Skip to content
2000
Volume 21, Issue 3
  • ISSN: 1573-4099
  • E-ISSN: 1875-6697

Abstract

Background

One of the most important targets in cancer immunotherapy is programmed cell death ligand 1 (PD-L1). Monoclonal antibodies developed for this target have disadvantages due to their low bioavailability and some immune-related adverse effects. Additionally, small molecules targeting PD-L1 are still in the experimental stage. At this point, discovering non-toxic natural compounds that directly or indirectly target PD-L1 is essential. In this study, a comprehensive literature search was conducted to identify publications reporting the master regulator of PD-L1, which was suggested as a Signal Transducer and Activator of Transcription 3 (STAT3). The relationship between STAT3 and PD-L1 was further investigated through bioinformatic analysis.

Methods

Subsequently, natural compounds targeting PD-L1 and STAT3 were screened, and compounds with suitable toxicity profiles were docked against both PD-L1 and STAT3. Following molecular docking, the selected molecules underwent DNA docking, ADMET profile analysis, and assessment of biological activities. The relationship between PD-L1 and STAT3 was determined in 52 out of the 453 articles, and it was further demonstrated in gene-gene interactions. Following the virtual screening, 76 natural compounds were identified, and after pre-filtering based on physicochemical properties, drug-likeness, and ADMET profiles, 29 compounds remained.

Results

Subsequent docking revealed that two compounds, 6-Prenylapigenin, and Gelomulide J, persisted. ADMET and biological activity prediction results suggested that 6-Prenylapigenin is non-toxic and has the potential to inhibit PD-L1 and STAT3 . The present study highlights that STAT3 serves as the master regulator of PD-L1, and it further suggests that 6-Prenylapigenin exhibits the potential to modulate PD-L1 and/or STAT3.

Conclusion

This finding could pave the way for the development of small molecules designed to block the PD-1/PD-L1 interaction by silencing the PD-L1 and/or STAT3 genes or reducing protein levels.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cad/10.2174/0115734099307259240522093710
2024-05-28
2025-11-07

