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image of An Immune Cell Activation Signature for Non - Small Cell Lung Cancer Revealed Tumor Microenvironment Heterogeneity and the Role of RORA in Regulating ZNF490/NDUFA12 Axis
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Abstract

Introduction

The development and progression of non-small cell lung cancer (NSCLC) are intricately linked to immune cell activation, but its related signature has not been reported.

Methods

This study combines and approaches. TCGA-NSCLC and Gene Expression Omnibus (GEO) datasets were utilized to develop and validate a prognostic signature based on cell activation genes. The signature’s validity was assessed through the identification of genomic, transcriptomic, tumor microenvironment (TME), and single-cell infiltration characteristics. The function of the candidate gene RORA was verified using CCK8, apoptosis, colony formation, wound healing, and transwell assays. The detailed mechanism of RORA was investigated through ChIP-PCR, luciferase assays, Western blot, and ROS detection.

Results

The prognostic signature was constructed from TCGA-NSCLC datasets and validated in six independent datasets (GSE30219, GSE33072, GSE37745, GSE41271, GSE42127, GSE50081). The signature was associated with LRP1B and RYR2 mutations, NSCLC-related pathways, drug response, and immune cell infiltration. The candidate gene RORA significantly inhibits the proliferation and migration abilities of NSCLC cell lines (A549 and NCI-H1299). Furthermore, the transcription factor RORA promotes ZNF490 expression, which subsequently inhibits NUDFs expression and oxidative phosphorylation (oxphos).

Discussion

The signature highlighted its significance with genomic features that were frequently reported as prognostic indicators (LRP1B and RYR2 mutations, cancer-related infiltration and pathway infiltration), and putative treatment response (IC in the TCGA dataset). Its detailed mechanism of candidate gene RORA revealed its role in oxphos, highlighting the crosstalk between metabolism and immune activation.

Conclusion

The model is robust and effectively reflects NSCLC heterogeneity while predicting prognosis. RORA promotes the expression of ZNF490 to inhibit NUDFs and oxidative phosphorylation.

© 2026 The Author(s). Published by Bentham Science Publishers.
This is an open access article published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode
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2026-01-23
2026-01-31

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References

  1. Chen P. Liu Y. Wen Y. Zhou C. Non-small cell lung cancer in China. Cancer Commun. 2022 42 10 937 970 10.1002/cac2.12359 36075878
    [Google Scholar]
  2. Garon E.B. Hellmann M.D. Rizvi N.A. Carcereny E. Leighl N.B. Ahn M.J. Eder J.P. Balmanoukian A.S. Aggarwal C. Horn L. Patnaik A. Gubens M. Ramalingam S.S. Felip E. Goldman J.W. Scalzo C. Jensen E. Kush D.A. Hui R. Five-year overall survival for patients with advanced non‒small-cell lung cancer treated with pembrolizumab: Results from the phase I KEYNOTE-001 study. J. Clin. Oncol. 2019 37 28 2518 2527 10.1200/JCO.19.00934 31154919
    [Google Scholar]
