Skip to content
2000
  1. Home
  2. A-Z Publications
  3. Recent Patents on Anti-Cancer Drug Discovery
  4. Volume 20, Issue 1
  5. Article
Volume 20, Issue 1
  • ISSN: 1574-8928
  • E-ISSN: 2212-3970
file format pdf download PDF
file format text download EPUB
side by side viewer icon HTML

Abstract

Digestive system neoplasms are highly heterogeneous and exhibit complex resistance mechanisms that render anti-programmed cell death protein (PD) therapies poorly effective. The tumor microenvironment (TME) plays a pivotal role in tumor development, apart from supplying energy for tumor proliferation and impeding the body's anti-tumor immune response, the TME actively facilitates tumor progression and immune escape diverse pathways, which include the modulation of heritable gene expression alterations and the intricate interplay with the gut microbiota. In this review, we aim to elucidate the mechanisms underlying drug resistance in digestive tumors, focusing on immune-mediated resistance, microbial crosstalk, metabolism, and epigenetics. We will highlight the unique characteristics of each digestive tumor and emphasize the significance of the tumor immune microenvironment (TIME). Furthermore, we will discuss the current therapeutic strategies that hold promise for combination with cancer immune normalization therapies. This review aims to provide a thorough understanding of the resistance mechanisms in digestive tumors and offer insights into potential therapeutic interventions.

© 2025 Bentham Science Publishers
© 2025 The Author(s). Published by Bentham Science Publisher. This is an open access article published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode
Loading

Article metrics loading...

/content/journals/pra/10.2174/0115748928269276231120103256
2024-01-04
2025-01-04

  • From This Site

    /content/journals/pra/10.2174/0115748928269276231120103256
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

/deliver/fulltext/pra/20/1/PRA-20-1-02.html?itemId=/content/journals/pra/10.2174/0115748928269276231120103256&mimeType=html&fmt=ahah

References

  1. RebeccaL SiegelMPH KimberlyD MillerMPH Nikita Sandeep Wagle MBBS, M., PhD, Ahmedin Jemal DVM, PhD Cancer statistics,20222023
     [Google Scholar]
  2. KalafatiL. KourtzelisI. Schulte-SchreppingJ. Innate immune training of granulopoiesis promotes anti-tumor activity.Cell20201833771785.e1210.1016/j.cell.2020.09.058 33125892
     [Google Scholar]
  3. LekoV. RosenbergS.A. Identifying and targeting human tumor antigens for t cell-based immunotherapy of solid tumors.Cancer Cell202038445447210.1016/j.ccell.2020.07.013 32822573
     [Google Scholar]
  4. SchürchC.M. BhateS.S. BarlowG.L. Coordinated cellular neighborhoods orchestrate antitumoral immunity at the colorectal cancer invasive front.Cell2020182513411359.e1910.1016/j.cell.2020.07.005 32763154
     [Google Scholar]
  5. El-KhoueiryA.B. SangroB. YauT. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): An open-label, non-comparative, phase 1/2 dose escalation and expansion trial.Lancet2017389100882492250210.1016/S0140‑6736(17)31046‑2 28434648
     [Google Scholar]
  6. DuW. FrankelT.L. GreenM. ZouW. IFNγ signaling integrity in colorectal cancer immunity and immunotherapy.Cell. Mol. Immunol.2022191233210.1038/s41423‑021‑00735‑3 34385592
     [Google Scholar]
  7. WangF. WeiX.L. WangF.H. Safety, efficacy and tumor mutational burden as a biomarker of overall survival benefit in chemo-refractory gastric cancer treated with toripalimab, a PD-1 antibody in phase Ib/II clinical trial NCT02915432.Ann. Oncol.20193091479148610.1093/annonc/mdz197 31236579
     [Google Scholar]
  8. WeiX.L. RenC. WangF.H. A phase I study of toripalimab, an anti‐PD‐1 antibody, in patients with refractory malignant solid tumors.Cancer Commun.202040834535410.1002/cac2.12068 32589350
     [Google Scholar]
  9. KimS.T. CristescuR. BassA.J. Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer.Nat. Med.20182491449145810.1038/s41591‑018‑0101‑z 30013197
     [Google Scholar]
  10. ZhuA.X. FinnR.S. EdelineJ. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): A non-randomised, open-label phase 2 trial.Lancet Oncol.201819794095210.1016/S1470‑2045(18)30351‑6 29875066
     [Google Scholar]
  11. SchreiberR.D. OldL.J. SmythM.J. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion.Science201133160241565157010.1126/science.1203486 21436444
     [Google Scholar]
  12. MittalD. GubinM.M. SchreiberR.D. SmythM.J. New insights into cancer immunoediting and its three component phases—elimination, equilibrium and escape.Curr. Opin. Immunol.201427162510.1016/j.coi.2014.01.004 24531241
     [Google Scholar]
  13. TengM.W.L. GalonJ. FridmanW.H. SmythM.J. From mice to humans: Developments in cancer immunoediting.J. Clin. Invest.201512593338334610.1172/JCI80004 26241053
     [Google Scholar]
  14. SmythM.J. NgiowS.F. RibasA. TengM.W.L. Combination cancer immunotherapies tailored to the tumour microenvironment.Nat. Rev. Clin. Oncol.201613314315810.1038/nrclinonc.2015.209 26598942
     [Google Scholar]
  15. O’DonnellJ.S. TengM.W.L. SmythM.J. Cancer immunoediting and resistance to T cell-based immunotherapy.Nat. Rev. Clin. Oncol.201916315116710.1038/s41571‑018‑0142‑8 30523282
     [Google Scholar]
  16. ShergoldA.L. MillarR. NibbsR.J.B. Understanding and overcoming the resistance of cancer to PD-1/PD-L1 blockade.Pharmacol. Res.201914510425810.1016/j.phrs.2019.104258 31063806
     [Google Scholar]
  17. JiangY. ChenM. NieH. YuanY. PD-1 and PD-L1 in cancer immunotherapy: Clinical implications and future considerations.Hum. Vaccin. Immunother.20191551111112210.1080/21645515.2019.1571892 30888929
     [Google Scholar]
  18. RotteA. Combination of CTLA-4 and PD-1 blockers for treatment of cancer. Journal of experimental & clinical cancer research.CR (East Lansing Mich.)2019381255
