AccScience Publishing / CP / Online First / DOI: 10.36922/CP026190029
Submit to CP
Cite this article
1
Download
66
Views
Supplementary Material
article_cp026190029_supplement_fb4426.pdf
Related Info Links
Google Scholar
More by Authors Links
Xiaozheng Zhang
Yongqiang Fu
Journal Browser
Volume | Year
Issue
Search
Forthcoming Issue
Current Issue
View All
News and Announcements
View All
ORIGINAL RESEARCH ARTICLE

Reduced FOXO1 expression is associated with tumor progression through metabolic and immune dysregulation in kidney renal clear cell carcinoma

Wenyi Hou1 ,  Mengwei Wang1,2 ,  Xiaozheng Zhang3,4,5* ,  Yongqiang Fu6*
Show Less
1 Department of Pharmacy, Academy of Medical Sciences, Shanxi Medical University, Taiyuan, Shanxi, China
2 Department of Medical Statistics, School of Public Health, Shanxi Medical University, Taiyuan, Shanxi, China
3 Key Laboratory of Coal Environmental Pathogenicity and Prevention (Shanxi Medical University), Ministry of Education, Taiyuan, Shanxi, China
4 Shanxi Key Laboratory of Birth Defect and Cell Regeneration, Shanxi Medical University, Taiyuan, Shanxi, China
5 Department of Basic Medicine, Shanxi Medical University, Taiyuan, Shanxi, China
6 Department of Urology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, Taiyuan, Shanxi, China
CP, 026190029 https://doi.org/10.36922/CP026190029
Received: 5 May 2026 | Revised: 3 July 2026 | Accepted: 7 July 2026 | Published online: 21 July 2026
© 2026 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
Download PDF
XML
Cite
Abstract

Kidney renal clear cell carcinoma (KIRC), the most aggressive subtype of renal cancer, is characterized by metabolic reprogramming and an immunosuppressive microenvironment. While forkhead box O1 (FOXO1) is recognized as a pleiotropic regulator of cellular metabolism and immune responses, its potential tumor-suppressive roles in KIRC remain undefined, particularly regarding metabolic–immune crosstalk. We integrated The Cancer Genome Atlas bulk RNA sequencing and clinical data, immunohistochemical validation (The Human Protein Atlas database), and bioinformatics algorithms (single-sample Gene Set Enrichment Analysis [GSEA] and GSEA). Survival modeling (Cox regression and Kaplan–Meier), differential gene expression profiling, and protein–protein interaction network construction were systematically performed to delineate FOXO1’s prognostic relevance and candidate associated mechanisms. Lower FOXO1 expression was associated with unfavorable overall clinical outcomes and more advanced pathology stages and histologic grades. Reduced FOXO1 expression was accompanied by an immunosuppressive tumor microenvironment, marked by elevated regulatory T cell infiltration and diminished effector and memory T cell signatures. Gene Ontology together with GSEA analyses showed a strong association between FOXO1 and lipid metabolism-related pathways. In addition, FOXO1 expression correlated with altered expression of epigenetic regulators, including higher lysine acetyltransferase 2A (KAT2A) and lower E1A-binding protein P300 (EP300), which may be associated with T cell functional states. This study, based on bulk RNA sequencing data and in silico analyses, suggests that FOXO1 could represent a potential regulator of metabolic–immune interactions in KIRC and is associated with tumor progression and remodeling of the immune landscape. Our results support that FOXO1 emerges as a potential indicator of patient prognosis. However, additional experimental studies are required to further substantiate these observations.

Keywords
Forkhead box O1
Kidney renal clear cell carcinoma
Metabolic reprogramming
Immune infiltration
Epigenetic modification
Funding
This work was supported by the Fundamental Research Program of Shanxi Province (202203021221244).
Conflict of interest
The authors declare no conflict of interest.
