Academic Journal
Προβολή σε EDS

Resistance to PD-1/PD-L1 blockade: Mechanism and pharmacological strategies.

Λεπτομέρειες βιβλιογραφικής εγγραφής
Τίτλος: Resistance to PD-1/PD-L1 blockade: Mechanism and pharmacological strategies.
Συγγραφείς: Kim AMJ; University of Chicago Medicine Comprehensive Cancer Center, 5841 S Maryland Ave, Chicago, IL 60637, USA; Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL, USA., Lee N; Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA., Chen HY; Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA., Lim SO; Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA; Purdue Institute for Cancer Research, Purdue University, West Lafayette, IN 47907, USA; Purdue Institute for Drug Discovery, Purdue University, West Lafayette, IN 47907, USA. Electronic address: limsoe@purdue.edu.
Πηγή: Pharmacological research [Pharmacol Res] 2026 Oct; Vol. 232, pp. 108404. Date of Electronic Publication: 2026 Aug 18.
Τύπος έκδοσης: Journal Article; Review
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Elsevier Country of Publication: Netherlands NLM ID: 8907422 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1096-1186 (Electronic) Linking ISSN: 10436618 NLM ISO Abbreviation: Pharmacol Res Subsets: MEDLINE
Imprint Name(s): Publication: Oct. 2015- : Amsterdam ; Elsevier
Original Publication: London ; San Diego : Academic Press, c1989-
Ιατρικοί όροι (MeSH): Neoplasms*/drug therapy , Neoplasms*/immunology , Neoplasms*/metabolism , Programmed Cell Death 1 Receptor*/antagonists & inhibitors , Programmed Cell Death 1 Receptor*/immunology , Immune Checkpoint Inhibitors*/therapeutic use , Immune Checkpoint Inhibitors*/pharmacology , B7-H1 Antigen*/antagonists & inhibitors , B7-H1 Antigen*/immunology , Drug Resistance, Neoplasm*, Tumor Microenvironment/drug effects ; Humans ; Animals
Περίληψη: Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis have transformed the realm of cancer treatment. Nevertheless, fewer than one in five patients derive durable benefit, and a substantial proportion of initial responders eventually relapse, reflecting a heterogeneous milieu of intrinsic and acquired mechanisms of resistance. Resistance to ICIs can arise from impaired neoantigen generation and presentation (low tumor mutational burden, loss of functional HLA class I and β2-microglobulin), defective IFN-γ/JAK-STAT signaling, co-expression of alternative checkpoints (LAG-3, TIM-3, TIGIT, CTLA-4), an immunosuppressive and metabolically hostile "cold" tumor microenvironment enriched in regulatory T cells, myeloid-derived suppressor cells, and M2-polarized macrophages, and clonal immunoediting. In this review, we synthesize the current landscape of PD-1/PD-L1-directed ICIs, dissect the molecular and cellular determinants of intrinsic and acquired resistance, and discuss emerging pharmacological strategies to overcome them, including next-generation checkpoint combinations (anti-LAG-3, anti-TIGIT), bispecific antibodies (e.g., PD-1/VEGF, PD-L1/TGF-β), antibody-drug conjugates, targeted-therapy and epigenetic combinations, innate immune agonists, oncolytic viruses, gut microbiome modulation, and biomarker-guided patient selection, with the goal of informing rational combination regimens capable of extending the benefit of checkpoint blockade to a substantially broader patient population.
(Copyright © 2026 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
References: N Engl J Med. 2012 Jun 28;366(26):2455-65. (PMID: 22658128)
Clin Cancer Res. 2017 Sep 15;23(18):5349-5357. (PMID: 28634283)
Int J Mol Sci. 2019 Feb 14;20(4):. (PMID: 30769852)