  3. Mathieson L. Koppensteiner L. Dorward D.A. O’Connor R.A. Akram A.R. Cancer-associated fibroblasts expressing fibroblast activation protein and podoplanin in non-small cell lung cancer predict poor clinical outcome. Br. J. Cancer 2024 130 11 1758 1769 10.1038/s41416‑024‑02671‑1 38582812
    [Google Scholar]
  4. Liu X. Zhang Z. Yuan J. Yu J. Chen D. Spatial interaction and functional status of CD68+SHP2+ macrophages in tumor microenvironment correlate with overall survival of NSCLC. Front. Immunol. 2024 15 1396719 10.3389/fimmu.2024.1396719 38799432
    [Google Scholar]
  5. Fan G. Xie T. Yang M. Li L. Tang L. Han X. Shi Y. Spatial analyses revealed S100P + TFF1 + tumor cells in spread through air spaces samples correlated with undesirable therapy response in non-small cell lung cancer. J. Transl. Med. 2024 22 1 917 10.1186/s12967‑024‑05722‑6 39385235
    [Google Scholar]
  6. Arora S. Singh P. Ahmad S. Ahmad T. Dohare R. Almatroodi S.A. Alrumaihi F. Rahmani A.H. Syed M.A. Comprehensive integrative analysis reveals the association of KLF4 with macrophage infiltration and polarization in lung cancer microenvironment. Cells 2021 10 8 2091 10.3390/cells10082091 34440860
    [Google Scholar]
  7. Sarsembayeva A. Kienzl M. Gruden E. Ristic D. Maitz K. Valadez-Cosmes P. Santiso A. Hasenoehrl C. Brcic L. Lindenmann J. Kargl J. Schicho R. Cannabinoid receptor 2 plays a pro-tumorigenic role in non-small cell lung cancer by limiting anti-tumor activity of CD8+ T and NK cells. Front. Immunol. 2023 13 997115 10.3389/fimmu.2022.997115 36700219
    [Google Scholar]
  8. Chen X. Gao A. Zhang F. Yang Z. Wang S. Fang Y. Li J. Wang J. Shi W. Wang L. Zheng Y. Sun Y. ILT4 inhibition prevents TAM- and dysfunctional T cell- mediated immunosuppression and enhances the efficacy of anti-PD-L1 therapy in NSCLC with EGFR activation. Theranostics 2021 11 7 3392 3416 10.7150/thno.52435 33537094
    [Google Scholar]
  9. Ceccarelli S. Pasqua Marzolesi V. Vannucci J. Bellezza G. Floridi C. Nocentini G. Cari L. Traina G. Petri D. Puma F. Conte C. Toll-like receptor 4 and 8 are overexpressed in lung biopsies of human non-small cell lung carcinoma. Lung 2025 203 1 38 10.1007/s00408‑025‑00793‑8 40025339
    [Google Scholar]
  10. Kim J.Y. Shin J.H. Kim M.J. Kang Y. Lee J.S. Son J. Jeong S.K. Kim D. Kim D.H. Chun E. Lee K.Y. β-arrestin 2 negatively regulates lung cancer progression by inhibiting the TRAF6 signaling axis for NF-κB activation and autophagy induced by TLR3 and TLR4. Cell Death Dis. 2023 14 7 422 10.1038/s41419‑023‑05945‑3 37443143
    [Google Scholar]
  11. Wu S. Chen J. Huang E. Zhang Y. Pan-cancer analysis and validation of opioid-related receptors reveals the immunotherapeutic value of toll-like receptor 4. Int. J. Gen. Med. 2023 16 5527 5548 10.2147/IJGM.S434076 38034898
    [Google Scholar]
  12. Baker K.J. Buskiewicz E. Finucane M. Chelliah A. Burke L. Houston A. Brint E. IL-36 expression is increased in NSCLC with IL-36 stimulation of lung cancer cells promoting a pro-tumorigenic phenotype. Cytokine 2023 165 156170 10.1016/j.cyto.2023.156170 36931148
    [Google Scholar]