References
  1. Lopez-Beltran A, Scarpelli M, Montironi R, Kirkali Z. 2004 WHO classification of the renal tumors of the adults. Eur Urol. 2006;49(5):798-805. doi: 10.1016/j.eururo.2005.11.035
  2. Bukavina L, Bensalah K, Bray F, et al. Epidemiology of Renal Cell Carcinoma: 2022 Update. Eur Urol. 2022;82(5):529-542. doi: 10.1016/j.eururo.2022.08.019
  3. Young M, Jackson-Spence F, Beltran L, et al. Renal cell carcinoma. Lancet. 2024;404(10451):476-491. doi: 10.1016/s0140-6736(24)00917-6
  4. Rose TL, Kim WY. Renal Cell Carcinoma: A Review. JAMA. 2024;332(12):1001-1010. doi: 10.1001/jama.2024.12848
  5. Choueiri TK, Powles T, Burotto M, et al. Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2021;384(9):829-841. doi: 10.1056/NEJMoa2026982
  6. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2019;380(12):1116-1127. doi: 10.1056/NEJMoa1816714
  7. Braun DA, Hou Y, Bakouny Z, et al. Interplay of somatic alterations and immune infiltration modulates response to PD-1 blockade in advanced clear cell renal cell carcinoma. Nat Med. 2020;26(6):909-918. doi: 10.1038/s41591-020-0839-y
  8. Jonasch E, Walker CL, Rathmell WK. Clear cell renal cell carcinoma ontogeny and mechanisms of lethality. Nat Rev Nephrol. 2021;17(4):245-261. doi: 10.1038/s41581-020-00359-2
  9. Du W, Zhang L, Brett-Morris A, et al. HIF drives lipid deposition and cancer in ccRCC via repression of fatty acid metabolism. Nat Commun. 2017;8(1):1769. doi: 10.1038/s41467-017-01965-8
  10. Kim WY, Kaelin WG. Role of VHL gene mutation in human cancer. J Clin Oncol. 2004;22(24):4991-5004. doi: 10.1200/jco.2004.05.061
  11. Hakimi AA, Reznik E, Lee CH, et al. An Integrated Metabolic Atlas of Clear Cell Renal Cell Carcinoma. Cancer Cell. 2016;29(1):104-116. doi: 10.1016/j.ccell.2015.12.004
  12. Díaz-Montero CM, Rini BI, Finke JH. The immunology of renal cell carcinoma. Nat Rev Nephrol. 2020;16(12):721-735. doi: 10.1038/s41581-020-0316-3
  13. Chevrier S, Levine JH, Zanotelli VRT, et al. An Immune Atlas of Clear Cell Renal Cell Carcinoma. Cell. 2017;169(4):736-749.e18. doi: 10.1016/j.cell.2017.04.016
  14. Hah YS, Koo KC. Immunology and Immunotherapeutic Approaches for Advanced Renal Cell Carcinoma: A Comprehensive Review. Int J Mol Sci. 2021;22(9):4452. doi: 10.3390/ijms22094452
  15. Giraldo NA, Becht E, Pagès F, et al. Orchestration and Prognostic Significance of Immune Checkpoints in the Microenvironment of Primary and Metastatic Renal Cell Cancer. Clin Cancer Res. 2015;21(13):3031-3040. doi: 10.1158/1078-0432.Ccr-14-2926
  16. Porta C, Bonomi L, Lillaz B, et al. Renal cell carcinoma-induced immunosuppression: an immunophenotypic study of lymphocyte subpopulations and circulating dendritic cells. Anticancer Res. 2007;27(1a):165-173.