  • From This Site

    /content/journals/cad/10.2174/0115734099307259240522093710
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. HanahanD. WeinbergR.A. Hallmarks of cancer: The next generation.Cell2011144564667410.1016/j.cell.2011.02.013 21376230
     [Google Scholar]
  2. DongH. ZhuG. TamadaK. ChenL. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion.Nat. Med.19995121365136910.1038/70932 10581077
     [Google Scholar]
  3. DongH. StromeS.E. SalomaoD.R. TamuraH. HiranoF. FliesD.B. RocheP.C. LuJ. ZhuG. TamadaK. LennonV.A. CelisE. ChenL. Tumor-associated B7-H1 promotes T-cell apoptosis: A potential mechanism of immune evasion.Nat. Med.20028879380010.1038/nm730 12091876
     [Google Scholar]
  4. ThompsonR.H. GillettM.D. ChevilleJ.C. LohseC.M. DongH. WebsterW.S. KrejciK.G. LoboJ.R. SenguptaS. ChenL. ZinckeH. BluteM.L. StromeS.E. LeibovichB.C. KwonE.D. Costimulatory B7-H1 in renal cell carcinoma patients: Indicator of tumor aggressiveness and potential therapeutic target.Proc. Natl. Acad. Sci. USA200410149171741717910.1073/pnas.0406351101 15569934
     [Google Scholar]
  5. FreemanG.J. LongA.J. IwaiY. BourqueK. ChernovaT. NishimuraH. FitzL.J. MalenkovichN. OkazakiT. ByrneM.C. HortonH.F. FouserL. CarterL. LingV. BowmanM.R. CarrenoB.M. CollinsM. WoodC.R. HonjoT. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation.J. Exp. Med.200019271027103410.1084/jem.192.7.1027 11015443
     [Google Scholar]
  6. AhmadzadehM. JohnsonL.A. HeemskerkB. WunderlichJ.R. DudleyM.E. WhiteD.E. RosenbergS.A. Tumor antigen–specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired.Blood200911481537154410.1182/blood‑2008‑12‑195792 19423728
     [Google Scholar]
  7. KeirM.E. ButteM.J. FreemanG.J. SharpeA.H. PD-1 and its ligands in tolerance and immunity.Annu. Rev. Immunol.200826167770410.1146/annurev.immunol.26.021607.090331 18173375
     [Google Scholar]
  8. TopalianS.L. DrakeC.G. PardollD.M. Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity.Curr. Opin. Immunol.201224220721210.1016/j.coi.2011.12.009 22236695
     [Google Scholar]
  9. GuptaH.B. ClarkC.A. YuanB. SareddyG. PandeswaraS. PadronA.S. HurezV. Conejo-GarciaJ. VadlamudiR. LiR. CurielT.J. Tumor cell-intrinsic PD-L1 promotes tumor-initiating cell generation and functions in melanoma and ovarian cancer.Signal Transduct. Target. Ther.2016111603010.1038/sigtrans.2016.30 28798885
     [Google Scholar]
  10. YuJ. WangX. TengF. KongL. PD-L1 expression in human cancers and its association with clinical outcomes.OncoTargets Ther.201695023503910.2147/OTT.S105862 27574444
     [Google Scholar]
  11. ChenL. XiongY. LiJ. ZhengX. ZhouQ. PD-L1 expression promotes epithelial to mesenchymal transition in human esophageal cancer.Cell. Physiol. Biochem.20174262267228010.1159/000480000
     [Google Scholar]
  12. KraftS. Fernandez-FiguerasM.T. RicharzN.A. FlahertyK.T. HoangM.P. PDL1 expression in desmoplastic melanoma is associated with tumor aggressiveness and progression.J. Am. Acad. Dermatol.201777353454210.1016/j.jaad.2017.05.007 28728868
     [Google Scholar]
  13. LukeJ.J. OttP.A. PD-1 pathway inhibitors: The next generation of immunotherapy for advanced melanoma.Oncotarget2015663479349210.18632/oncotarget.2980 25682878
     [Google Scholar]
  14. ZuazoM. Gato-CañasM. LlorenteN. Ibañez-VeaM. ArasanzH. KochanG. EscorsD. Molecular mechanisms of programmed cell death-1 dependent T cell suppression: Relevance for immunotherapy.Ann. Transl. Med.201751938510.21037/atm.2017.06.11 29114543
     [Google Scholar]
  15. TolbaM.F. OmarH.A. Immunotherapy, an evolving approach for the management of triple negative breast cancer: Converting non-responders to responders.Crit. Rev. Oncol. Hematol.201812220220710.1016/j.critrevonc.2018.01.005 29373180