     [Google Scholar]
  19. BoussiotisV.A. Molecular and biochemical aspects of the PD-1 checkpoint pathway.N. Engl. J. Med.2016375181767177810.1056/NEJMra1514296 27806234
     [Google Scholar]
  20. ZouW. WolchokJ.D. ChenL. PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations.Sci. Transl. Med.20168328328rv410.1126/scitranslmed.aad7118 26936508
     [Google Scholar]
  21. PoltavetsV. KochetkovaM. PitsonS.M. SamuelM.S. The role of the extracellular matrix and its molecular and cellular regulators in cancer cell plasticity.Front. Oncol.2018843110.3389/fonc.2018.00431 30356678
     [Google Scholar]
  22. VeselyM.D. ZhangT. ChenL. Resistance mechanisms to anti-PD cancer immunotherapy.Annu. Rev. Immunol.2022401457410.1146/annurev‑immunol‑070621‑030155 35471840
     [Google Scholar]
  23. KimT.K. VandsembE.N. HerbstR.S. ChenL. Adaptive immune resistance at the tumour site: Mechanisms and therapeutic opportunities.Nat. Rev. Drug Discov.202221752954010.1038/s41573‑022‑00493‑5 35701637
     [Google Scholar]
  24. GalonJ. BruniD. Approaches to treat immune hot, altered and cold tumours with combination immunotherapies.Nat. Rev. Drug Discov.201918319721810.1038/s41573‑018‑0007‑y 30610226
     [Google Scholar]
  25. MajidpoorJ. MortezaeeK. The efficacy of PD-1/PD-L1 blockade in cold cancers and future perspectives.Clin. Immunol.202122610870710.1016/j.clim.2021.108707 33662590
     [Google Scholar]
  26. BinnewiesM. RobertsE.W. KerstenK. Understanding the tumor immune microenvironment (TIME) for effective therapy.Nat. Med.201824554155010.1038/s41591‑018‑0014‑x 29686425
     [Google Scholar]
  27. SprangerS. GajewskiT.F. Impact of oncogenic pathways on evasion of antitumour immune responses.Nat. Rev. Cancer201818313914710.1038/nrc.2017.117 29326431
     [Google Scholar]
  28. WangQ. ShenX. ChenG. DuJ. How to overcome resistance to immune checkpoint inhibitors in colorectal cancer: From mechanisms to translation.Int. J. Cancer2023153470972210.1002/ijc.34464 36752642
     [Google Scholar]
  29. GrassoC.S. GiannakisM. WellsD.K. Genetic mechanisms of immune evasion in colorectal cancer.Cancer Discov.20188673074910.1158/2159‑8290.CD‑17‑1327 29510987
     [Google Scholar]
  30. Ruiz de GalarretaM. BresnahanE. Molina-SánchezP. β-Catenin activation promotes immune escape and resistance to Anti–PD-1 therapy in hepatocellular carcinoma.Cancer Discov.2019981124114110.1158/2159‑8290.CD‑19‑0074 31186238
     [Google Scholar]
  31. LiJ. LeeY. LiY. Co-inhibitory Molecule B7 Superfamily Member 1 expressed by tumor-infiltrating myeloid cells induces dysfunction of anti-tumor CD8+ T Cells.Immunity2018484773786.e510.1016/j.immuni.2018.03.018 29625896
     [Google Scholar]
  32. Abril-RodriguezG. RibasA. SnapShot: Immune checkpoint inhibitors.Cancer Cell2017316848848.e110.1016/j.ccell.2017.05.010 28609660
     [Google Scholar]
  33. ZhangJ. DangF. RenJ. WeiW. Biochemical aspects of PD-L1 regulation in cancer immunotherapy.Trends Biochem. Sci.201843121014103210.1016/j.tibs.2018.09.004 30287140
     [Google Scholar]
  34. ZhaoT. LiY. ZhangJ. ZhangB.P.D. L1 expression increased by IFN γ via JAK2 STAT1 signaling and predicts a poor survival in colorectal cancer.Oncol. Lett.20202021127113410.3892/ol.2020.11647 32724352
     [Google Scholar]
  35. ChenC. WangZ. DingY. QinY. Tumor microenvironment-mediated immune evasion in hepatocellular carcinoma.Front. Immunol.202314113330810.3389/fimmu.2023.1133308 36845131
     [Google Scholar]
  36. SundarR. SmythE.C. PengS. YeongJ.P.S. TanP. Predictive biomarkers of immune checkpoint inhibition in gastroesophageal cancers.Front. Oncol.20201076310.3389/fonc.2020.00763 32500029
     [Google Scholar]
  37. MandalR. SamsteinR.M. LeeK.W. Genetic diversity of tumors with mismatch repair deficiency influences anti–PD-1 immunotherapy response.Science2019364643948549110.1126/science.aau0447 31048490
     [Google Scholar]
  38. LeD.T. DurhamJ.N. SmithK.N. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade.Science2017357634940941310.1126/science.aan6733 28596308
     [Google Scholar]
  39. SchumacherT.N. SchreiberR.D. Neoantigens in cancer immunotherapy.Science20153486230697410.1126/science.aaa4971 25838375
     [Google Scholar]
  40. SalemM.E. PucciniA. GrotheyA. Landscape of tumor mutation load, mismatch repair deficiency, and PD-L1 expression in a large patient cohort of gastrointestinal cancers.Mol. Cancer Res.201816580581210.1158/1541‑7786.MCR‑17‑0735 29523759
     [Google Scholar]
  41. ChanT.A. YarchoanM. JaffeeE. Development of tumor mutation burden as an immunotherapy biomarker: Utility for the oncology clinic.Ann. Oncol.2019301445610.1093/annonc/mdy495 30395155
     [Google Scholar]
  42. CampbellB.B. LightN. FabrizioD. Comprehensive analysis of hypermutation in human cancer.Cell2017171510421056.e1010.1016/j.cell.2017.09.048 29056344
     [Google Scholar]
  43. MabyP. TougeronD. HamiehM. Correlation between Density of CD8+ T-cell infiltrate in microsatellite unstable colorectal cancers and frameshift mutations: A rationale for personalized immunotherapy.Cancer Res.201575173446345510.1158/0008‑5472.CAN‑14‑3051 26060019
     [Google Scholar]
  44. QamraA. XingM. PadmanabhanN. Epigenomic promoter alterations amplify gene isoform and immunogenic diversity in gastric adenocarcinoma.Cancer Discov.20177663065110.1158/2159‑8290.CD‑16‑1022 28320776
     [Google Scholar]
  45. AndersonP. AptsiauriN. Ruiz-CabelloF. GarridoF. HLA class I loss in colorectal cancer: Implications for immune escape and immunotherapy.Cell. Mol. Immunol.202118355656510.1038/s41423‑021‑00634‑7 33473191
     [Google Scholar]
  46. GiannakisM. MuX.J. ShuklaS.A. Genomic correlates of immune-cell infiltrates in colorectal carcinoma.Cell Rep.2016174120610.1016/j.celrep.2016.10.009 27760322
     [Google Scholar]