  17. Reina-Campos M, Scharping NE, Goldrath AW. CD8(+) T cell metabolism in infection and cancer. Nat Rev Immunol. 2021;21(11):718-738. doi: 10.1038/s41577-021-00537-8
  18. Zhang L, Romero P. Metabolic Control of CD8(+) T Cell Fate Decisions and Antitumor Immunity. Trends Mol Med. 2018;24(1):30-48. doi: 10.1016/j.molmed.2017.11.005
  19. Ho PC, Bihuniak JD, Macintyre AN, et al. Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses. Cell. 2015;162(6):1217-1228. doi: 10.1016/j.cell.2015.08.012
  20. Nakaya M, Xiao Y, Zhou X, et al. Inflammatory T cell responses rely on amino acid transporter ASCT2 facilitation of glutamine uptake and mTORC1 kinase activation. Immunity. 2014;40(5):692-705. doi: 10.1016/j.immuni.2014.04.007
  21. Sinclair LV, Rolf J, Emslie E, Shi YB, Taylor PM, Cantrell DA. Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation. Nat Immunol. 2013;14(5):500-508. doi: 10.1038/ni.2556
  22. Wang R, Dillon CP, Shi LZ, et al. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity. 2011;35(6):871-882. doi: 10.1016/j.immuni.2011.09.021
  23. Gabriel SS, Tsui C, Chisanga D, et al. Transforming growth factor-β-regulated mTOR activity preserves cellular metabolism to maintain long-term T cell responses in chronic infection. Immunity. 2021;54(8):1698-1714.e5. doi: 10.1016/j.immuni.2021.06.007
  24. Yu YR, Imrichova H, Wang H, et al. Disturbed mitochondrial dynamics in CD8(+) TILs reinforce T cell exhaustion. Nat Immunol. 2020;21(12):1540-1551. doi: 10.1038/s41590-020-0793-3
  25. Scharping NE, Menk AV, Moreci RS, et al. The Tumor Microenvironment Represses T Cell Mitochondrial Biogenesis to Drive Intratumoral T Cell Metabolic Insufficiency and Dysfunction. Immunity. 2016;45(2):374-388. doi: 10.1016/j.immuni.2016.07.009
  26. Reinfeld BI, Madden MZ, Wolf MM, et al. Cell-programmed nutrient partitioning in the tumour microenvironment. Nature. 2021;593(7858):282-288. doi: 10.1038/s41586-021-03442-1
  27. Xu S, Chaudhary O, Rodríguez-Morales P, 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(7):1561-1577.e7. doi: 10.1016/j.immuni.2021.05.003
  28. Webb AE, Kundaje A, Brunet A. Characterization of the direct targets of FOXO transcription factors throughout evolution. Aging Cell. 2016;15(4):673-685. doi: 10.1111/acel.12479
  29. Lin A, Yao J, Zhuang L, et al. The FoxO-BNIP3 axis exerts a unique regulation of mTORC1 and cell survival under energy stress. Oncogene. 2014;33(24):3183-3194. doi: 10.1038/onc.2013.273
  30. Accili D, Arden KC. FoxOs at the crossroads of cellular metabolism, differentiation, and transformation. Cell. 2004;117(4):421-426. doi: 10.1016/s0092-8674(04)00452-0
  31. Doan AE, Mueller KP, Chen AY, et al. FOXO1 is a master regulator of memory programming in CAR T cells. Nature. 2024;629(8010):211-218. doi: 10.1038/s41586-024-07300-8
  32. Marcel N, Hedrick SM. A key control point in the T cell response to chronic infection and neoplasia: FOXO1. Curr Opin Immunol. 2020;63:51-60. doi: 10.1016/j.coi.2020.02.001
  33. Li J, Wang C, Xu X, Chen J, Guo H. An extensive analysis of the prognostic and immune role of FOXO1 in various types of cancer. Braz J Med Biol Res. 2024;57:e13378. doi: 10.1590/1414-431X2024e13378
  34. Gan B, Lim C, Chu G, et al. FoxOs enforce a progression checkpoint to constrain mTORC1-activated renal tumorigenesis. Cancer Cell. 2010;18(5):472-484. doi: 10.1016/j.ccr.2010.10.019