  13. Wu J. Zhang Q. Wu J. Yang Z. Liu X. Lou C. Wang X. Peng J. Zhang J. Shang Z. Xiao J. Wang N. Zhang R. Zhou J. Wang Y. Hu Z. Zhang R. Zhang J. Zeng Z. IL-8 from CD248-expressing cancer-associated fibroblasts generates cisplatin resistance in non-small cell lung cancer. J. Cell. Mol. Med. 2024 28 4 18185 10.1111/jcmm.18185 38396325
    [Google Scholar]
  14. Oryani M.A. Mohammad Al- Mosawi A.K. Javid H. Tajaldini M. Karimi-Shahri M. A bioligical perspective on the role of miR-206 in colorectal cancer. Gene 2025 961 149552 10.1016/j.gene.2025.149552 40339768
    [Google Scholar]
  15. Abbosh C. Hodgson D. Doherty G.J. Gale D. Black J.R.M. Horn L. Reis-Filho J.S. Swanton C. Implementing circulating tumor DNA as a prognostic biomarker in resectable non-small cell lung cancer. Trends Cancer 2024 10 7 643 654 10.1016/j.trecan.2024.04.004 38839544
    [Google Scholar]
  16. Wood C. Lyniv L. Isaacs J.M. Kaufman J.M. Oduah E.I. Clarke J. Crawford J. Stinchcombe T. Tong B.C. Wang X. Gu L. Wigle D. Dragnev K.H. Antonia S.J. Weinhold K. Ready N. Perioperative pembrolizumab in early-stage non-small cell lung cancer (NSCLC): Safety, efficacy, and exploratory biomarker analysis. J. Immunother. Cancer 2025 13 2 010395 10.1136/jitc‑2024‑010395 39904561
    [Google Scholar]
  17. Liu T.Y. Yan J.S. Li X. Xu L. Hao J.L. Zhao S.Y. Hu Q.L. Na F.J. Li H.M. Zhao Y. Zhao M.F. FGL1: A novel biomarker and target for non-small cell lung cancer, promoting tumor progression and metastasis through KDM4A/STAT3 transcription mechanism. J. Exp. Clin. Cancer Res. 2024 43 1 213 10.1186/s13046‑024‑03140‑6 39085849
    [Google Scholar]
  18. Wang S. Fan G. Li L. He Y. Lou N. Xie T. Dai L. Gao R. Yang M. Shi Y. Han X. Integrative analyses of bulk and single-cell RNA-seq identified cancer-associated fibroblasts-related signature as a prognostic factor for immunotherapy in NSCLC. Cancer Immunol. Immunother. 2023 72 7 2423 2442 10.1007/s00262‑023‑03428‑0 37010552
    [Google Scholar]
  19. Koeck S. Amann A. Kern J. Zwierzina M. Lorenz E. Sopper S. Zwierzina H. Mildner F. Sykora M. Sprung S. Hackl H. Augustin F. Maier H.T. Pircher A. Pall G. Wolf D. Gamerith G. Whole stromal fibroblast signature is linked to specific chemokine and immune infiltration patterns and to improved survival in NSCLC. Onco. Immunology 2023 12 1 2274130 10.1080/2162402X.2023.2274130 38126028
    [Google Scholar]
  20. Rousseaux S. Debernardi A. Jacquiau B. Vitte A.L. Vesin A. Nagy-Mignotte H. Moro-Sibilot D. Brichon P.Y. Lantuejoul S. Hainaut P. Laffaire J. de Reyniès A. Beer D.G. Timsit J.F. Brambilla C. Brambilla E. Khochbin S. Ectopic activation of germline and placental genes identifies aggressive metastasis-prone lung cancers. Sci. Transl. Med. 2013 5 186 186ra66 10.1126/scitranslmed.3005723 23698379
    [Google Scholar]
  21. Byers L.A. Diao L. Wang J. Saintigny P. Girard L. Peyton M. Shen L. Fan Y. Giri U. Tumula P.K. Nilsson M.B. Gudikote J. Tran H. Cardnell R.J.G. Bearss D.J. Warner S.L. Foulks J.M. Kanner S.B. Gandhi V. Krett N. Rosen S.T. Kim E.S. Herbst R.S. Blumenschein G.R. Lee J.J. Lippman S.M. Ang K.K. Mills G.B. Hong W.K. Weinstein J.N. Wistuba I.I. Coombes K.R. Minna J.D. Heymach J.V. An epithelial-mesenchymal transition gene signature predicts resistance to EGFR and PI3K inhibitors and identifies Axl as a therapeutic target for overcoming EGFR inhibitor resistance. Clin. Cancer Res. 2013 19 1 279 290 10.1158/1078‑0432.CCR‑12‑1558 23091115