     [Google Scholar]
  16. MarzecM. ZhangQ. GoradiaA. RaghunathP.N. LiuX. PaesslerM. WangH.Y. WysockaM. ChengM. RuggeriB.A. WasikM.A. Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive protein CD274 (PD-L1, B7-H1).Proc. Natl. Acad. Sci. USA200810552208522085710.1073/pnas.0810958105 19088198
     [Google Scholar]
  17. WölfleS.J. StrebovskyJ. BartzH. SährA. ArnoldC. KaiserC. DalpkeA.H. HeegK. PD‐L1 expression on tolerogenic APCs is controlled by STAT‐3.Eur. J. Immunol.201141241342410.1002/eji.201040979 21268011
     [Google Scholar]
  18. AbdelhamedS. OguraK. YokoyamaS. SaikiI. HayakawaY. akt-stat3 pathway as a downstream target of EGFR signaling to regulate PD-L1 expression on NSCLC cells.J. Cancer20167121579158610.7150/jca.14713 27698894
     [Google Scholar]
  19. AtsavesV. TsesmetzisN. ChioureasD. KisL. LeventakiV. DrakosE. PanaretakisT. GranderD. MedeirosL.J. YoungK.H. RassidakisG.Z. PD-L1 is commonly expressed and transcriptionally regulated by STAT3 and MYC in ALK-negative anaplastic large-cell lymphoma.Leukemia20173171633163710.1038/leu.2017.103 28344319
     [Google Scholar]
  20. Sasidharan NairV. ToorS.M. AliB.R. ElkordE. Dual inhibition of STAT1 and STAT3 activation downregulates expression of PD-L1 in human breast cancer cells.Expert Opin. Ther. Targets201822654755710.1080/14728222.2018.1471137 29702007
     [Google Scholar]
  21. KwonH.J. YangJ.M. LeeJ.O. LeeJ.S. PaikJ.H. Clinicopathologic implication of PD-L1 and phosphorylated STAT3 expression in diffuse large B cell lymphoma.J. Transl. Med.201816132010.1186/s12967‑018‑1689‑y 30458835
     [Google Scholar]
  22. SongT.L. NairismägiM.L. LaurensiaY. LimJ.Q. TanJ. LiZ.M. PangW.L. KizhakeyilA. WijayaG.C. HuangD.C. NagarajanS. ChiaB.K.H. CheahD. LiuY.H. ZhangF. RaoH.L. TangT. WongE.K.Y. BeiJ.X. IqbalJ. GrigoropoulosN.F. NgS.B. ChngW.J. TehB.T. TanS.Y. VermaN.K. FanH. LimS.T. OngC.K. Oncogenic activation of the STAT3 pathway drives PD-L1 expression in natural killer/T-cell lymphoma.Blood2018132111146115810.1182/blood‑2018‑01‑829424 30054295
     [Google Scholar]
  23. Yoyen-ErmisD. TunaliG. TavukcuogluE. HorzumU. OzkazancD. SutluT. BuyukasikY. EsendagliG. Myeloid maturation potentiates STAT3-mediated atypical IFN-γ signaling and upregulation of PD-1 ligands in AML and MDS.Sci. Rep.2019911169710.1038/s41598‑019‑48256‑4 31406210
     [Google Scholar]
  24. ShenJ. LiS. MedeirosL.J. LinP. WangS.A. TangG. YinC.C. YouM.J. KhouryJ.D. IyerS.P. MirandaR.N. XuJ. PD-L1 expression is associated with ALK positivity and STAT3 activation, but not outcome in patients with systemic anaplastic large cell lymphoma.Mod. Pathol.202033332433310.1038/s41379‑019‑0336‑3 31383967
     [Google Scholar]
  25. TomasichE. TopakianT. HellerG. UdovicaS. KrainerM. MarholdM. Loss of HCRP1 leads to upregulation of PD-L1 via STAT3 activation and is of prognostic significance in EGFR-dependent cancer.Transl. Res.2021230213310.1016/j.trsl.2020.11.005 33197651
     [Google Scholar]
  26. KwonY.J. SeoE.B. JeongA.J. LeeS.H. NohK.H. LeeS. ChoC.H. LeeC.H. ShinH.M. KimH.R. MoonH.G. YeS.K. The acidic tumor microenvironment enhances PD-L1 expression via activation of STAT3 in MDA-MB-231 breast cancer cells.BMC Cancer202222185210.1186/s12885‑022‑09956‑9 35927628
     [Google Scholar]
  27. ChengH. WangS. HuangA. MaJ. GaoD. LiM. ChenH. GuoK. HSF1 is involved in immunotherapeutic response through regulating APOJ/STAT3-mediated PD-L1 expression in hepatocellular carcinoma.Cancer Biol. Ther.20232411910.1080/15384047.2022.2156242 36482717
     [Google Scholar]
  28. ZhangX. ZengY. QuQ. ZhuJ. LiuZ. NingW. ZengH. ZhangN. DuW. ChenC. HuangJ. PD-L1 induced by IFN-γ from tumor-associated macrophages via the JAK/STAT3 and PI3K/AKT signaling pathways promoted progression of lung cancer.Int. J. Clin. Oncol.20172261026103310.1007/s10147‑017‑1161‑7 28748356