  35. Lin A, Piao HL, Zhuang L, Sarbassov dos D, Ma L, Gan B. FoxO transcription factors promote AKT Ser473 phosphorylation and renal tumor growth in response to pharmacologic inhibition of the PI3K-AKT pathway. Cancer Res. 2014;74(6):1682-1693. doi: 10.1158/0008-5472.Can-13-1729
  36. Liu J, Lichtenberg T, Hoadley KA, et al. An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics. Cell. 2018;173(2):400-416.e11. doi: 10.1016/j.cell.2018.02.052
  37. Bindea G, Mlecnik B, Tosolini M, et al. Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer. Immunity. 2013;39(4):782-795. doi: 10.1016/j.immuni.2013.10.003
  38. Ma S, Dahabieh MS, Mann TH, et al. Nutrient-driven histone code determines exhausted CD8(+) T cell fates. Science. 2025;387(6734):eadj3020. doi: 10.1126/science.adj3020
  39. Kaymak I, Watson MJ, Oswald BM, et al. ACLY and ACSS2 link nutrient-dependent chromatin accessibility to CD8 T cell effector responses. J Exp Med. 2024;221(9). doi: 10.1084/jem.20231820
  40. Deng Y, Wang F, Hughes T, Yu J. FOXOs in cancer immunity: Knowns and unknowns. Semin Cancer Biol. 2018;50:53-64. doi: 10.1016/j.semcancer.2018.01.005
  41. Fan W, Morinaga H, Kim JJ, et al. FoxO1 regulates Tlr4 inflammatory pathway signalling in macrophages. EMBO J. 2010;29(24):4223-4236. doi: 10.1038/emboj.2010.268
  42. Xiao W, Dong G, Pacios S, et al. FOXO1 deletion reduces dendritic cell function and enhances susceptibility to periodontitis. Am J Pathol. 2015;185(4):1085-1093. doi: 10.1016/j.ajpath.2014.12.006
  43. Dengler HS, Baracho GV, Omori SA, et al. Distinct functions for the transcription factor Foxo1 at various stages of B cell differentiation. Nat Immunol. 2008;9(12):1388-1398. doi: 10.1038/ni.1667
  44. Chen J, Limon JJ, Blanc C, Peng SL, Fruman DA. Foxo1 regulates marginal zone B-cell development. Eur J Immunol. 2010;40(7):1890-1896. doi: 10.1002/eji.200939817
  45. Kerdiles YM, Stone EL, Beisner DR, et al. Foxo transcription factors control regulatory T cell development and function. Immunity. 2010;33(6):890-904. doi: 10.1016/j.immuni.2010.12.002
  46. Kim EH, Sullivan JA, Plisch EH, et al. Signal integration by Akt regulates CD8 T cell effector and memory differentiation. J Immunol. 2012;188(9):4305-4314. doi: 10.4049/jimmunol.1103568
  47. Rao RR, Li Q, Gubbels Bupp MR, Shrikant PA. Transcription factor Foxo1 represses T-bet-mediated effector functions and promotes memory CD8(+) T cell differentiation. Immunity. 2012;36(3):374-387. doi: 10.1016/j.immuni.2012.01.015
  48. Hess Michelini R, Doedens AL, Goldrath AW, Hedrick SM. Differentiation of CD8 memory T cells depends on Foxo1. J Exp Med. 2013;210(6):1189-1200. doi: 10.1084/jem.20130392
  49. Vuong L, Kotecha RR, Voss MH, Hakimi AA. Tumor Microenvironment Dynamics in Clear-Cell Renal Cell Carcinoma. Cancer Discov. 2019;9(10):1349-1357. doi: 10.1158/2159-8290.Cd-19-0499
  50. Şenbabaoğlu Y, Gejman RS, Winer AG, et al. Tumor immune microenvironment characterization in clear cell renal cell carcinoma identifies prognostic and immunotherapeutically relevant messenger RNA signatures. Genome Biol. 2016;17(1):231. doi: 10.1186/s13059-016-1092-z
  51. Nakano O, Sato M, Naito Y, et al. Proliferative activity of intratumoral CD8(+) T-lymphocytes as a prognostic factor in human renal cell carcinoma: clinicopathologic demonstration of antitumor immunity. Cancer Res. 2001;61(13):5132-5136.
