The Mevalonate Pathway Drives Tumor Immune Evasion via RalB-Mediated PD-L1 Trafficking
摘要
Tumor metabolic rewiring supports malignant growth and can concurrently dampen antitumor immunity, yet how the tumor-intrinsic mevalonate (MVA) pathway enforces immune escape remains insufficiently defined. Here we show that genetic or pharmacologic disruption of the MVA pathway in tumor cells elicits a robust immune response, increasing intratumoral CD8⁺ T cell infiltration and effector function and thereby constraining tumor growth. Mechanistically, we identify farnesyl pyrophosphate synthase (FDPS) as a central metabolic-immune node that modulates the isoprenoid pool, altering levels of geranylgeranyl pyrophosphate (GGPP) and consequently the geranylgeranylation status of the small GTPase RalB. RalB geranylgeranylation in turn exerts dual control of tumor cell PD-L1, promoting PD-L1 surface availability through regulation of protein trafficking while also augmenting PD-L1 expression at the transcriptional level. Therapeutically, inhibition of FDPS using clinically established nitrogen-containing bisphosphonates potentiates PD-1/CTLA-4 blockades and yields marked antitumor activity in vivo. Collectively, these findings define a tumor-intrinsic MVA-GGPP-RalB axis that drives PD-L1-dependent immune evasion and provide a mechanistic rationale for repurposing nitrogen-containing bisphosphonates as rational combinatorial agents to improve the efficacy of immune checkpoint blockade
参考文献
1. Wherry, E.J., T cell exhaustion. Nature immunology, 2011. 12(6): p. 492-499.
2. Dyck, L. and K.H. Mills, Immune checkpoints and their inhibition in cancer and infectious diseases. European journal of immunology, 2017. 47(5): p. 765-779.
3. Arner, E.N. and J.C. Rathmell, Metabolic programming and immune suppression in the tumor microenvironment. Cancer cell, 2023. 41(3): p. 421-433.
4. Juarez, D. and D.A. Fruman, Targeting the mevalonate pathway in cancer. Trends in cancer, 2021. 7(6): p. 525-540.
5. Hebert, P.R., et al., Cholesterol lowering with statin drugs, risk of stroke, and total mortality: an overview of randomized trials. Jama, 1997. 278(4): p. 313-321.
6. Jain, M.K. and P.M. Ridker, Anti-inflammatory effects of statins: clinical evidence and basic mechanisms. Nature reviews Drug discovery, 2005. 4(12): p. 977-987.
7. Vaughan, C.J., M.B. Murphy, and B.M. Buckley, Statins do more than just lower cholesterol. The Lancet, 1996. 348(9034): p. 1079-1082.
8. Ma, X., et al., Cholesterol Induces CD8(+) T Cell Exhaustion in the Tumor Microenvironment. Cell Metab, 2019. 30(1): p. 143-156.e5.
9. Wang, M. and P.J. Casey, Protein prenylation: unique fats make their mark on biology. Nat Rev Mol Cell Biol, 2016. 17(2): p. 110-22.
10. Charron, G., et al., Alkynyl-farnesol reporters for detection of protein S-prenylation in cells. Mol Biosyst, 2011. 7(1): p. 67-73.
11. Burr, M.L., et al., CMTM6 maintains the expression of PD-L1 and regulates anti-tumour immunity. Nature, 2017. 549(7670): p. 101-105.
12. Chen, X., et al., A membrane-associated MHC-I inhibitory axis for cancer immune evasion. Cell, 2023. 186(18): p. 3903-3920.e21.
13. Li, B., et al., Serotonin transporter inhibits antitumor immunity through regulating the intratumoral serotonin axis. Cell, 2025. 188(14): p. 3823-3842.e21.
14. Thurnher, M. and G. Gruenbacher, T lymphocyte regulation by mevalonate metabolism. Sci Signal, 2015. 8(370): p. re4.
15. Harly, C., et al., Key implication of CD277/butyrophilin-3(BTN3A) in cellular stress sensing by a major human yδ T-cell subset. Blood, 2012. 120(11): p. 2269-79.
16. Vavassori, S., et al., Butyrophilin 3A1 binds phosphorylated antigens and stimulates human y T cells. Nat Immunol, 2013. 14(9): p. 908-16.
17. Yang, W., et al., Potentiating the antitumour response of CD8(+) T cells by modulating cholesterol metabolism. Nature, 2016. 531(7596): p. 651-5.
18. Zhang, X., et al., Farnesyl pyrophosphate potentiates dendritic cell migration in autoimmunity through mitochondrial remodelling. Nat Metab, 2024. 6(11): p. 2118-2137.
19. Lemma, E.Y., et al., Regulation of PD-L1 Trafficking from Synthesis to Degradation. Cancer Immunol Res, 2023. 11(7): p. 866-874.
20. Zerdes, I., et al., Genetic, transcriptional and post-translational regulation of the programmed death protein ligand 1 in cancer: biology and clinical correlations. Oncogene, 2018. 37(34): p. 4639-4661.
21. Chen, S., et al., Mechanisms regulating PD-L1 expression on tumor and immune cells. J Immunother Cancer, 2019. 7(1): p. 305.