  47. KloorM. BeckerC. BennerA. Immunoselective pressure and human leukocyte antigen class I antigen machinery defects in microsatellite unstable colorectal cancers.Cancer Res.200565146418642410.1158/0008‑5472.CAN‑05‑0044 16024646
     [Google Scholar]
  48. DierssenJ.W.F. de MirandaN.F.C.C. FerroneS. HNPCC versus sporadic microsatellite-unstable colon cancers follow different routes toward loss of HLA class I expression.BMC Cancer2007713310.1186/1471‑2407‑7‑33 17316446
     [Google Scholar]
  49. IjsselsteijnM.E. PetitprezF. LacroixL. Revisiting immune escape in colorectal cancer in the era of immunotherapy.Br. J. Cancer2019120881581810.1038/s41416‑019‑0421‑x 30862951
     [Google Scholar]
  50. BeattyG.L. GladneyW.L. Immune escape mechanisms as a guide for cancer immunotherapy.Clin. Cancer Res.201521468769210.1158/1078‑0432.CCR‑14‑1860 25501578
     [Google Scholar]
  51. de CharetteM. MarabelleA. HouotR. Turning tumour cells into antigen presenting cells: The next step to improve cancer immunotherapy.Eur. J. Cancer201668134147
     [Google Scholar]
  52. KawazuM. UenoT. SaekiK. HLA Class I analysis provides insight into the genetic and epigenetic background of immune evasion in colorectal cancer with high microsatellite instability.Gastroenterology2022162379981210.1053/j.gastro.2021.10.010 34687740
     [Google Scholar]
  53. PangK ShiZ D WeiL Y Research progress of therapeutic effects and drug resistance of immunotherapy based on PD-1/PDL1 blockade.Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy202366100907
     [Google Scholar]
  54. LinC. HeH. LiuH. Tumour-associated macrophages-derived CXCL8 determines immune evasion through autonomous PD-L1 expression in gastric cancer.Gut201968101764177310.1136/gutjnl‑2018‑316324 30661053
     [Google Scholar]
  55. HussainS.M. KansalR.G. AlvarezM.A. Role of TGF-β in pancreatic ductal adenocarcinoma progression and PD-L1 expression.Cell. Oncol.202144367368710.1007/s13402‑021‑00594‑0 33694102
     [Google Scholar]
  56. TsukamotoM. ImaiK. IshimotoT. PD ‐L1 expression enhancement by infiltrating macrophage‐derived tumor necrosis factor‐α leads to poor pancreatic cancer prognosis.Cancer Sci.2019110131032010.1111/cas.13874 30426611
     [Google Scholar]
  57. HeQ. LiuM. HuangW. IL‐1β‐Induced elevation of solute carrier family 7 member 11 promotes hepatocellular carcinoma metastasis through up‐regulating programmed death ligand 1 and colony‐stimulating factor 1.Hepatology20217463174319310.1002/hep.32062 34288020
     [Google Scholar]
  58. LoeuillardE. YangJ. BuckarmaE. Targeting tumor-associated macrophages and granulocytic myeloid-derived suppressor cells augments PD-1 blockade in cholangiocarcinoma.J. Clin. Invest.2020130105380539610.1172/JCI137110 32663198
     [Google Scholar]
  59. JuX. ZhangH. ZhouZ. ChenM. WangQ. Tumor-associated macrophages induce PD-L1 expression in gastric cancer cells through IL-6 and TNF-ɑ signaling.Exp. Cell Res.2020396211231510.1016/j.yexcr.2020.112315 33031808
     [Google Scholar]
  60. ZhangH. LiuL. LiuJ. Roles of tumor-associated macrophages in anti-PD-1/PD-L1 immunotherapy for solid cancers.Mol. Cancer20232215810.1186/s12943‑023‑01725‑x 36941614
     [Google Scholar]
  61. SakaguchiS. YamaguchiT. NomuraT. OnoM. Regulatory T cells and immune tolerance.Cell2008133577578710.1016/j.cell.2008.05.009 18510923
     [Google Scholar]
  62. FridmanW.H. PagèsF. Sautès-FridmanC. GalonJ. The immune contexture in human tumours: Impact on clinical outcome.Nat. Rev. Cancer201212429830610.1038/nrc3245 22419253
     [Google Scholar]
  63. Overacre-DelgoffeA.E. ChikinaM. DadeyR.E. Interferon-γ Drives Treg fragility to promote anti-tumor immunity.Cell2017169611301141.e1110.1016/j.cell.2017.05.005 28552348
     [Google Scholar]
  64. MerghoubT. WolchokJ.D. Curbing Tregs’ (Lack of).Enthusiasm. Cell2017169698198210.1016/j.cell.2017.05.027 28575677
     [Google Scholar]
  65. SieminskaI. BaranJ. Myeloid-derived suppressor cells in colorectal cancer.Front. Immunol.202011152610.3389/fimmu.2020.01526 32849517
     [Google Scholar]
  66. LuT. RamakrishnanR. AltiokS. Tumor-infiltrating myeloid cells induce tumor cell resistance to cytotoxic T cells in mice.J. Clin. Invest.2011121104015402910.1172/JCI45862 21911941
     [Google Scholar]
  67. KatohH. WangD. DaikokuT. SunH. DeyS.K. DuBoisR.N. CXCR2-expressing myeloid-derived suppressor cells are essential to promote colitis-associated tumorigenesis.Cancer Cell201324563164410.1016/j.ccr.2013.10.009 24229710
     [Google Scholar]
  68. SolitoS. FalisiE. Diaz-MonteroC.M. A human promyelocytic-like population is responsible for the immune suppression mediated by myeloid-derived suppressor cells.Blood201111882254226510.1182/blood‑2010‑12‑325753 21734236
     [Google Scholar]
  69. SiricaA.E. The role of cancer-associated myofibroblasts in intrahepatic cholangiocarcinoma.Nat. Rev. Gastroenterol. Hepatol.201291445410.1038/nrgastro.2011.222 22143274
     [Google Scholar]
  70. GanL.L. HiiL.W. WongS.F. LeongC.O. MaiC.W. Molecular mechanisms and potential therapeutic reversal of pancreatic cancer-induced immune evasion.Cancers2020127187210.3390/cancers12071872 32664564
     [Google Scholar]
  71. ValkenburgK.C. de GrootA.E. PientaK.J. Targeting the tumour stroma to improve cancer therapy.Nat. Rev. Clin. Oncol.201815636638110.1038/s41571‑018‑0007‑1 29651130
     [Google Scholar]
  72. GorchsL. Fernández MoroC. BankheadP. Human pancreatic carcinoma-associated fibroblasts promote expression of co-inhibitory markers on CD4+ and CD8+ T-Cells.Front. Immunol.20191084710.3389/fimmu.2019.00847 31068935
     [Google Scholar]
  73. VirginH.W. WherryE.J. AhmedR. Redefining chronic viral infection.Cell20091381305010.1016/j.cell.2009.06.036 19596234
     [Google Scholar]
  74. WherryE.J. T cell exhaustion.Nat. Immunol.201112649249910.1038/ni.2035 21739672
     [Google Scholar]