Nat Rev Drug Discov. 2022 Nov;21(11):799-820. (PMID: 35974096)
Cell. 2017 Feb 9;168(4):707-723. (PMID: 28187290)
Nat Rev Clin Oncol. 2018 May;15(5):325-340. (PMID: 29508855)
N Engl J Med. 2022 Jan 6;386(1):24-34. (PMID: 34986285)
Cell Rep. 2015 May 19;11(7):1018-30. (PMID: 25959818)
Nat Rev Clin Oncol. 2019 Jul;16(7):425-441. (PMID: 30914826)
Cell Res. 2018 Aug;28(8):862-864. (PMID: 29959401)
Cancer Cell. 2019 Oct 14;36(4):385-401.e8. (PMID: 31564637)
Science. 2021 Feb 5;371(6529):602-609. (PMID: 33303685)
Sci Transl Med. 2018 Jan 17;10(424):. (PMID: 29343622)
Cell. 2017 Nov 30;171(6):1259-1271.e11. (PMID: 29107330)
Science. 2011 Mar 25;331(6024):1565-70. (PMID: 21436444)
Nature. 2006 Feb 9;439(7077):682-7. (PMID: 16382236)
J Clin Oncol. 2015 Sep 1;33(25):2780-8. (PMID: 26014293)
Nat Rev Immunol. 2026 Jan;26(1):23-34. (PMID: 40781552)
Int J Cancer. 2025 Jun 15;156(12):2352-2359. (PMID: 39887747)
J Clin Invest. 2017 Aug 1;127(8):2930-2940. (PMID: 28650338)
Nat Commun. 2017 Oct 26;8(1):1136. (PMID: 29070816)
Neurosci Bull. 2021 Aug;37(8):1188-1202. (PMID: 33877518)
N Engl J Med. 2010 Aug 19;363(8):711-23. (PMID: 20525992)
Annu Rev Immunol. 2008;26:677-704. (PMID: 18173375)
Proc Natl Acad Sci U S A. 2002 Sep 17;99(19):12293-7. (PMID: 12218188)
Lancet Oncol. 2020 Oct;21(10):1353-1365. (PMID: 32919526)
Ann Oncol. 2025 Jul;36(7):775-785. (PMID: 40157574)
N Engl J Med. 2015 Jun 25;372(26):2509-20. (PMID: 26028255)
Nature. 2017 Jul 13;547(7662):217-221. (PMID: 28678778)
Front Immunol. 2020 Nov 25;11:584626. (PMID: 33324403)
Mol Cell. 2020 Mar 5;77(5):930-931. (PMID: 32142689)
Nat Med. 2019 Jun;25(6):936-940. (PMID: 31171879)
Blood. 2009 Aug 20;114(8):1537-44. (PMID: 19423728)
Immunotherapy. 2018 Feb;10(2):149-160. (PMID: 29260623)
Nature. 2014 Sep 25;513(7519):559-63. (PMID: 25043024)
Clin Cancer Res. 2014 Oct 1;20(19):5064-74. (PMID: 24714771)
N Engl J Med. 2012 Jun 28;366(26):2443-54. (PMID: 22658127)
Science. 2021 Dec 24;374(6575):1632-1640. (PMID: 34941392)
Cancer Discov. 2021 Apr;11(4):933-959. (PMID: 33811125)
Mol Ther. 2025 Feb 5;33(2):723-733. (PMID: 40308191)
J Exp Med. 2000 Oct 2;192(7):1027-34. (PMID: 11015443)
Clin Cancer Res. 2018 Mar 15;24(6):1287-1295. (PMID: 29298798)
Front Immunol. 2023 May 16;14:1163633. (PMID: 37261359)
N Engl J Med. 2025 Jul 3;393(1):37-50. (PMID: 40532178)
Nat Rev Immunol. 2021 Aug;21(8):485-498. (PMID: 33526920)
Nat Cancer. 2020 Sep;1(9):873-881. (PMID: 35121950)
J Immunother Cancer. 2019 Nov 15;7(1):305. (PMID: 31730010)
Cell Metab. 2016 Nov 8;24(5):657-671. (PMID: 27641098)
Ann Oncol. 2025 Jan;36(1):99-107. (PMID: 39288844)
Int J Mol Sci. 2019 Apr 04;20(7):. (PMID: 30987269)
Nature. 2014 Nov 27;515(7528):568-71. (PMID: 25428505)
Cancer Discov. 2018 Sep;8(9):1069-1086. (PMID: 30115704)
Lancet. 2023 Dec 9;402(10418):2197-2208. (PMID: 37871604)
Lancet Oncol. 2022 Jun;23(6):781-792. (PMID: 35576957)
Cancer Cell. 2025 Feb 10;43(2):308-316.e6. (PMID: 39933900)
Signal Transduct Target Ther. 2026 Apr 08;11(1):. (PMID: 41946687)
Cancer Discov. 2017 Feb;7(2):188-201. (PMID: 27903500)
Neuron. 2023 Sep 6;111(17):2709-2726.e9. (PMID: 37348508)
Nat Rev Clin Oncol. 2022 Jan;19(1):37-50. (PMID: 34580473)
Nat Commun. 2019 Jan 28;10(1):465. (PMID: 30692527)
Cancer Discov. 2017 Mar;7(3):264-276. (PMID: 28031159)
Blood Sci. 2023 Jan 13;5(2):77-91. (PMID: 37228770)
Nat Rev Cancer. 2017 Dec;17(12):709-724. (PMID: 29059149)
Nat Rev Clin Oncol. 2019 Jun;16(6):356-371. (PMID: 30705439)
N Engl J Med. 2019 Oct 17;381(16):1535-1546. (PMID: 31562797)
Cancer Res. 2020 Jun 1;80(11):2298-2310. (PMID: 32156778)
J Clin Oncol. 2022 Jan 10;40(2):127-137. (PMID: 34818112)