    [Google Scholar]
  22. Khadse A. Haakensen V.D. Silwal-Pandit L. Hamfjord J. Micke P. Botling J. Brustugun O.T. Lingjærde O.C. Helland Å. Kure E.H. Prognostic significance of the loss of heterozygosity of KRAS in early-stage lung adenocarcinoma. Front. Oncol. 2022 12 873532 10.3389/fonc.2022.873532 35574381
    [Google Scholar]
  23. Parra E.R. Behrens C. Rodriguez-Canales J. Lin H. Mino B. Blando J. Zhang J. Gibbons D.L. Heymach J.V. Sepesi B. Swisher S.G. Weissferdt A. Kalhor N. Izzo J. Kadara H. Moran C. Lee J.J. Wistuba I.I. Image analysis–based assessment of pd-l1 and tumor-associated immune cells density supports distinct intratumoral microenvironment groups in non–small cell lung carcinoma patients. Clin. Cancer Res. 2016 22 24 6278 6289 10.1158/1078‑0432.CCR‑15‑2443 27252415
    [Google Scholar]
  24. Hight S.K. Mootz A. Kollipara R.K. McMillan E. Yenerall P. Otaki Y. Li L.S. Avila K. Peyton M. Rodriguez-Canales J. Mino B. Villalobos P. Girard L. Dospoy P. Larsen J. White M.A. Heymach J.V. Wistuba I.I. Kittler R. Minna J.D. An in vivo functional genomics screen of nuclear receptors and their co-regulators identifies FOXA1 as an essential gene in lung tumorigenesis. Neoplasia 2020 22 8 294 310 10.1016/j.neo.2020.04.005 32512502
    [Google Scholar]
  25. Der S.D. Sykes J. Pintilie M. Zhu C.Q. Strumpf D. Liu N. Jurisica I. Shepherd F.A. Tsao M.S. Validation of a histology-independent prognostic gene signature for early-stage, non-small-cell lung cancer including stage IA patients. J. Thorac. Oncol. 2014 9 1 59 64 10.1097/JTO.0000000000000042 24305008
    [Google Scholar]
  26. Zhu J. Fan Y. Xiong Y. Wang W. Chen J. Xia Y. Lei J. Gong L. Sun S. Jiang T. Delineating the dynamic evolution from preneoplasia to invasive lung adenocarcinoma by integrating single-cell RNA sequencing and spatial transcriptomics. Exp. Mol. Med. 2022 54 11 2060 2076 10.1038/s12276‑022‑00896‑9 36434043
    [Google Scholar]
  27. Liberzon A. Birger C. Thorvaldsdóttir H. Ghandi M. Mesirov J.P. Tamayo P. The Molecular Signatures Database (MSigDB) hallmark gene set collection. Cell Syst. 2015 1 6 417 425 10.1016/j.cels.2015.12.004 26771021
    [Google Scholar]
  28. Ritchie M.E. Phipson B. Wu D. Hu Y. Law C.W. Shi W. Smyth G.K. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015 43 7 47 10.1093/nar/gkv007 25605792
    [Google Scholar]
  29. Wu T. Hu E. Xu S. Chen M. Guo P. Dai Z. Feng T. Zhou L. Tang W. Zhan L. Fu X. Liu S. Bo X. Yu G. clusterProfiler 4.0: A universal enrichment tool for interpreting omics data. Innovation 2021 2 3 100141 10.1016/j.xinn.2021.100141 34557778
    [Google Scholar]
  30. Skidmore Z.L. Wagner A.H. Lesurf R. Campbell K.M. Kunisaki J. Griffith O.L. Griffith M. GenVisR: Genomic Visualizations in R. Bioinformatics 2016 32 19 3012 3014 10.1093/bioinformatics/btw325 27288499
    [Google Scholar]
  31. Li T. Fu J. Zeng Z. Cohen D. Li J. Chen Q. Li B. Liu X.S. TIMER2.0 for analysis of tumor-infiltrating immune cells. Nucleic Acids Res. 2020 48 W1 W509 W514 10.1093/nar/gkaa407 32442275