     [Google Scholar]
  29. DelanoyN. MichotJ.M. ComontT. KramkimelN. LazaroviciJ. DupontR. ChampiatS. ChahineC. RobertC. HerbauxC. BesseB. GuilleminA. MateusC. PautierP. SaïagP. MadonnaE. MaerevoetM. BoutJ.C. LeducC. BiscayP. QuereG. NardinC. EbboM. AlbigèsL. MarretG. LevratV. DujonC. VargaftigJ. LaghouatiS. CroisilleL. VoisinA.L. GodeauB. MassardC. RibragV. MarabelleA. MichelM. LambotteO. Haematological immune-related adverse events induced by anti-PD-1 or anti-PD-L1 immunotherapy: A descriptive observational study.Lancet Haematol.201961e48e5710.1016/S2352‑3026(18)30175‑3 30528137
     [Google Scholar]
  30. ZakK.M. GrudnikP. GuzikK. ZiebaB.J. MusielakB. DömlingA. DubinG. HolakT.A. Structural basis for small molecule targeting of the programmed death ligand 1 (PD-L1).Oncotarget2016721303233033510.18632/oncotarget.8730 27083005
     [Google Scholar]
  31. Warde-FarleyD. DonaldsonS.L. ComesO. ZuberiK. BadrawiR. The GeneMANIA prediction server: Biological network integration for gene prioritization and predicting gene function.Nuc. Asids Res.201038Suppl. 2W214W22010.1093/nar/gkq537
     [Google Scholar]
  32. YanD. ZhengG. WangC. ChenZ. MaoT. GaoJ. YanY. ChenX. JiX. YuJ. MoS. WenH. HanW. ZhouM. WangY. WangJ. TangK. CaoZ. HIT 2.0: An enhanced platform for Herbal Ingredients’.Targets. Nucleic Acids Res.202250D1D1238D124310.1093/nar/gkab1011 34986599
     [Google Scholar]
  33. KuzuB. KarakuşF. Natural compounds targeting VEGFRs in kidney cancer: An in silico prediction.Iğdır Üniversitesi Fen Bilimleri Enstitüsü Dergisi20221231711172210.21597/jist.1108551
     [Google Scholar]
  34. MorrisG.M. HueyR. LindstromW. SannerM.F. BelewR.K. GoodsellD.S. OlsonA.J. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility.J. Comput. Chem.200930162785279110.1002/jcc.21256 19399780
     [Google Scholar]
  35. BaiL. ZhouH. XuR. ZhaoY. ChinnaswamyK. McEachernD. ChenJ. YangC.Y. LiuZ. WangM. LiuL. JiangH. WenB. KumarP. MeagherJ.L. SunD. StuckeyJ.A. WangS. A potent and selective small-molecule degrader of STAT3 achieves complete tumor regression in vivo.Cancer Cell2019365498511.e1710.1016/j.ccell.2019.10.002 31715132
     [Google Scholar]
  36. DrewH.R. WingR.M. TakanoT. BrokaC. TanakaS. ItakuraK. DickersonR.E. Structure of a B-DNA dodecamer: Conformation and dynamics.Proc. Natl. Acad. Sci. USA19817842179218310.1073/pnas.78.4.2179 6941276
     [Google Scholar]
  37. DainaA. MichielinO. ZoeteV. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules.Sci. Rep.2017714271710.1038/srep42717 28256516
     [Google Scholar]
  38. PiresD.E.V. BlundellT.L. AscherD.B. pkCSM: Predicting small-molecule pharmacokinetic and toxicity properties using graph-based signatures.J. Med. Chem.20155894066407210.1021/acs.jmedchem.5b00104 25860834
     [Google Scholar]
  39. BanerjeeP. EckertA.O. SchreyA.K. PreissnerR. ProTox-II: A webserver for the prediction of toxicity of chemicals.Nucleic Acids Res.201846W1W257W26310.1093/nar/gky318 29718510
     [Google Scholar]
  40. FilimonovD.A. LaguninA.A. GloriozovaT.A. RudikA.V. DruzhilovskiiD.S. PogodinP.V. PoroikovV.V. Prediction of the biological activity spectra of organic compounds using the pass online web resource.Chem. Heterocycl. Compd.201450344445710.1007/s10593‑014‑1496‑1
     [Google Scholar]
  41. MattaB.M. RaimondiG. RosboroughB.R. SumpterT.L. ThomsonA.W. IL-27 production and STAT3-dependent upregulation of B7-H1 mediate immune regulatory functions of liver plasmacytoid dendritic cells.J. Immunol.2012188115227523710.4049/jimmunol.1103382 22508931
     [Google Scholar]