  75. ChiuD.K.C. YuenV.W.H. CheuJ.W.S. Hepatocellular carcinoma cells up-regulate PVRL1, Stabilizing PVR and Inhibiting the Cytotoxic T-Cell Response via TIGIT to Mediate Tumor Resistance to PD1 Inhibitors in Mice.Gastroenterology2020159260962310.1053/j.gastro.2020.03.074 32275969
     [Google Scholar]
  76. ZhouS. WangY. ZhangR. Association of Sialic Acid–Binding Immunoglobulin-Like Lectin 15 With Phenotypes in Esophageal Squamous Cell Carcinoma in the Setting of Neoadjuvant Chemoradiotherapy.JAMA Netw. Open202361e225096510.1001/jamanetworkopen.2022.50965 36648946
     [Google Scholar]
  77. LiH. ZhuR. LiuX. ZhaoK. HongD. Siglec-15 regulates the inflammatory response and polarization of tumor-associated macrophages in pancreatic cancer by inhibiting the cgas-sting signaling pathway.Oxid. Med. Cell. Longev.2022202211410.1155/2022/3341038 36105484
     [Google Scholar]
  78. SunJ. LuQ. SanmamedM.F. WangJ. Siglec-15 as an emerging target for next-generation cancer immunotherapy.Clin. Cancer Res.202127368068810.1158/1078‑0432.CCR‑19‑2925 32958700
     [Google Scholar]
  79. EscorsD. Gato-CañasM. ZuazoM. The intracellular signalosome of PD-L1 in cancer cells.Signal Transduct. Target. Ther.2018312610.1038/s41392‑018‑0022‑9 30275987
     [Google Scholar]
  80. AhmedA. TaitS.W.G. Targeting immunogenic cell death in cancer.Mol. Oncol.202014122994300610.1002/1878‑0261.12851 33179413
     [Google Scholar]
  81. XiaC. YinS. ToK.K.W. FuL. CD39/CD73/A2AR pathway and cancer immunotherapy.Mol. Cancer20232214410.1186/s12943‑023‑01733‑x 36859386
     [Google Scholar]
  82. ZhangP.F. GaoC. HuangX.Y. Cancer cell-derived exosomal circUHRF1 induces natural killer cell exhaustion and may cause resistance to anti-PD1 therapy in hepatocellular carcinoma.Mol. Cancer202019111010.1186/s12943‑020‑01222‑5 32593303
     [Google Scholar]
  83. LuoC. XinH. ZhouZ. Tumor‐derived exosomes induce immunosuppressive macrophages to foster intrahepatic cholangiocarcinoma progression.Hepatology202276498299910.1002/hep.32387 35106794
     [Google Scholar]
  84. IidaN. DzutsevA. StewartC.A. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment.Science2013342616196797010.1126/science.1240527 24264989
     [Google Scholar]
  85. SivanA. CorralesL. HubertN. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti–PD-L1 efficacy.Science201535062641084108910.1126/science.aac4255 26541606
     [Google Scholar]
  86. VétizouM. PittJ.M. DaillèreR. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota.Science201535062641079108410.1126/science.aad1329 26541610
     [Google Scholar]
  87. PengZ. ChengS. KouY. The gut microbiome is associated with clinical response to Anti–PD-1/PD-L1 immunotherapy in gastrointestinal cancer.Cancer Immunol. Res.20208101251126110.1158/2326‑6066.CIR‑19‑1014 32855157
     [Google Scholar]
  88. ZhengY. WangT. TuX. Gut microbiome affects the response to anti-PD-1 immunotherapy in patients with hepatocellular carcinoma.J. Immunother. Cancer20197119310.1186/s40425‑019‑0650‑9 31337439
     [Google Scholar]
  89. MaoJ. WangD. LongJ. Gut microbiome is associated with the clinical response to anti-PD-1 based immunotherapy in hepatobiliary cancers.J. Immunother. Cancer2021912e00333410.1136/jitc‑2021‑003334 34873013
     [Google Scholar]
  90. DerosaL. HellmannM.D. SpazianoM. Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small-cell lung cancer.Ann. Oncol.20182961437144410.1093/annonc/mdy103 29617710
     [Google Scholar]
  91. ZhouJ. HuangG. WongW.C. The impact of antibiotic use on clinical features and survival outcomes of cancer patients treated with immune checkpoint inhibitors.Front. Immunol.20221396872910.3389/fimmu.2022.968729 35967438
     [Google Scholar]
  92. PinatoD.J. GramenitskayaD. AltmannD.M. Antibiotic therapy and outcome from immune-checkpoint inhibitors.J. Immunother. Cancer20197128710.1186/s40425‑019‑0775‑x 31694714
     [Google Scholar]
  93. YinP. LiuX. MansfieldA.S. CpG-induced antitumor immunity requires IL-12 in expansion of effector cells and down-regulation of PD-1.Oncotarget2016743702237023110.18632/oncotarget.11833 27602959
     [Google Scholar]
  94. WangS. CamposJ. GallottaM. Intratumoral injection of a CpG oligonucleotide reverts resistance to PD-1 blockade by expanding multifunctional CD8 + T cells.Proc. Natl. Acad. Sci.201611346E7240E724910.1073/pnas.1608555113 27799536
     [Google Scholar]
  95. PeukerK. StrigliA. TaurielloD.V.F. Microbiota-dependent activation of the myeloid calcineurin-NFAT pathway inhibits B7H3- and B7H4-dependent anti-tumor immunity in colorectal cancer.Immunity2022554701717.e710.1016/j.immuni.2022.03.008 35364006
     [Google Scholar]
  96. PeukerK. MuffS. WangJ. Epithelial calcineurin controls microbiota-dependent intestinal tumor development.Nat. Med.201622550651510.1038/nm.4072 27043494
     [Google Scholar]
  97. DongX. PanP. ZhengD.W. BaoP. ZengX. ZhangX.Z. Bioinorganic hybrid bacteriophage for modulation of intestinal microbiota to remodel tumor-immune microenvironment against colorectal cancer.Sci. Adv.2020620159010.1126/sciadv.aba1590
     [Google Scholar]
  98. HezavehK. ShindeR.S. KlötgenA. Tryptophan-derived microbial metabolites activate the aryl hydrocarbon receptor in tumor-associated macrophages to suppress anti-tumor immunity.Immunity2022552324340.e810.1016/j.immuni.2022.01.006 35139353
     [Google Scholar]
  99. LooT.M. KamachiF. WatanabeY. Gut microbiota promotes obesity-associated liver cancer through PGE2-mediated suppression of antitumor immunity.Cancer Discov.20177552253810.1158/2159‑8290.CD‑16‑0932 28202625
     [Google Scholar]
  100. BellH.N. HuberA.K. SinghalR. Microenvironmental ammonia enhances T cell exhaustion in colorectal cancer.Cell Metab.2023351134149.e610.1016/j.cmet.2022.11.013 36528023
     [Google Scholar]