    [Google Scholar]
  32. Aran D. Hu Z. Butte A.J. xCell: Digitally portraying the tissue cellular heterogeneity landscape. Genome Biol. 2017 18 1 220 10.1186/s13059‑017‑1349‑1 29141660
    [Google Scholar]
  33. Chen B. Khodadoust M.S. Liu C.L. Newman A.M. Alizadeh A.A. Profiling tumor infiltrating immune cells with CIBERSORT. Methods Mol. Biol. 2018 1711 243 259 10.1007/978‑1‑4939‑7493‑1_12 29344893
    [Google Scholar]
  34. Plattner C. Finotello F. Rieder D. Deconvoluting tumor-infiltrating immune cells from RNA-seq data using quanTIseq. Methods Enzymol. 2020 636 261 285 10.1016/bs.mie.2019.05.056 32178821
    [Google Scholar]
  35. Racle J. Gfeller D. EPIC: A tool to estimate the proportions of different cell types from bulk gene expression data. Methods Mol. Biol. 2020 2120 233 248 10.1007/978‑1‑0716‑0327‑7_17 32124324
    [Google Scholar]
  36. Becht E. Giraldo N.A. Lacroix L. Buttard B. Elarouci N. Petitprez F. Selves J. Laurent-Puig P. Sautès-Fridman C. Fridman W.H. de Reyniès A. Estimating the population abundance of tissue-infiltrating immune and stromal cell populations using gene expression. Genome Biol. 2016 17 1 218 10.1186/s13059‑016‑1070‑5 27765066
    [Google Scholar]
  37. Maeser D. Gruener R.F. Huang R.S. oncoPredict: An R package for predicting in vivo or cancer patient drug response and biomarkers from cell line screening data. Brief. Bioinform. 2021 22 6 bbab260 10.1093/bib/bbab260 34260682
    [Google Scholar]
  38. Hao Y. Stuart T. Kowalski M.H. Choudhary S. Hoffman P. Hartman A. Srivastava A. Molla G. Madad S. Fernandez-Granda C. Satija R. Dictionary learning for integrative, multimodal and scalable single-cell analysis. Nat. Biotechnol. 2024 42 2 293 304 10.1038/s41587‑023‑01767‑y 37231261
    [Google Scholar]
  39. Murphy A.E. Skene N.G. A balanced measure shows superior performance of pseudobulk methods in single-cell RNA-sequencing analysis. Nat. Commun. 2022 13 1 7851 10.1038/s41467‑022‑35519‑4 36550119
    [Google Scholar]
  40. Brunson J. ggalluvial: Layered Grammar for Alluvial Plots. J. Open Source Softw. 2020 5 49 2017 10.21105/joss.02017 36919162
    [Google Scholar]
  41. Jin S. Guerrero-Juarez C.F. Zhang L. Chang I. Ramos R. Kuan C.H. Myung P. Plikus M.V. Nie Q. Inference and analysis of cell-cell communication using CellChat. Nat. Commun. 2021 12 1 1088 10.1038/s41467‑021‑21246‑9 33597522
    [Google Scholar]
  42. Xu X. Chai K. Chen Y. Lin Y. Zhang S. Li X. Qiao W. Tan J. Interferon activates promoter of Nmi gene via interferon regulator factor-1. Mol. Cell. Biochem. 2018 441 1-2 165 171 10.1007/s11010‑017‑3182‑y 28913576
    [Google Scholar]
  43. Ji D. Feng Y. Peng W. Li J. Gu Q. Zhang Z. Qian W. Wang Q. Zhang Y. Sun Y. NMI promotes cell proliferation through TGFβ/Smad pathway by upregulating STAT1 in colorectal cancer. J. Cell. Physiol. 2020 235 1 429 441 10.1002/jcp.28983 31230364
    [Google Scholar]
  44. Finotto L. Cole B. Giese W. Baumann E. Claeys A. Vanmechelen M. Decraene B. Derweduwe M. Dubroja Lakic N. Shankar G. Nagathihalli Kantharaju M. Albrecht J.P. Geudens I. Stanchi F. Ligon K.L. Boeckx B. Lambrechts D. Harrington K. Van Den Bosch L. De Vleeschouwer S. De Smet F. Gerhardt H. Single- cell profiling and zebrafish avatars reveal LGALS1 as immunomodulating target in glioblastoma. EMBO Mol. Med. 2023 15 11 18144 10.15252/emmm.202318144 37791581