  52. Wang QJ, Hanada K, Robbins PF, Li YF, Yang JC. Distinctive features of the differentiated phenotype and infiltration of tumor-reactive lymphocytes in clear cell renal cell carcinoma. Cancer Res. 2012;72(23):6119-6129. doi: 10.1158/0008-5472.Can-12-0588
  53. Lasorsa F, di Meo NA, Rutigliano M, et al. Immune Checkpoint Inhibitors in Renal Cell Carcinoma: Molecular Basis and Rationale for Their Use in Clinical Practice. Biomedicines. 2023;11(4):1071. doi: 10.3390/biomedicines11041071
  54. Lasorsa F, Rutigliano M, Milella M, et al. Cellular and Molecular Players in the Tumor Microenvironment of Renal Cell Carcinoma. J Clin Med. 2023;12(12):3888. doi: 10.3390/jcm12123888
  55. Boreddy SR, Pramanik KC, Srivastava SK. Pancreatic tumor suppression by benzyl isothiocyanate is associated with inhibition of PI3K/AKT/FOXO pathway. Clin Cancer Res. 2011;17(7):1784-1795. doi: 10.1158/1078-0432.Ccr-10-1891
  56. Duan S, Huang W, Liu X, et al. IMPDH2 promotes colorectal cancer progression through activation of the PI3K/AKT/ mTOR and PI3K/AKT/FOXO1 signaling pathways. J Exp Clin Cancer Res. 2018;37(1):304. doi: 10.1186/s13046-018-0980-3
  57. Wang D, Yang L, Yu W, et al. Colorectal cancer cell-derived CCL20 recruits regulatory T cells to promote chemoresistance via FOXO1/CEBPB/NF-κB signaling. J Immunother Cancer. 2019;7(1):215. doi: 10.1186/s40425-019-0701-2
  58. Lucarelli G, Loizzo D, Franzin R, et al. Metabolomic insights into pathophysiological mechanisms and biomarker discovery in clear cell renal cell carcinoma. Expert Rev Mol Diagn. 2019;19(5):397-407. doi: 10.1080/14737159.2019.1607729
  59. di Meo NA, Lasorsa F, Rutigliano M, et al. Renal Cell Carcinoma as a Metabolic Disease: An Update on Main Pathways, Potential Biomarkers, and Therapeutic Targets. Int J Mol Sci. 2022;23(22):14360. doi: 10.3390/ijms232214360
  60. Hu J, Wang SG, Hou Y, et al. Multi-omic profiling of clear cell renal cell carcinoma identifies metabolic reprogramming associated with disease progression. Nat Genet. 2024;56(3):442-457. doi: 10.1038/s41588-024-01662-5
  61. Eijkelenboom A, Burgering BM. FOXOs: signalling integrators for homeostasis maintenance. Nat Rev Mol Cell Biol. 2013;14(2):83-97. doi: 10.1038/nrm3507
  62. Kousteni S. FoxO1: a molecule for all seasons. J Bone Miner Res. 2011;26(5):912-917. doi: 10.1002/jbmr.306
  63. Fu X, Shi Y, Qi T, et al. Precise design strategies of nanomedicine for improving cancer therapeutic efficacy using subcellular targeting. Signal Transduct Target Ther. 2020;5(1):262. doi: 10.1038/s41392-020-00342-0
  64. Bennie LA, McCarthy HO, Coulter JA. Enhanced nanoparticle delivery exploiting tumour-responsive formulations. Cancer Nanotechnol. 2018;9(1):10. doi: 10.1186/s12645-018-0044-6
  65. Yamada Y, Sato Y, Nakamura T, Harashima H. Evolution of drug delivery system from viewpoint of controlled intracellular trafficking and selective tissue targeting toward future nanomedicine. J Control Release. 2020;327:533-545. doi: 10.1016/j.jconrel.2020.09.007
Share
Back to top
Cancer Plus, Electronic ISSN: 2661-3840 Print ISSN: 2661-3832, Published by AccScience Publishing
We use cookies on our website to ensure you get the best experience.
Read more about our cookies here
Accept