2018;24:5368–80. https://doi.org/10.1158/1078-0432.CCR-18-1038.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Oweida AJ, Darragh L, Phan A, Binder D, Bhatia S, Mueller A, et al. STAT3 modulation of regulatory T cells in response to radiation therapy in head and neck cancer. J Natl Cancer Inst. 2019;111:1339–49. https://doi.org/10.1093/jnci/djz036.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Altwairgi AK, Alghareeb WA, AlNajjar FH, Alhussain H, Alsaeed E, Balbaid AAO, et al. Atorvastatin in combination with radiotherapy and temozolomide for glioblastoma: a prospective phase II study. Invest New Drugs. 2021;39:226–31. https://doi.org/10.1007/s10637-020-00992-5.

    Article  CAS  PubMed  Google Scholar 

  186. Liao Z, Komaki R, Milas L, Yuan C, Kies M, Chang JY, et al. A phase I clinical trial of thoracic radiotherapy and concurrent celecoxib for patients with unfavorable performance status inoperable/unresectable non-small cell lung cancer. Clin Cancer Res. 2005;11:3342–8. https://doi.org/10.1158/1078-0432.CCR-04-1741.

    Article  CAS  PubMed  Google Scholar 

  187. Bi N, Liang J, Zhou Z, Chen D, Fu Z, Yang X, et al. Effect of concurrent chemoradiation with celecoxib vs concurrent chemoradiation alone on survival among patients with non-small cell lung cancer with and without cyclooxygenase 2 genetic variants: a phase 2 randomized clinical trial. JAMA Netw Open. 2019;2: e1918070. https://doi.org/10.1001/jamanetworkopen.2019.18070.

    Article  PubMed  PubMed Central  Google Scholar 

  188. Takhar H, Singhal N, Mislang A, Kumar R, Kim L, Selva-Nayagam S, et al. Phase II study of celecoxib with docetaxel chemoradiotherapy followed by consolidation chemotherapy docetaxel plus cisplatin with maintenance celecoxib in inoperable stage III nonsmall cell lung cancer. Asia Pac J Clin Oncol. 2018;14:91–100. https://doi.org/10.1111/ajco.12749.

    Article  PubMed  Google Scholar 

  189. Cleary JM, Mamon HJ, Szymonifka J, Bueno R, Choi N, Donahue DM, et al. Neoadjuvant irinotecan, cisplatin, and concurrent radiation therapy with celecoxib for patients with locally advanced esophageal cancer. BMC Cancer. 2016;16:468. https://doi.org/10.1186/s12885-016-2485-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Smith MR, Manola J, Kaufman DS, Oh WK, Bubley GJ, Kantoff PW. Celecoxib versus placebo for men with prostate cancer and a rising serum prostate-specific antigen after radical prostatectomy and/or radiation therapy. J Clin Oncol. 2006;24:2723–8. https://doi.org/10.1200/JCO.2005.03.7804.

    Article  CAS  PubMed  Google Scholar 

  191. Weppelmann B, Monkemeier D. The influence of prostaglandin antagonists on radiation therapy of carcinoma of the cervix. Gynecol Oncol. 1984;17:196–9. https://doi.org/10.1016/0090-8258(84)90077-5.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported by the National Natural Science Foundation of China (Grant nos. 82102201, 81874222), and the Key R & D program of Hubei Province (Grant no. 2020BCA068).

Author information

Authors and Affiliations

Authors

Contributions

DA: Investigation, Software, Visualization, Writing—original draft. DZ: Investigation, Visualization. CW: Funding acquisition, Investigation, Project administration, Supervision, Validation, Visualization, Writing—review and editing. KY: Funding acquisition, Project administration, Supervision, Validation, Writing—review and editing.

Corresponding author

Correspondence to Kunyu Yang.

Ethics declarations

Conflict of interest

The authors have no conflict of interest.

Ethical approval and consent to participate

The manuscript does not contain clinical studies or patient data.

Additional information

Publisher's Note

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

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

An, D., Zhai, D., Wan, C. et al. The role of lipid metabolism in cancer radioresistance. Clin Transl Oncol 25, 2332–2349 (2023). https://doi.org/10.1007/s12094-023-03134-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12094-023-03134-4

Keywords

Navigation