    [Google Scholar]
  45. Ye C. Chong W. Liu Y. Zhu X. Ren H. Xu K. Xie X. Du F. Zhang Z. Wang M. Ma T. Shang L. Li L. Chen H. Suppression of tumorigenesis in LUAD by LRP1B through regulation of the IL-6-JAK-STAT3 pathway. Am. J. Cancer Res. 2023 13 7 2886 2905 37560001
    [Google Scholar]
  46. Moutafi M.K. Molero M. Martinez Morilla S. Baena J. Vathiotis I.A. Gavrielatou N. Castro-Labrador L. de Garibay G.R. Adradas V. Orive D. Valencia K. Calvo A. Montuenga L.M. Ponce Aix S. Schalper K.A. Herbst R.S. Paz-Ares L. Rimm D.L. Zugazagoitia J. Spatially resolved proteomic profiling identifies tumor cell CD44 as a biomarker associated with sensitivity to PD-1 axis blockade in advanced non-small-cell lung cancer. J. Immunother. Cancer 2022 10 8 004757 10.1136/jitc‑2022‑004757 36002182
    [Google Scholar]
  47. Nurwidya F. Takahashi F. Kato M. Baskoro H. Hidayat M. Wirawan A. Takahashi K. CD44 silencing decreases the expression of stem cell-related factors induced by transforming growth factor β1 and tumor necrosis factor α in lung cancer: Preliminary findings. Bosn. J. Basic Med. Sci. 2017 17 3 228 234 10.17305/bjbms.2017.1966 28446126
    [Google Scholar]
  48. Garrido-Martin E.M. Mellows T.W.P. Clarke J. Ganesan A.P. Wood O. Cazaly A. Seumois G. Chee S.J. Alzetani A. King E.V. Hedrick C.C. Thomas G. Friedmann P.S. Ottensmeier C.H. Vijayanand P. Sanchez-Elsner T. M1hot tumor-associated macrophages boost tissue-resident memory T cells infiltration and survival in human lung cancer. J. Immunother. Cancer 2020 8 2 000778 10.1136/jitc‑2020‑000778 32699181
    [Google Scholar]
  49. Watanabe H. Ohashi K. Nishii K. Seike K. Makimoto G. Hotta K. Maeda Y. Kiura K. A long-term response to nivolumab in a case of PD-L1-negative lung adenocarcinoma with an EGFR Mutation and surrounding PD-L1-positive tumor-associated macrophages. Intern. Med. 2019 58 20 3033 3037 10.2169/internalmedicine.2875‑19 31292383
    [Google Scholar]
  50. Guo X. Zhang Y. Zheng L. Zheng C. Song J. Zhang Q. Kang B. Liu Z. Jin L. Xing R. Gao R. Zhang L. Dong M. Hu X. Ren X. Kirchhoff D. Roider H.G. Yan T. Zhang Z. Global characterization of T cells in non-small-cell lung cancer by single-cell sequencing. Nat. Med. 2018 24 7 978 985 10.1038/s41591‑018‑0045‑3 29942094
    [Google Scholar]
  51. Zheng Z. Wieder T. Mauerer B. Schäfer L. Kesselring R. Braumüller H. T cells in colorectal cancer: Unravelling the function of different T cell subsets in the tumor microenvironment. Int. J. Mol. Sci. 2023 24 14 11673 10.3390/ijms241411673 37511431
    [Google Scholar]
  52. Anichini A. Perotti V.E. Sgambelluri F. Mortarini R. Immune escape mechanisms in non small cell lung cancer. Cancers 2020 12 12 3605 10.3390/cancers12123605 33276569
    [Google Scholar]
  53. Sun S.Y. Is tumor microenvironment important for targeted therapy in lung cancer? Cancer Lett. 2024 604 217203 10.1016/j.canlet.2024.217203 39236847
    [Google Scholar]