  42. ChenJ. LiG. MengH. FanY. SongY. WangS. ZhuF. GuoC. ZhangL. ShiY. Upregulation of B7-H1 expression is associated with macrophage infiltration in hepatocellular carcinomas.Cancer Immunol. Immunother.201261110110810.1007/s00262‑011‑1094‑3 21853301
     [Google Scholar]
  43. JiangX. ZhouJ. Giobbie-HurderA. WargoJ. HodiF.S. The activation of MAPK in melanoma cells resistant to BRAF inhibition promotes PD-L1 expression that is reversible by MEK and PI3K inhibition.Clin. Cancer Res.201319359860910.1158/1078‑0432.CCR‑12‑2731 23095323
     [Google Scholar]
  44. LeeY. ShinJ.H. LongmireM. WangH. KohrtH.E. ChangH.Y. SunwooJ.B. CD44+ cells in head and neck squamous cell carcinoma suppress T-Cell–mediated immunity by selective constitutive and inducible expression of PD-L1.Clin. Cancer Res.201622143571358110.1158/1078‑0432.CCR‑15‑2665 26864211
     [Google Scholar]
  45. LuoF. LuoM. RongQ.X. ZhangH. ChenZ. WangF. ZhaoH.Y. FuL.W. Niclosamide, an antihelmintic drug, enhances efficacy of PD-1/PD-L1 immune checkpoint blockade in non-small cell lung cancer.J. Immunother. Cancer20197124510.1186/s40425‑019‑0733‑7 31511071
     [Google Scholar]
  46. CavazzoniA. DigiacomoG. AlfieriR. La MonicaS. FumarolaC. GalettiM. BonelliM. CretellaD. BariliV. ZeccaA. GiovannettiE. FiorentinoM. TiseoM. PetroniniP.G. ArdizzoniA. Pemetrexed enhances membrane PD-L1 expression and potentiates T cell-mediated cytotoxicity by anti-PD-L1 antibody therapy in non-small-cell lung cancer.Cancers (Basel)202012366610.3390/cancers12030666 32178474
     [Google Scholar]
  47. KangD.Y. SpN. LeeJ.M. JangK.J. Antitumor effects of ursolic acid through mediating the inhibition of STAT3/PD-L1 signaling in non-small cell lung cancer cells.Biomedicines20219329710.3390/biomedicines9030297 33805840
     [Google Scholar]
  48. LiuZ. WenJ. HuF. WangJ. HuC. ZhangW. Thrombospondin‐1 induced programmed death‐ligand 1‐mediated immunosuppression by activating the STAT3 pathway in osteosarcoma.Cancer Sci.2022113243244510.1111/cas.15237 34927311
     [Google Scholar]
  49. XiaW. HeL. BaoJ. QiY. ZhangJ.Z.H. Insights into small molecule inhibitor bindings to PD-L1 with residue-specific binding free energy calculation.J. Biomol. Struct. Dyn.20224022122771228510.1080/07391102.2021.1971558 34486939
     [Google Scholar]
  50. KumarG.S. MoustafaM. SahooA.K. MalýP. BharadwajS. Computational investigations on the natural small molecule as an inhibitor of programmed death ligand 1 for cancer immunotherapy.Life (Basel)202212565910.3390/life12050659 35629327
     [Google Scholar]
  51. UrbanV.A. DavidovskiiA.I. VeresovV.G. Computational discovery of small drug-like compounds as potential inhibitors of PD-1/PD-L1 interactions.J. Biomol. Struct. Dyn.2022411111710.1080/07391102.2022.2085805 35696453
     [Google Scholar]
  52. WaqasM. HalimS.A. AlsalmanA. KhanA. ElkordE. Al-HarrasiA. Structure-based small inhibitors search combined with molecular dynamics driven energies for human programmed cell death-1 (PD-1) protein.J. Biomol. Struct. Dyn.20234124147711478510.1080/07391102.2023.2188958 36927289
     [Google Scholar]
  53. HanQ.B. QiaoC.F. SongJ.Z. YangN.Y. CaoX.W. PengY. YangD.J. ChenS.L. XuH.X. Cytotoxic prenylated phenolic compounds from the twig bark of Garcinia xanthochymus.Chem. Biodivers.20074594094610.1002/cbdv.200790083 17511007
     [Google Scholar]
  54. KueteV. NgameniB. WienchB. KruscheB. HorwedelC. NgadjuiB. EfferthT. Cytotoxicity and mode of action of four naturally occuring flavonoids from the genus Dorstenia: Gancaonin Q, 4-hydroxylonchocarpin, 6-prenylapigenin, and 6,8-diprenyleriodictyol.Planta Med.201177181984198910.1055/s‑0031‑1280023 21800276
     [Google Scholar]