  101. TanoueT. MoritaS. PlichtaD.R. A defined commensal consortium elicits CD8 T cells and anti-cancer immunity.Nature2019565774160060510.1038/s41586‑019‑0878‑z 30675064
     [Google Scholar]
  102. MohseniA.H. Taghinezhad-SS. CasolaroV. LvZ. LiD. Potential links between the microbiota and T cell immunity determine the tumor cell fate.Cell Death Dis.202314215410.1038/s41419‑023‑05560‑2 36828830
     [Google Scholar]
  103. FluckigerA. DaillèreR. SassiM. Cross-reactivity between tumor MHC class I–restricted antigens and an enterococcal bacteriophage.Science2020369650693694210.1126/science.aax0701 32820119
     [Google Scholar]
  104. KalaoraS. NaglerA. NejmanD. Identification of bacteria-derived HLA-bound peptides in melanoma.Nature2021592785213814310.1038/s41586‑021‑03368‑8 33731925
     [Google Scholar]
  105. BolteL.A. LeeK.A. BjörkJ.R. Association of a mediterranean diet with outcomes for patients treated with immune checkpoint blockade for advanced melanoma.JAMA Oncol.20239570570910.1001/jamaoncol.2022.7753 36795408
     [Google Scholar]
  106. SpencerC.N. McQuadeJ.L. GopalakrishnanV. Dietary fiber and probiotics influence the gut microbiome and melanoma immunotherapy response.Science202137465751632164010.1126/science.aaz7015 34941392
     [Google Scholar]
  107. WestheimA.J.F. StoffelsL.M. DuboisL.J. Fatty acids as a tool to boost cancer immunotherapy efficacy.Front. Nutr.2022986843610.3389/fnut.2022.868436 35811951
     [Google Scholar]
  108. DePeauxK. DelgoffeG.M. Metabolic barriers to cancer immunotherapy.Nat. Rev. Immunol.2021211278579710.1038/s41577‑021‑00541‑y 33927375
     [Google Scholar]
  109. Martinez-OutschoornU.E. Peiris-PagésM. PestellR.G. SotgiaF. LisantiM.P. Cancer metabolism: A therapeutic perspective.Nat. Rev. Clin. Oncol.2017141113110.1038/nrclinonc.2016.60 27141887
     [Google Scholar]
  110. LongL. WeiJ. LimS.A. CRISPR screens unveil signal hubs for nutrient licensing of T cell immunity.Nature2021600788830831310.1038/s41586‑021‑04109‑7 34795452
     [Google Scholar]
  111. HsuP.P. SabatiniD.M. Cancer cell metabolism: Warburg and beyond.Cell2008134570370710.1016/j.cell.2008.08.021 18775299
     [Google Scholar]
  112. ChangC.H. QiuJ. O’SullivanD. Metabolic competition in the tumor microenvironment is a driver of cancer progression.Cell201516261229124110.1016/j.cell.2015.08.016 26321679
     [Google Scholar]
  113. DelgoffeG.M. KoleT.P. ZhengY. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment.Immunity200930683284410.1016/j.immuni.2009.04.014 19538929
     [Google Scholar]
  114. ChenD.P. NingW.R. JiangZ.Z. Glycolytic activation of peritumoral monocytes fosters immune privilege via the PFKFB3-PD-L1 axis in human hepatocellular carcinoma.J. Hepatol.201971233334310.1016/j.jhep.2019.04.007 31071366
     [Google Scholar]
  115. VasaikarS. HuangC. WangX. Proteogenomic analysis of human colon cancer reveals new therapeutic opportunities.Cell2019177410351049.e1910.1016/j.cell.2019.03.030 31031003
     [Google Scholar]
  116. WildeL. RocheM. Domingo-VidalM. Metabolic coupling and the Reverse Warburg Effect in cancer: Implications for novel biomarker and anticancer agent development.Semin. Oncol.201744319820310.1053/j.seminoncol.2017.10.004 29248131
     [Google Scholar]
  117. WangZ.H. PengW.B. ZhangP. YangX.P. ZhouQ. Lactate in the tumour microenvironment: From immune modulation to therapy.EBioMedicine20217310362710.1016/j.ebiom.2021.103627 34656878
     [Google Scholar]
  118. HayesC. DonohoeC.L. DavernM. DonlonN.E. The oncogenic and clinical implications of lactate induced immunosuppression in the tumour microenvironment.Cancer Lett.2021500758610.1016/j.canlet.2020.12.021 33347908
     [Google Scholar]
  119. LundøK. TrauelsenM. PedersenS.F. SchwartzT.W. Why warburg works: Lactate controls immune evasion through GPR81.Cell Metab.202031466666810.1016/j.cmet.2020.03.001 32268113
     [Google Scholar]
  120. KumagaiS. KoyamaS. ItahashiK. Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments.Cancer Cell2022402201218.e910.1016/j.ccell.2022.01.001 35090594
     [Google Scholar]
  121. WardP.S. ThompsonC.B. Metabolic reprogramming: A cancer hallmark even warburg did not anticipate.Cancer Cell201221329730810.1016/j.ccr.2012.02.014 22439925
     [Google Scholar]
  122. MasoudR. Reyes-CastellanosG. LacS. Targeting mitochondrial complex I overcomes chemoresistance in high OXPHOS pancreatic cancer.Cell Rep. Med.20201810014310.1016/j.xcrm.2020.100143 33294863
     [Google Scholar]
  123. YuW. LeiQ. YangL. Contradictory roles of lipid metabolism in immune response within the tumor microenvironment.J. Hematol. Oncol.202114118710.1186/s13045‑021‑01200‑4 34742349
     [Google Scholar]
  124. EricksenR.E. LimS.L. McDonnellE. Loss of BCAA catabolism during carcinogenesis enhances mTORC1 activity and promotes tumor development and progression.Cell Metab.201929511511165.e610.1016/j.cmet.2018.12.020 30661928
     [Google Scholar]
  125. LauriaG. CurcioR. LunettiP. Role of mitochondrial transporters on metabolic rewiring of pancreatic adenocarcinoma: A comprehensive review.Cancers202315241110.3390/cancers15020411 36672360
     [Google Scholar]
  126. NajumudeenA.K. CeteciF. FeyS.K. The amino acid transporter SLC7A5 is required for efficient growth of KRAS-mutant colorectal cancer.Nat. Genet.2021531162610.1038/s41588‑020‑00753‑3 33414552
     [Google Scholar]
  127. ScaliseM. PochiniL. GalluccioM. ConsoleL. IndiveriC. Glutamine transport and mitochondrial metabolism in cancer cell growth.Front. Oncol.2017730610.3389/fonc.2017.00306 29376023
     [Google Scholar]
  128. WangD WanX Progress in research on the role of amino acid metabolic reprogramming in tumour therapy: A review.Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie2022156113923
     [Google Scholar]
  129. MullenN.J. SinghP.K. Nucleotide metabolism: A pan-cancer metabolic dependency.Nat. Rev. Cancer202323527529410.1038/s41568‑023‑00557‑7 36973407