  54. Tu E. McGlinchey K. Wang J. Martin P. Ching S.L.K. Floc’h N. Kurasawa J. Starrett J.H. Lazdun Y. Wetzel L. Nuttall B. Ng F.S.L. Coffman K.T. Smith P.D. Politi K. Cooper Z.A. Streicher K. Anti–PD-L1 and anti-CD73 combination therapy promotes T cell response to EGFR-mutated NSCLC. JCI Insight 2022 7 3 142843 10.1172/jci.insight.142843 35132961
    [Google Scholar]
  55. Zhao Y. Guo S. Deng J. Shen J. Du F. Wu X. Chen Y. Li M. Chen M. Li X. Li W. Gu L. Sun Y. Wen Q. Li J. Xiao Z. VEGF/VEGFR-targeted therapy and immunotherapy in non-small cell lung cancer: Targeting the tumor microenvironment. Int. J. Biol. Sci. 2022 18 9 3845 3858 10.7150/ijbs.70958 35813484
    [Google Scholar]
  56. Pitt J.M. Marabelle A. Eggermont A. Soria J.C. Kroemer G. Zitvogel L. Targeting the tumor microenvironment: Removing obstruction to anticancer immune responses and immunotherapy. Ann. Oncol. 2016 27 8 1482 1492 10.1093/annonc/mdw168 27069014
    [Google Scholar]
  57. Mascaux C. Angelova M. Vasaturo A. Beane J. Hijazi K. Anthoine G. Buttard B. Rothe F. Willard-Gallo K. Haller A. Ninane V. Burny A. Sculier J.P. Spira A. Galon J. Immune evasion before tumour invasion in early lung squamous carcinogenesis. Nature 2019 571 7766 570 575 10.1038/s41586‑019‑1330‑0 31243362
    [Google Scholar]
  58. Tarin M. Oryani M.A. Javid H. Karimi-Shahri M. Exosomal PD-L1 in non-small cell lung Cancer: Implications for immune evasion and resistance to immunotherapy. Int. Immunopharmacol. 2025 155 114519 10.1016/j.intimp.2025.114519 40199140
    [Google Scholar]
  59. Rastin F. Javid H. Oryani M.A. Rezagholinejad N. Afshari A.R. Karimi-Shahri M. Immunotherapy for colorectal cancer: Rational strategies and novel therapeutic progress. Int. Immunopharmacol. 2024 126 111055 10.1016/j.intimp.2023.111055 37992445
    [Google Scholar]
  60. Jin M.Z. Jin W.L. The updated landscape of tumor microenvironment and drug repurposing. Signal Transduct. Target. Ther. 2020 5 1 166 10.1038/s41392‑020‑00280‑x 32843638
    [Google Scholar]
  61. Lei G. Zhuang L. Gan B. The roles of ferroptosis in cancer: Tumor suppression, tumor microenvironment, and therapeutic interventions. Cancer Cell 2024 42 4 513 534 10.1016/j.ccell.2024.03.011 38593779
    [Google Scholar]
  62. Liu D. Wei B. Liang L. Sheng Y. Sun S. Sun X. Li M. Li H. Yang C. Peng Y. Xie Y. Wen C. Chen L. Liu X. Chen X. Liu H. Liu J. The circadian clock component RORA increases immunosurveillance in melanoma by inhibiting PD-L1 expression. Cancer Res. 2024 84 14 2265 2281 10.1158/0008‑5472.CAN‑23‑3942 38718296
    [Google Scholar]
  63. Haim-Vilmovsky L. Henriksson J. Walker J.A. Miao Z. Natan E. Kar G. Clare S. Barlow J.L. Charidemou E. Mamanova L. Chen X. Proserpio V. Pramanik J. Woodhouse S. Protasio A.V. Efremova M. Griffin J.L. Berriman M. Dougan G. Fisher J. Marioni J.C. McKenzie A.N.J. Teichmann S.A. Mapping Rora expression in resting and activated CD4+ T cells. PLoS One 2021 16 5 0251233 10.1371/journal.pone.0251233 34003838
    [Google Scholar]
  64. Hsu A.Y. Wang T. Syahirah R. Liu S. Li K. Zhang W. Wang J. Cao Z. Tian S. Matosevic S. Staiger C.J. Wan J. Deng Q. Rora regulates neutrophil migration and activation in zebrafish. Front. Immunol. 2022 13 756034 10.3389/fimmu.2022.756034 35309302
    [Google Scholar]