  55. FangW. ZhangJ. HongS. ZhanJ. ChenN. QinT. TangY. ZhangY. KangS. ZhouT. WuX. LiangW. HuZ. MaY. ZhaoY. TianY. YangY. XueC. YanY. HouX. HuangP. HuangY. ZhaoH. ZhangL. EBV-driven LMP1 and IFN-γ up-regulate PD-L1 in nasopharyngeal carcinoma: Implications for oncotargeted therapy.Oncotarget2014523121891220210.18632/oncotarget.2608 25361008
     [Google Scholar]
  56. FujitaY. YagishitaS. HagiwaraK. YoshiokaY. KosakaN. TakeshitaF. FujiwaraT. TsutaK. NokiharaH. TamuraT. AsamuraH. KawaishiM. KuwanoK. OchiyaT. The clinical relevance of the miR-197/CKS1B/STAT3-mediated PD-L1 network in chemoresistant non-small-cell lung cancer.Mol. Ther.201523471772710.1038/mt.2015.10 25597412
     [Google Scholar]
  57. CarbottiG. BarisioneG. AiroldiI. MezzanzanicaD. BagnoliM. FerreroS. PetrettoA. FabbiM. FerriniS. IL-27 induces the expression of IDO and PD-L1 in human cancer cells.Oncotarget2015641432674328010.18632/oncotarget.6530 26657115
     [Google Scholar]
  58. KohJ. JangJ.Y. KeamB. KimS. KimM.Y. GoH. KimT.M. KimD.W. KimC.W. JeonY.K. ChungD.H. EML4-ALK enhances programmed cell death-ligand 1 expression in pulmonary adenocarcinoma via hypoxia-inducible factor (HIF)-1α and STAT3.OncoImmunology201653e110851410.1080/2162402X.2015.1108514 27141364
     [Google Scholar]
  59. LienlafM. Perez-VillarroelP. KnoxT. PabonM. SahakianE. PowersJ. WoanK.V. LeeC. ChengF. DengS. SmalleyK.S.M. MontecinoM. KozikowskiA. Pinilla-IbarzJ. SarnaikA. SetoE. WeberJ. SotomayorE.M. VillagraA. Essential role of HDAC6 in the regulation of PD‐L1 in melanoma.Mol. Oncol.201610573575010.1016/j.molonc.2015.12.012 26775640
     [Google Scholar]
  60. HorladH. MaC. YanoH. PanC. OhnishiK. FujiwaraY. EndoS. KikukawaY. OkunoY. MatsuokaM. TakeyaM. KomoharaY. An IL‐27/Stat3 axis induces expression of programmed cell death 1 ligands (PD ‐L1/2) on infiltrating macrophages in lymphoma.Cancer Sci.2016107111696170410.1111/cas.13065 27564404
     [Google Scholar]
  61. SumimotoH. TakanoA. TeramotoK. DaigoY. RAS–mitogen-activated protein kinase signal is required for enhanced PD-L1 Expression in Human Lung Cancers.PLoS One20161111e016662610.1371/journal.pone.0166626 27846317
     [Google Scholar]
  62. KimK.J. KimJ.H. LeeS.J. LeeE.J. ShinE.C. SeongJ. Radiation improves antitumor effect of immune checkpoint inhibitor in murine hepatocellular carcinoma model.Oncotarget2017825412424125510.18632/oncotarget.17168 28465485
     [Google Scholar]
  63. BuL.L. YuG.T. WuL. MaoL. DengW.W. LiuJ.F. KulkarniA.B. ZhangW.F. ZhangL. SunZ.J. STAT3 induces immunosuppression by upregulating PD-1/PD-L1 in HNSCC.J. Dent. Res.20179691027103410.1177/0022034517712435 28605599
     [Google Scholar]
  64. ZhengB. RenT. HuangY. GuoW. Apatinib inhibits migration and invasion as well as PD-L1 expression in osteosarcoma by targeting STAT3.Biochem. Biophys. Res. Commun.201849521695170110.1016/j.bbrc.2017.12.032 29225166
     [Google Scholar]
  65. PrestipinoA. EmhardtA.J. AumannK. O’SullivanD. GorantlaS.P. DuquesneS. MelchingerW. BraunL. VuckovicS. BoerriesM. BuschH. HalbachS. PennisiS. PoggioT. ApostolovaP. VerattiP. HettichM. NiedermannG. BartholomäM. ShoumariyehK. JutziJ.S. WehrleJ. DierksC. BeckerH. Schmitt-GraeffA. FolloM. PfeiferD. RohrJ. FuchsS. EhlS. HartlF.A. MinguetS. MiethingC. HeidelF.H. KrögerN. TriviaiI. BrummerT. FinkeJ. IllertA.L. RuggieroE. BoniniC. DuysterJ. PahlH.L. LaneS.W. HillG.R. BlazarB.R. von BubnoffN. PearceE.L. ZeiserR. Oncogenic JAK2 V617F causes PD-L1 expression, mediating immune escape in myeloproliferative neoplasms.Sci. Transl. Med.201810429eaam772910.1126/scitranslmed.aam7729 29467301
     [Google Scholar]
  66. XuL. ChenX. ShenM. YangD.R. FangL. WengG. TsaiY. KengP.C. ChenY. LeeS.O. Inhibition of IL‐6‐JAK/Stat3 signaling in castration‐resistant prostate cancer cells enhances the NK cell‐mediated cytotoxicity via alteration of PD‐L1/NKG2D ligand levels.Mol. Oncol.201812326928610.1002/1878‑0261.12135 28865178