Cancer Immunol Res. 2017 Aug;5(8):676-684. (PMID: 28674082)
Science. 2018 Jan 5;359(6371):104-108. (PMID: 29302014)
Lab Invest. 2017 Sep;97(9):1063-1071. (PMID: 28737763)
J Clin Oncol. 2024 Jan 20;42(3):324-335. (PMID: 37976444)
Lancet. 2025 May 24;405(10492):1851-1864. (PMID: 40349714)
Science. 2015 Nov 27;350(6264):1084-9. (PMID: 26541606)
Science. 2018 Jan 5;359(6371):97-103. (PMID: 29097493)
Science. 2021 Feb 5;371(6529):595-602. (PMID: 33542131)
Mol Cancer. 2024 Nov 29;23(1):266. (PMID: 39614285)
Nat Rev Drug Discov. 2019 Mar;18(3):197-218. (PMID: 30610226)
Cell. 2023 Apr 13;186(8):1652-1669. (PMID: 37059068)
Nat Med. 2002 Aug;8(8):793-800. (PMID: 12091876)
Nat Rev Drug Discov. 2018 Jul;17(7):509-527. (PMID: 29904196)
Am J Cancer Res. 2020 Mar 01;10(3):727-742. (PMID: 32266087)
N Engl J Med. 2018 Jan 11;378(2):158-168. (PMID: 29320654)
JAMA Netw Open. 2024 Mar 4;7(3):e241215. (PMID: 38446479)
Immunol Rev. 2010 Jul;236:219-42. (PMID: 20636820)
Nat Rev Immunol. 2018 Feb;18(2):91-104. (PMID: 28990586)
Int J Mol Sci. 2022 Oct 11;23(20):. (PMID: 36292922)
Lancet. 2025 Mar 08;405(10481):839-849. (PMID: 40057343)
Nat Commun. 2016 Aug 30;7:12632. (PMID: 27572267)
Cancer Cell. 2015 Sep 14;28(3):285-95. (PMID: 26373277)
Lancet. 2026 Apr 18;407(10538):1525-1537. (PMID: 41974150)
Science. 2015 Apr 3;348(6230):69-74. (PMID: 25838375)
Cell. 2017 Sep 7;170(6):1109-1119.e10. (PMID: 28886381)
Immunity. 2016 May 17;44(5):989-1004. (PMID: 27192565)
Sci Transl Med. 2017 May 10;9(389):. (PMID: 28490665)
J Exp Med. 2012 Jun 4;209(6):1201-17. (PMID: 22641383)
J Clin Invest. 2021 Apr 15;131(8):. (PMID: 33855973)
Science. 2018 Jan 5;359(6371):91-97. (PMID: 29097494)
Br J Cancer. 2015 Apr 28;112(9):1421-7. (PMID: 25856776)
Nat Rev Cancer. 2012 Mar 22;12(4):252-64. (PMID: 22437870)
Sci Adv. 2020 Sep 18;6(38):. (PMID: 32948597)
Nature. 2017 Jan 18;541(7637):321-330. (PMID: 28102259)
Cell Rep. 2017 May 9;19(6):1189-1201. (PMID: 28494868)
Nat Commun. 2016 Feb 17;7:10501. (PMID: 26883990)
Oncol Rep. 2019 May;41(5):2833-2843. (PMID: 30864729)
Nat Immunol. 2007 Mar;8(3):239-45. (PMID: 17304234)
N Engl J Med. 2024 Nov 28;391(21):2014-2026. (PMID: 39602630)
Science. 2018 Mar 23;359(6382):1350-1355. (PMID: 29567705)
Cancer Cell. 2018 Feb 12;33(2):187-201.e10. (PMID: 29438695)
EMBO J. 2021 Dec 15;40(24):e108662. (PMID: 34825707)
Int Urol Nephrol. 2021 Dec;53(12):2493-2503. (PMID: 33797012)
N Engl J Med. 2016 Sep 1;375(9):819-29. (PMID: 27433843)
Nature. 2019 Mar;567(7749):479-485. (PMID: 30894752)
N Engl J Med. 2024 Nov 14;391(19):1773-1786. (PMID: 39282910)
J Immunother Cancer. 2021 Feb;9(2):. (PMID: 33589525)
N Engl J Med. 2025 Jan 2;392(1):11-22. (PMID: 39282897)
Cell. 2015 Aug 27;162(5):974-86. (PMID: 26317466)
J Immunother Cancer. 2020 Sep;8(2):. (PMID: 32900861)
Science. 2015 Apr 3;348(6230):56-61. (PMID: 25838373)
Nat Rev Immunol. 2026 Jan;26(1):35-51. (PMID: 40813802)
Cancers (Basel). 2020 Jul 02;12(7):. (PMID: 32630675)
Grant Information: U01 CA272280 United States CA NCI NIH HHS
Contributed Indexing: Keywords: Antibody engineering; Combination immunotherapy; Gut microbiome; Immune checkpoint inhibitor resistance; PD-1/PD-L1 blockade; Tumor microenvironment
Substance Nomenclature: 0 (Programmed Cell Death 1 Receptor)
0 (Immune Checkpoint Inhibitors)
0 (B7-H1 Antigen)
0 (CD274 protein, human)
0 (PDCD1 protein, human)
Entry Date(s): Date Created: 20260818 Date Completed: 20260919 Latest Revision: 20261014
Update Code: 20261014
PubMed Central ID: PMC13659229
DOI: 10.1016/j.phrs.2026.108404
PMID: 42612932
Βάση Δεδομένων: MEDLINE
Περιγραφή
ISSN:1096-1186
DOI:10.1016/j.phrs.2026.108404