     [Google Scholar]
  130. YoungA. MittalD. StaggJ. SmythM.J. Targeting cancer-derived adenosine: New therapeutic approaches.Cancer Discov.20144887988810.1158/2159‑8290.CD‑14‑0341 25035124
     [Google Scholar]
  131. OhtaA. GorelikE. PrasadS.J. A2A adenosine receptor protects tumors from antitumor T cells.Proc. Natl. Acad. Sci. USA200610335131321313710.1073/pnas.0605251103 16916931
     [Google Scholar]
  132. MajT. WangW. CrespoJ. Oxidative stress controls regulatory T cell apoptosis and suppressor activity and PD-L1-blockade resistance in tumor.Nat. Immunol.201718121332134110.1038/ni.3868 29083399
     [Google Scholar]
  133. CaiX.Y. WangX.F. LiJ. High expression of CD39 in gastric cancer reduces patient outcome following radical resection.Oncol. Lett.20161254080408610.3892/ol.2016.5189 27895775
     [Google Scholar]
  134. KingR.J. ShuklaS.K. HeC. CD73 induces GM-CSF/MDSC-mediated suppression of T cells to accelerate pancreatic cancer pathogenesis.Oncogene202241797198210.1038/s41388‑021‑02132‑6 35001076
     [Google Scholar]
  135. VijayanD. YoungA. TengM.W.L. SmythM.J. Targeting immunosuppressive adenosine in cancer.Nat. Rev. Cancer2017171270972410.1038/nrc.2017.86 29059149
     [Google Scholar]
  136. WangJ. WangY. ChuY. Tumor-derived adenosine promotes macrophage proliferation in human hepatocellular carcinoma.J. Hepatol.202174362763710.1016/j.jhep.2020.10.021 33137360
     [Google Scholar]
  137. BarsoumI.B. SmallwoodC.A. SiemensD.R. GrahamC.H. A mechanism of hypoxia-mediated escape from adaptive immunity in cancer cells.Cancer Res.201474366567410.1158/0008‑5472.CAN‑13‑0992 24336068
     [Google Scholar]
  138. FeigC. GopinathanA. NeesseA. ChanD.S. CookN. TuvesonD.A. The pancreas cancer microenvironment.Clin. Cancer Res.201218164266427610.1158/1078‑0432.CCR‑11‑3114 22896693
     [Google Scholar]
  139. NomanM.Z. DesantisG. JanjiB. PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation.J. Exp. Med.2014211578179010.1084/jem.20131916 24778419
     [Google Scholar]
  140. KumarV. GabrilovichD.I. Hypoxia‐inducible factors in regulation of immune responses in tumour microenvironment.Immunology2014143451251910.1111/imm.12380 25196648
     [Google Scholar]
  141. DoedensA.L. PhanA.T. StradnerM.H. Hypoxia-inducible factors enhance the effector responses of CD8+ T cells to persistent antigen.Nat. Immunol.201314111173118210.1038/ni.2714 24076634
     [Google Scholar]
  142. IntlekoferA.M. DematteoR.G. VennetiS. Hypoxia induces production of L-2-Hydroxyglutarate.Cell Metab.201522230431110.1016/j.cmet.2015.06.023 26212717
     [Google Scholar]
  143. GuptaV.K. SharmaN.S. DurdenB. Hypoxia-driven oncometabolite L-2HG maintains stemness-differentiation balance and facilitates immune evasion in pancreatic cancer.Cancer Res.202181154001401310.1158/0008‑5472.CAN‑20‑2562 33990397
     [Google Scholar]
  144. JungG. Hernández-IllánE. MoreiraL. BalaguerF. GoelA. Epigenetics of colorectal cancer: Biomarker and therapeutic potential.Nat. Rev. Gastroenterol. Hepatol.202017211113010.1038/s41575‑019‑0230‑y 31900466
     [Google Scholar]
  145. AllisC.D. JenuweinT. The molecular hallmarks of epigenetic control.Nat. Rev. Genet.201617848750010.1038/nrg.2016.59 27346641
     [Google Scholar]
  146. EhrlichM. DNA methylation in cancer: Too much, but also too little.Oncogene200221355400541310.1038/sj.onc.1205651 12154403
     [Google Scholar]
  147. ShiR. ZhaoH. ZhaoS. YuanH. Molecular subtypes, prognostic and immunotherapeutic relevant gene signatures mediated by DNA methylation regulators in hepatocellular carcinoma.Aging202214125271529110.18632/aging.204155 35771147
     [Google Scholar]
  148. SundarR. HuangK.K. QamraA. Epigenomic promoter alterations predict for benefit from immune checkpoint inhibition in metastatic gastric cancer.Ann. Oncol.201930342443010.1093/annonc/mdy550 30624548
     [Google Scholar]
  149. SundarR. HuangK.K. KumarV. Epigenetic promoter alterations in GI tumour immune-editing and resistance to immune checkpoint inhibition.Gut20227171277128810.1136/gutjnl‑2021‑324420 34433583
     [Google Scholar]
  150. BassA.J. ThorssonV. ShmulevichI. Comprehensive molecular characterization of gastric adenocarcinoma.Nature2014513751720220910.1038/nature13480 25079317
     [Google Scholar]
  151. KataokaK. ShiraishiY. TakedaY. Aberrant PD-L1 expression through 3′-UTR disruption in multiple cancers.Nature2016534760740240610.1038/nature18294 27281199
     [Google Scholar]
  152. FuY. DominissiniD. RechaviG. HeC. Gene expression regulation mediated through reversible m6A RNA methylation.Nat. Rev. Genet.201415529330610.1038/nrg3724 24662220
     [Google Scholar]
  153. LiuX. WangC. LiuW. Distinct features of H3K4me3 and H3K27me3 chromatin domains in pre-implantation embryos.Nature2016537762155856210.1038/nature19362 27626379
     [Google Scholar]
  154. LuC. LiuZ. KlementJ.D. WDR5-H3K4me3 epigenetic axis regulates OPN expression to compensate PD-L1 function to promote pancreatic cancer immune escape.J. Immunother. Cancer202197e00262410.1136/jitc‑2021‑002624 34326167
     [Google Scholar]
  155. WangY. CaoK. KDM1A promotes immunosuppression in hepatocellular carcinoma by regulating PD-L1 through demethylating MEF2D.J. Immunol. Res.2021202111910.1155/2021/9965099 34307695
     [Google Scholar]
  156. WangX. ZhaoJ. Targeted cancer therapy based on acetylation and deacetylation of key proteins involved in double-strand break repair.Cancer Manag. Res.20221425927110.2147/CMAR.S346052 35115826
     [Google Scholar]
  157. SimW. LimW.M. HiiL.W. LeongC.O. MaiC.W. Targeting pancreatic cancer immune evasion by inhibiting histone deacetylases.World J. Gastroenterol.202228181934194510.3748/wjg.v28.i18.1934 35664961
     [Google Scholar]