     [Google Scholar]
  67. SunL. WangQ. ChenB. ZhaoY. ShenB. WangH. XuJ. ZhuM. ZhaoX. XuC. ChenZ. WangM. XuW. ZhuW. Gastric cancer mesenchymal stem cells derived IL-8 induces PD-L1 expression in gastric cancer cells via STAT3/mTOR-c-Myc signal axis.Cell Death Dis.20189992810.1038/s41419‑018‑0988‑9 30206229
     [Google Scholar]
  68. WangY.F. LiuF. SherwinS. FarrellyM. YanX.G. CroftA. LiuT. JinL. ZhangX.D. JiangC.C. Cooperativity of HOXA5 and STAT3 is critical for HDAC8 inhibition-mediated transcriptional activation of PD-L1 in human melanoma cells.J. Invest. Dermatol.2018138492293210.1016/j.jid.2017.11.009 29174371
     [Google Scholar]
  69. LiuJ. YangY. WangH. WangB. ZhaoK. JiangW. BaiW. LiuJ. YinJ. Syntenin1/MDA-9 (SDCBP) induces immune evasion in triple-negative breast cancer by upregulating PD-L1.Breast Cancer Res. Treat.2018171234535710.1007/s10549‑018‑4833‑8 29845474
     [Google Scholar]
  70. XingY. MiC. WangZ. ZhangZ.H. LiM.Y. ZuoH.X. WangJ.Y. JinX. MaJ. Fraxinellone has anticancer activity in vivo by inhibiting programmed cell death-ligand 1 expression by reducing hypoxia-inducible factor-1α and STAT3.Pharmacol. Res.201813516618010.1016/j.phrs.2018.08.004 30103001
     [Google Scholar]
  71. BoC. WuQ. ZhaoH. LiX. ZhouQ. Thymosin α1 suppresses migration and invasion of PD-L1 high-expressing non-small-cell lung cancer cells via inhibition of STAT3–MMP2 signaling.OncoTargets Ther.2018117255727010.2147/OTT.S177943 30425517
     [Google Scholar]
  72. LiL. ZhangJ. ChenJ. Xu-MonetteZ.Y. MiaoY. XiaoM. YoungK.H. WangS. MedeirosL.J. WangM. FordR.J. PhamL.V. B-cell receptor–mediated NFATc1 activation induces IL-10/STAT3/PD-L1 signaling in diffuse large B-cell lymphoma.Blood2018132171805181710.1182/blood‑2018‑03‑841015 30209121
     [Google Scholar]
  73. KeremuA. AimaitiA. LiangZ. ZouX. Role of the HDAC6/STAT3 pathway in regulating PD-L1 expression in osteosarcoma cell lines.Cancer Chemother. Pharmacol.201983225526410.1007/s00280‑018‑3721‑6 30430228
     [Google Scholar]
  74. HanL. YaoS. CaoS. MoG. LiJ. CaoY. HuangF. Triterpenoid saponins from Anemone flaccida suppress tumor cell proliferation by regulating MAPK, PD1/PDL1, and STAT3 Signaling pathways and altering cancer metabolism.OncoTargets Ther.201912109171093010.2147/OTT.S212666 31849495
     [Google Scholar]
  75. WangS. YaoF. LuX. LiQ. SuZ. LeeJ.H. WangC. DuL. Temozolomide promotes immune escape of GBM cellsvia upregulating PD-L1.Am. J. Cancer Res.20199611611171 31285949
     [Google Scholar]
  76. ChenX.J. HeM.J. ZhouG. All‐trans retinoic acid induces anti‐tumor effects via STAT3 signaling inhibition in oral squamous cell carcinoma and oral dysplasia.J. Oral Pathol. Med.201948983283910.1111/jop.12931 31323146
     [Google Scholar]
  77. AotsukaA. MatsumotoY. ArimotoT. KawataA. OgishimaJ. TaguchiA. TanikawaM. SoneK. Mori-UchinoM. TsurugaT. OdaK. KawanaK. OsugaY. FujiiT. Interleukin‐17 is associated with expression of programmed cell death 1 ligand 1 in ovarian carcinoma.Cancer Sci.2019110103068307810.1111/cas.14174 31432577
     [Google Scholar]
  78. KeM. ZhangZ. XuB. ZhaoS. DingY. WuX. WuR. LvY. DongJ. Baicalein and baicalin promote antitumor immunity by suppressing PD-L1 expression in hepatocellular carcinoma cells.Int. Immunopharmacol.20197510582410.1016/j.intimp.2019.105824 31437792
     [Google Scholar]
  79. ZerdesI. WalleriusM. SifakisE. WallmannT. BettsS. BartishM. TsesmetzisN. TobinN. CoucoravasC. BerghJ. RassidakisG. RolnyC. FoukakisT. STAT3 activity promotes programmed-death ligand 1 expression and suppresses immune responses in breast cancer.Cancers (Basel)20191110147910.3390/cancers11101479 31581535
     [Google Scholar]