  65. Wculek S.K. Heras-Murillo I. Mastrangelo A. Mañanes D. Galán M. Miguel V. Curtabbi A. Barbas C. Chandel N.S. Enríquez J.A. Lamas S. Sancho D. Oxidative phosphorylation selectively orchestrates tissue macrophage homeostasis. Immunity 2023 56 3 516 530.e9 10.1016/j.immuni.2023.01.011 36738738
    [Google Scholar]
  66. Newman L.E. Weiser Novak S. Rojas G.R. Tadepalle N. Schiavon C.R. Grotjahn D.A. Towers C.G. Tremblay M.È. Donnelly M.P. Ghosh S. Medina M. Rocha S. Rodriguez-Enriquez R. Chevez J.A. Lemersal I. Manor U. Shadel G.S. Mitochondrial DNA replication stress triggers a pro-inflammatory endosomal pathway of nucleoid disposal. Nat. Cell Biol. 2024 26 2 194 206 10.1038/s41556‑023‑01343‑1 38332353
    [Google Scholar]
  67. Zhao R. Yang J. Zhai Y. Zhang H. Zhou Y. Hong L. Yuan D. Xia R. Liu Y. Pan J. Shafi S. Shi G. Zhang R. Luo D. Yuan J. Pan D. Peng C. Li S. Sun M. Nucleophosmin 1 promotes mucosal immunity by supporting mitochondrial oxidative phosphorylation and ILC3 activity. Nat. Immunol. 2024 25 9 1565 1579 10.1038/s41590‑024‑01921‑x 39103576
    [Google Scholar]
  68. Marx C. Sonnemann J. Maddocks O.D.K. Marx-Blümel L. Beyer M. Hoelzer D. Thierbach R. Maletzki C. Linnebacher M. Heinzel T. Krämer O.H. Global metabolic alterations in colorectal cancer cells during irinotecan-induced DNA replication stress. Cancer Metab. 2022 10 1 10 10.1186/s40170‑022‑00286‑9 35787728
    [Google Scholar]
  69. Glorieux C. Liu S. Trachootham D. Huang P. Targeting ROS in cancer: Rationale and strategies. Nat. Rev. Drug Discov. 2024 23 8 583 606 10.1038/s41573‑024‑00979‑4 38982305
    [Google Scholar]
  70. Chang H.C. Tsai C.Y. Hsu C.L. Tai T.S. Cheng M.L. Chuang Y.M. Tang H.Y. Lin K.J. Chen J.J. Chang S.H. Ko Y.C. Chi Y.W. Liu H. Tan B.C.M. Shen C.R. Yang C.W. Ho P.C. Yang H.Y. Asparagine deprivation enhances T cell antitumour response in patients via ROS-mediated metabolic and signal adaptations. Nat. Metab. 2025 7 5 918 927 10.1038/s42255‑025‑01245‑6 40045118
    [Google Scholar]
  71. Akbari Oryani M. Tarin M. Rahnama Araghi L. Rastin F. Javid H. Hashemzadeh A. Karimi-Shahri M. Synergistic cancer treatment using porphyrin-based metal-organic frameworks for photodynamic and photothermal therapy. J. Drug Target. 2025 33 4 473 491 10.1080/1061186X.2024.2433551 39618308
    [Google Scholar]
  72. Tarin M. Oryani M.A. Javid H. Hashemzadeh A. Karimi-Shahri M. Advancements in chitosan-based nanocomposites with ZIF-8 nanoparticles: Multifunctional platforms for wound healing applications. Carbohydr. Polym. 2025 362 123656 10.1016/j.carbpol.2025.123656 40409814
    [Google Scholar]
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An Immune Cell Activation Signature for Non - Small Cell Lung Cancer Revealed Tumor Microenvironment Heterogeneity and the Role of RORA in Regulating ZNF490/NDUFA12 Axis
Bentham Science Publishers ; https://doi.org/10.2174/0109298673399740251007015341
/content/journals/cmc/10.2174/0109298673399740251007015341
/content/journals/cmc/10.2174/0109298673399740251007015341
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  • Article Type:     Research Article
Keywords: antibody ; RORA ; NSCLC ; tumor microenvironment ; ZNF490 ; cell activation

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