  158. HuG HeN CaiC HDAC3 modulates cancer immunity via increasing PD-L1 expression in pancreatic cancer. Pancreatology : officialjournal of the International Association of Pancreatology (IAP)20191923839
     [Google Scholar]
  159. KitaY. YonemoriK. OsakoY. Noncoding RNA and colorectal cancer: Its epigenetic role.J. Hum. Genet.2017621414710.1038/jhg.2016.66 27278790
     [Google Scholar]
  160. ChenL. GibbonsD.L. GoswamiS. Metastasis is regulated via microRNA-200/ZEB1 axis control of tumour cell PD-L1 expression and intratumoral immunosuppression.Nat. Commun.201451524110.1038/ncomms6241 25348003
     [Google Scholar]
  161. WangY. WangD. XieG. MicroRNA-152 regulates immune response via targeting B7-H1 in gastric carcinoma.Oncotarget2017817281252813410.18632/oncotarget.15924 28427226
     [Google Scholar]
  162. MiliotisC. SlackF.J. miR-105-5p regulates PD-L1 expression and tumor immunogenicity in gastric cancer.Cancer Lett.202151811512610.1016/j.canlet.2021.05.037 34098061
     [Google Scholar]
  163. GuoW. WangY. YangM. LincRNA-immunity landscape analysis identifies EPIC1 as a regulator of tumor immune evasion and immunotherapy resistance.Sci. Adv.202177eabb355510.1126/sciadv.abb3555 33568470
     [Google Scholar]
  164. ChenL.L. The biogenesis and emerging roles of circular RNAs.Nat. Rev. Mol. Cell Biol.201617420521110.1038/nrm.2015.32 26908011
     [Google Scholar]
  165. ChenD.L. ShengH. ZhangD.S. The circular RNA circDLG1 promotes gastric cancer progression and anti-PD-1 resistance through the regulation of CXCL12 by sponging miR-141-3p.Mol. Cancer202120116610.1186/s12943‑021‑01475‑8 34911533
     [Google Scholar]
  166. BrudnoJ.N. KochenderferJ.N. Toxicities of chimeric antigen receptor T cells: Recognition and management.Blood2016127263321333010.1182/blood‑2016‑04‑703751 27207799
     [Google Scholar]
  167. VinayD.S. RyanE.P. PawelecG. Immune evasion in cancer: Mechanistic basis and therapeutic strategies.Semin. Cancer Biol.201535Suppl.S185S19810.1016/j.semcancer.2015.03.004 25818339
     [Google Scholar]
  168. SanmamedM.F. ChenL. A paradigm shift in cancer immunotherapy: From enhancement to normalization.Cell2018175231332610.1016/j.cell.2018.09.035 30290139
     [Google Scholar]
  169. BurtonE.M. TawbiH.A. Bispecific antibodies to PD-1 and CTLA4: Doubling down on t cells to decouple efficacy from toxicity.Cancer Discov.20211151008101010.1158/2159‑8290.CD‑21‑0257 33947716
     [Google Scholar]
  170. LiuF. LiuY. ChenZ. Tim-3 expression and its role in hepatocellular carcinoma.J. Hematol. Oncol.201811112610.1186/s13045‑018‑0667‑4 30309387
     [Google Scholar]
  171. WangP. ChenY. LongQ. Increased coexpression of PD-L1 and TIM3/TIGIT is associated with poor overall survival of patients with esophageal squamous cell carcinoma.J. Immunother. Cancer2021910e00283610.1136/jitc‑2021‑002836 34625514
     [Google Scholar]
  172. ZhouG. SprengersD. BoorP.P.C. Antibodies against immune checkpoint molecules restore functions of tumor-infiltrating t cells in hepatocellular carcinomas.Gastroenterology2017153411071119.e1010.1053/j.gastro.2017.06.017 28648905
     [Google Scholar]
  173. Freed-PastorW.A. LambertL.J. ElyZ.A. The CD155/TIGIT axis promotes and maintains immune evasion in neoantigen-expressing pancreatic cancer.Cancer Cell2021391013421360.e1410.1016/j.ccell.2021.07.007 34358448
     [Google Scholar]
  174. PengH. FuY.X. The inhibitory PVRL1/PVR/TIGIT axis in immune therapy for hepatocellular carcinoma.Gastroenterology2020159243443610.1053/j.gastro.2020.06.024 32574623
     [Google Scholar]
  175. HeW. ZhangH. HanF. CD155T/TIGIT signaling regulates CD8+ T-cell metabolism and promotes tumor progression in human gastric cancer.Cancer Res.201777226375638810.1158/0008‑5472.CAN‑17‑0381 28883004
     [Google Scholar]
  176. GeZ. ZhouG. Campos CarrascosaL. TIGIT and PD1 Co-blockade Restores ex vivo Functions of Human Tumor-Infiltrating CD8+ T Cells in Hepatocellular Carcinoma.Cell. Mol. Gastroenterol. Hepatol.202112244346410.1016/j.jcmgh.2021.03.003 33781741
     [Google Scholar]
  177. YanX. DuanH. NiY. Tislelizumab combined with chemotherapy as neoadjuvant therapy for surgically resectable esophageal cancer: A prospective, single-arm, phase II study (TD-NICE).Int. J. Surg.202210310668010.1016/j.ijsu.2022.106680 35595021
     [Google Scholar]
  178. LiY. ZhouA. LiuS. Comparing a PD-L1 inhibitor plus chemotherapy to chemotherapy alone in neoadjuvant therapy for locally advanced ESCC: A randomized Phase II clinical trial.BMC Med.20232118610.1186/s12916‑023‑02804‑y 36882775
     [Google Scholar]
  179. JanjigianY.Y. ShitaraK. MoehlerM. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): A randomised, open-label, phase 3 trial.Lancet202139810294274010.1016/S0140‑6736(21)00797‑2 34102137
     [Google Scholar]
  180. SongY. ZhangB. XinD. First-line serplulimab or placebo plus chemotherapy in PD-L1-positive esophageal squamous cell carcinoma: a randomized, double-blind phase 3 trial.Nat. Med.202329247348210.1038/s41591‑022‑02179‑2 36732627
     [Google Scholar]
  181. YangX. ChenB. WangY. Real-world efficacy and prognostic factors of lenvatinib plus PD-1 inhibitors in 378 unresectable hepatocellular carcinoma patients.Hepatol. Int.202317370971910.1007/s12072‑022‑10480‑y 36753026
     [Google Scholar]
  182. WangX.H. LiuC.J. WenH.Q. Effectiveness of lenvatinib plus immune checkpoint inhibitors in primary advanced hepatocellular carcinoma beyond oligometastasis.Clin. Transl. Med.2023133e121410.1002/ctm2.1214 36855781
     [Google Scholar]
  183. YarchoanM. CopeL. RuggieriA.N. Multicenter randomized phase II trial of atezolizumab with or without cobimetinib in biliary tract cancers.J. Clin. Invest.202113124e15267010.1172/JCI152670 34907910
     [Google Scholar]
  184. LiX. LiY. DongL. Decitabine priming increases anti–PD-1 antitumor efficacy by promoting CD8+ progenitor exhausted T cell expansion in tumor models.J. Clin. Invest.20231337e16567310.1172/JCI165673 36853831