  80. NguyenH.D. LiaoY.C. HoY.S. ChenL.C. ChangH.W. ChengT.C. LiuD. LeeW.R. ShenS.C. WuC.H. TuS.H. The α9 nicotinic acetylcholine receptor mediates nicotine-induced PD-L1 expression and regulates melanoma cell proliferation and migration.Cancers (Basel)20191112199110.3390/cancers11121991 31835799
     [Google Scholar]
  81. YouW. LiuX. YuY. ChenC. XiongY. LiuY. SunY. TanC. ZhangH. WangY. LiR. miR-502-5p affects gastric cancer progression by targeting PD-L1.Cancer Cell Int.202020139510.1186/s12935‑020‑01479‑2 32821248
     [Google Scholar]
  82. DuanX.L. GuoJ.P. LiF. XiuC. WangH. Sunitinib inhibits PD-L1 expression in osteosarcoma by targeting STAT3 and remodels the immune system in tumor-bearing mice.Future Oncol.202016241815182410.2217/fon‑2019‑0725 32511016
     [Google Scholar]
  83. EhexigeE. BaoM. BazarjavP. YuX. XiaoH. HanS. BaigudeH. Silencing of STAT3 via peptidomimetic LNP-mediated systemic delivery of RNAi downregulates PD-L1 and inhibits melanoma growth.Biomolecules202010228510.3390/biom10020285 32059541
     [Google Scholar]
  84. GaoW. WenH. LiangL. DongX. DuR. ZhouW. ZhangX. ZhangC. XiangR. LiN. IL20RA signaling enhances stemness and promotes the formation of an immunosuppressive microenvironment in breast cancer.Theranostics20211162564258010.7150/thno.45280 33456560
     [Google Scholar]
  85. FangW. ZhouT. ShiH. YaoM. ZhangD. QianH. ZengQ. WangY. JinF. ChaiC. ChenT. Progranulin induces immune escape in breast cancer via up-regulating PD-L1 expression on tumor-associated macrophages (TAMs) and promoting CD8+ T cell exclusion.J. Exp. Clin. Cancer Res.2021401410.1186/s13046‑020‑01786‑6 33390170
     [Google Scholar]
  86. ZhangG.Q. JiaoQ. ShenC.T. SongH.J. ZhangH.Z. QiuZ.L. LuoQ.Y. Interleukin 6 regulates the expression of programmed cell death ligand 1 in thyroid cancer.Cancer Sci.20211123997101010.1111/cas.14752 33247999
     [Google Scholar]
  87. XuQ. HuangS. XuZ.M. JiK. ZhangX. XuW.P. WeiW. Promotion effects of DEHP on hepatocellular carcinoma models: Up-regulation of PD-L1 by activating the JAK2/STAT3 pathway.Toxicol. Res. (Camb.)202110337638810.1093/toxres/tfab018 34141151
     [Google Scholar]
  88. ZhengS. WeiY. JiangY. HaoY. LRP8 activates STAT3 to induce PD-L1 expression in osteosarcoma.Tumori2020107310.1177/0300891620952872 33054597
     [Google Scholar]
  89. SunT.X. LiM.Y. ZhangZ.H. WangJ.Y. XingY. RiM. JinC.H. XuG.H. PiaoL.X. JinH.L. ZuoH.X. MaJ. JinX. Usnic acid suppresses cervical cancer cell proliferation by inhibiting PD‐L1 expression and enhancing T‐lymphocyte tumor‐killing activity.Phytother. Res.20213573916393510.1002/ptr.7103 33970512
     [Google Scholar]
  90. SuK.W. LinH.Y. ChiuH.C. ShenS.Y. ChangOu, C.A.; Crawford, D.R.; Yang, Y.C.S.H.; Shih, Y.J.; Li, Z.L.; Huang, H.M.; Whang-Peng, J.; Ho, Y.; Wang, K. Thyroid hormone induces oral cancer growth via the PD-L1-dependent signaling pathway.Cells20221119305010.3390/cells11193050 36231010
     [Google Scholar]
/content/journals/cad/10.2174/0115734099307259240522093710
Loading
Exploring Natural Compounds Targeting PD-L1 and STAT3: Toxicogenomic Analysis, Virtual Screening, Molecular Docking, ADMET Evaluation, and Biological Activity Prediction
Curr. Computeraided Drug Des. 21, 348 (2025); https://doi.org/10.2174/0115734099307259240522093710
/content/journals/cad/10.2174/0115734099307259240522093710
/content/journals/cad/10.2174/0115734099307259240522093710
Loading

Data & Media loading...

Supplements

Supplementary material is available on the publisher’s website along with the published article.

file format download Download

  • Article Type:     Research Article
Keyword(s): 6-Prenylapigenin; gelomulide J; natural compounds; PD-L1; protein; STAT3

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test