22. Yan, Y., et al., Interferon regulatory factor 1(IRF-1) and IRF-2 regulate PD-L1 expression in hepatocellular carcinoma(HCC) cells. Cancer Immunol Immunother, 2020. 69(9): p. 1891-1903.
23. Antonangeli, F., et al., Regulation of PD-L1 Expression by NF-KB in Cancer. Front Immunol, 2020. 11: p. 584626.
24. Marzec, M., et al., Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive protein CD274(PD-L1, B7-H1). Proc Natl Acad Sci U S A, 2008. 105(52): p. 20852-7.
25. Li, C.W., et al., Glycosylation and stabilization of programmed death ligand-1 suppresses T-cell activity. Nat Commun, 2016. 7: p. 12632.
26. Letian, A., et al., Proximity proteome mapping reveals PD-L1-dependent pathways disrupted by anti-PD-L1 antibody specifically in EGFR-mutant lung cancer cells. Cell Commun Signal, 2023. 21(1): p. 58.
27. Mezzadra, R., et al., Identification of CMTM6 and CMTM4 as PD-L1 protein regulators. Nature, 2017. 549(7670): p. 106-110.
28. Ren, Y., et al., TRAPPC4 regulates the intracellular trafficking of PD-L1 and antitumor immunity. Nat Commun, 2021. 12(1): p. 5405.
29. Wang, H., et al., HIP1R targets PD-L1 to lysosomal degradation to alter T cell-mediated cytotoxicity. Nat Chem Biol, 2019. 15(1): p. 42-50.
30. Nielsen, S.F., B.G. Nordestgaard, and S.E. Bojesen, Statin use and reduced cancer-related mortality. N Engl J Med, 2013. 368(6): p. 576-7.
31. Kubatka, P., et al., Statins in oncological research: from experimental studies to clinical practice. Crit Rev Oncol Hematol, 2014. 92(3): p. 296-311.
32. Chae, Y.K., et al., Reduced risk of breast cancer recurrence in patients using ACE inhibitors, ARBs, and/or statins. Cancer Invest, 2011. 29(9): p. 585-93.
33. Garwood, S., Statins and cardiac surgery. J Cardiothorac Vasc Anesth, 2010. 24(6): p. 909-12.
34. Sanfilippo, K.M., et al., Stains Are Associated With Reduced Mortality in Multiple Myeloma. J Clin Oncol, 2016. 34(33): p. 4008-4014.
35. Zhou, W., et al., Targeting the mevalonate pathway suppresses ARID1A-inactivated cancers by promoting pyroptosis. Cancer Cell, 2023. 41(4): p. 740-756.e10.
36. Yang, J., et al., Administration of statins is correlated with favourable prognosis in lung cancer patients receiving immune checkpoint inhibitors. Front Immunol, 2025. 16: p. 1638677.
37. Chen, Y., et al., Mevalonate pathway promotes liver cancer by suppressing ferroptosis through CoQ10 production and selenocysteine-tRNA modification. J Hepatol, 2025. 83(6): p. 1338-1352.
38. Okoye, I., et al., Atorvastatin downregulates co-inhibitory receptor expression by targeting Ras-activated mTOR signalling. Oncotarget, 2017. 8(58): p. 98215-98232.
39. Reszka, A.A. and G.A. Rodan, Nitrogen-containing bisphosphonate mechanism of action. Mini Rev Med Chem, 2004. 4(7): p. 711-9.
40. Xia, Y., et al., The Mevalonate Pathway Is a Druggable Target for Vaccine Adjuvant Discovery. Cell, 2018. 175(4): p. 1059-1073.e21.
41. Hiraga, T., et al., The bisphosphonate ibandronate promotes apoptosis in MDA-MB-231 human breast cancer cells in bone metastases. Cancer Res, 2001. 61(11): p. 4418-24.
42. Hurst, M. and S. Noble, Clodronate: a review of its use in breast cancer. Drugs Aging, 1999. 15(2): p. 143-67.
43. Hortobagyi, G.N., et al., Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastases. Protocol 19 Aredia Breast Cancer Study Group. N Engl J Med, 1996. 335(24): p. 1785-91.
44. Reszka, A.A., et al., Bisphosphonates act directly on the osteoclast to induce caspase cleavage of mst1 kinase during apoptosis. A link between inhibition of the mevalonate pathway and regulation of an apoptosis-promoting kinase. J Biol Chem, 1999. 274(49): p. 34967-73.
45. Sasaki, A., et al., Bisphosphonate risedronate reduces metastatic human breast cancer burden in bone in nude mice. Cancer Res, 1995. 55(16): p. 3551-7.
46. Singh, T., et al., The critical role of bisphosphonates to target bone cancer metastasis: an overview. J Drug Target, 2015. 23(1): p. 1-15.
指标
DOI：
Submission ID：
下载次数
已发布
如何引用
下载引用
利益冲突声明
作者声明无任何需要披露的利益冲突。
Copyright
本预印本的版权持有者为作者/资助方。
保留所有权利。本作品受版权保护。未经版权所有者事先书面许可，不得以任何形式或方式复制、分发或传播本作品的任何部分。