     [Google Scholar]
  185. ChristmasB.J. RafieC.I. HopkinsA.C. Entinostat converts immune-resistant breast and pancreatic cancers into checkpoint-responsive tumors by reprogramming tumor-infiltrating MDSCs.Cancer Immunol. Res.20186121561157710.1158/2326‑6066.CIR‑18‑0070 30341213
     [Google Scholar]
  186. WuY. SangM. LiuF. Epigenetic modulation combined with PD-1/PD-L1 blockade enhances immunotherapy based on MAGE-A11 antigen-specific CD8+T cells against esophageal carcinoma.Carcinogenesis202041789490310.1093/carcin/bgaa057 32529260
     [Google Scholar]
  187. RoutyB. Le ChatelierE. DerosaL. Gut microbiome influences efficacy of PD-1–based immunotherapy against epithelial tumors.Science20183596371919710.1126/science.aan3706 29097494
     [Google Scholar]
  188. GopalakrishnanV. SpencerC.N. NeziL. Gut microbiome modulates response to anti–PD-1 immunotherapy in melanoma patients.Science201835963719710310.1126/science.aan4236 29097493
     [Google Scholar]
  189. MatsonV. FesslerJ. BaoR. The commensal microbiome is associated with anti–PD-1 efficacy in metastatic melanoma patients.Science2018359637110410810.1126/science.aao3290 29302014
     [Google Scholar]
  190. MirjiG. WorthA. BhatS.A. The microbiome-derived metabolite TMAO drives immune activation and boosts responses to immune checkpoint blockade in pancreatic cancer.Sci. Immunol.2022775eabn070410.1126/sciimmunol.abn0704 36083892
     [Google Scholar]
  191. OginoS. NowakJ.A. HamadaT. MilnerD.A.Jr NishiharaR. Insights into pathogenic interactions among environment, host, and tumor at the crossroads of molecular pathology and epidemiology.Annu. Rev. Pathol.20191418310310.1146/annurev‑pathmechdis‑012418‑012818 30125150
     [Google Scholar]
  192. InamuraK. HamadaT. BullmanS. UgaiT. YachidaS. OginoS. Cancer as microenvironmental, systemic and environmental diseases: opportunity for transdisciplinary microbiomics science.Gut202271102107212210.1136/gutjnl‑2022‑327209 35820782
     [Google Scholar]
  193. HuB. YuM. MaX. IFNα potentiates Anti–PD-1 efficacy by remodeling glucose metabolism in the hepatocellular carcinoma microenvironment.Cancer Discov.20221271718174110.1158/2159‑8290.CD‑21‑1022 35412588
     [Google Scholar]
  194. CappellessoF. OrbanM.P. ShirgaonkarN. Targeting the bicarbonate transporter SLC4A4 overcomes immunosuppression and immunotherapy resistance in pancreatic cancer.Nat. Can.20223121464148310.1038/s43018‑022‑00470‑2 36522548
     [Google Scholar]
  195. QinL. WangL. ZhangJ. Therapeutic strategies targeting uPAR potentiate anti–PD-1 efficacy in diffuse-type gastric cancer.Sci. Adv.2022821eabn377410.1126/sciadv.abn3774 35613265
     [Google Scholar]
  196. AkiyamaT. YasudaT. UchiharaT. Stromal reprogramming through dual PDGFRα/β blockade boosts the efficacy of Anti–PD-1 immunotherapy in fibrotic tumors.Cancer Res.202383575377010.1158/0008‑5472.CAN‑22‑1890 36543251
     [Google Scholar]
  197. WangY. WeiB. GaoJ. Combination of fruquintinib and Anti-PD-1 for the treatment of colorectal cancer.J. Immun.20202051029052915
     [Google Scholar]
  198. DoleschelD. HoffS. KoletnikS. Regorafenib enhances anti-PD1 immunotherapy efficacy in murine colorectal cancers and their combination prevents tumor regrowth.J. Exp. Clin. Cancer Res.202140128810.1186/s13046‑021‑02043‑0 34517894
     [Google Scholar]
  199. FuY. PengY. ZhaoS. Combination foretinib and anti-PD-1 antibody immunotherapy for colorectal carcinoma.Front. Cell Dev. Biol.2021968972710.3389/fcell.2021.689727 34307367
     [Google Scholar]
  200. LinH. WuY. ChenJ. HuangS. WangY. (−)-4-O-(4-O-β-D-glucopyranosylcaffeoyl) quinic acid inhibits the function of myeloid-derived suppressor cells to enhance the efficacy of anti-pd1 against colon cancer.Pharm. Res.201835918310.1007/s11095‑018‑2459‑5 30062658
     [Google Scholar]
  201. GrecoR. QuH. QuH. Pan-TGFβ inhibition by SAR439459 relieves immunosuppression and improves antitumor efficacy of PD-1 blockade.OncoImmunology202091181160510.1080/2162402X.2020.1811605 33224628
     [Google Scholar]
  202. YouD. HillermanS. LockeG. Enhanced antitumor immunity by a novel small molecule HPK1 inhibitor.J. Immunother. Cancer202191e00140210.1136/jitc‑2020‑001402 33408094
     [Google Scholar]
  203. KotsilitiE. Targeting hyperactive tRNA modification improves anti-PD1 efficacy.Nat. Rev. Gastroenterol. Hepatol.2023201310.1038/s41575‑022‑00715‑6 36418437
     [Google Scholar]
  204. KatoY. TabataK. KimuraT. Lenvatinib plus anti-PD-1 antibody combination treatment activates CD8+ T cells through reduction of tumor-associated macrophage and activation of the interferon pathway.PLoS One2019142e021251310.1371/journal.pone.0212513 30811474
     [Google Scholar]
  205. HuZ. ChenG. ZhaoY. Exosome-derived circCCAR1 promotes CD8 + T-cell dysfunction and anti-PD1 resistance in hepatocellular carcinoma.Mol. Cancer20232215510.1186/s12943‑023‑01759‑1 36932387
     [Google Scholar]
  206. WeiC.Y. ZhuM.X. ZhangP.F. PKCα/ZFP64/CSF1 axis resets the tumor microenvironment and fuels anti-PD1 resistance in hepatocellular carcinoma.J. Hepatol.202277116317610.1016/j.jhep.2022.02.019 35219791
     [Google Scholar]
/content/journals/pra/10.2174/0115748928269276231120103256
Loading
Mechanisms of Anti-PD Therapy Resistance in Digestive System Neoplasms
Recent Patents on Anti-Cancer Drug Discovery 20, 1 (2025); https://doi.org/10.2174/0115748928269276231120103256
/content/journals/pra/10.2174/0115748928269276231120103256
/content/journals/pra/10.2174/0115748928269276231120103256
Loading

Data & Media loading...


  • Article Type:     Review Article
Keyword(s): anti-PD-1/PD-L1 therapy; digestive system neoplasms; Immunotherapy resistance; normalization cancer immunotherapy; pancreatic cancer; PD-1/B7-H1

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