胰腺癌靶向治疗及免疫治疗的研究新进展

doi:10.12114/j.issn.1007-9572.2024.0195

中国全科医学 ›› 2025, Vol. 28 ›› Issue (23): 2950-2960.DOI: 10.12114/j.issn.1007-9572.2024.0195

• 综述与专论 • 上一篇

胰腺癌靶向治疗及免疫治疗的研究新进展

阮万百¹^,², 李俊峰¹, 尹艳梅¹, 彭磊¹, 朱克祥³^,^*()

1．730000　甘肃省兰州市，兰州大学第一临床医学院
2．730000　甘肃省兰州市，中国人民解放军联勤保障部队第九四〇医院肝胆外科
3．730000　甘肃省兰州市，兰州大学第一医院普外科

收稿日期:2024-05-15 修回日期:2024-07-03 出版日期:2025-08-15 发布日期:2025-06-17
通讯作者: 朱克祥
作者贡献：
阮万百负责文章构思与设计，并查阅文献、起草和撰写文章；李俊峰、尹艳梅、彭磊修订论文格式、文章结构及文章重要论点；朱克祥予以指导性意见并对最终文稿的内容进行审阅。
基金资助:
甘肃省自然科学基金项目(22JR11RA023)

Research Progress of Targeted Therapy and Immunotherapy for Pancreatic Cancer

RUAN Wanbai¹^,², LI Junfeng¹, YIN Yanmei¹, PENG Lei¹, ZHU Kexiang³^,^*()

1. The First Clinical Medical College of Lanzhou University, Lanzhou 730000, China
2. Hepatobiliary Surgery Department, the 940 Hospital of Joint Logistic Support Force of PLA, Lanzhou 730000, China
3. Department of General Surgery, the First Hospital of Lanzhou university, Lanzhou 730000, China

Received:2024-05-15 Revised:2024-07-03 Published:2025-08-15 Online:2025-06-17
Contact: ZHU Kexiang

分享到

摘要/Abstract

摘要： 胰腺癌恶性程度高，患者整体预后差。目前缺乏有效的早期检测手段，多数患者确诊时已处于局部进展期或已发生远处转移，加之其独特的肿瘤微环境使得传统治疗模式（手术、放疗和化疗）遇到了瓶颈。本文系统、全面地探讨了国内外有关胰腺癌治疗的最新进展，并通过梳理相关文献，总结了胰腺癌靶向治疗及免疫治疗的相关研究。本文发现，随着基因测序和多组学研究的不断深入，人们对胰腺癌的分子机制和基因表达谱有了更深入了解，更多信号通路和作用靶点被发现，相应的靶向治疗和免疫治疗药物也越来越多，胰腺癌的治疗模式正逐渐从传统的"一刀切"方式向更加精准的个体化治疗转变，为胰腺癌治疗带来新的曙光。本文能够为针对胰腺癌靶向及免疫治疗的进一步研究提供新思路。

关键词: 胰腺癌, 肿瘤微环境, 靶向治疗, 免疫治疗, 综述

Abstract:

Pancreatic cancer is a highly malignant disease with a poor prognosis. Currently, there is a lack of effective early detection methods, resulting in most patients being diagnosed at an advanced stage or with distant metastasis. Furthermore, the unique tumor microenvironment poses challenges for traditional treatment modalities such as surgery, radiotherapy, and chemotherapy. This article provided a comprehensive review of the latest advancements in pancreatic cancer treatment both domestically and internationally. It also summarized relevant literature on targeted therapy and immunotherapy for pancreatic cancer. The article highlighted that continuous developments in gene sequencing and multi-omics research deepened our understanding of the molecular mechanisms and gene expression profiles associated with pancreatic cancer. Consequently, numerous signaling pathways and targets had been identified along with an array of targeted therapy and immunotherapy drugs. As a result, the treatment approach for pancreatic cancer was gradually shifting from a conventional "one-size-fits-all" strategy to more precise individualized treatments, ushering in new possibilities for combating this disease. This study offered novel insights that could guide further research on targeted therapy and immunotherapy for pancreatic cancer

Key words: Pancreatic cancer, Tumor microenvironment, Targeted therapy, Immunotherapy, Review

中图分类号:

R 735.9

阮万百,李俊峰,尹艳梅,等. 胰腺癌靶向治疗及免疫治疗的研究新进展[J]. 中国全科医学, 2025, 28(23): 2950-2960. DOI: 10.12114/j.issn.1007-9572.2024.0195.
RUAN Wanbai,LI Junfeng,YIN Yanmei, et al. Research Progress of Targeted Therapy and Immunotherapy for Pancreatic Cancer[J]. Chinese General Practice, 2025, 28(23): 2950-2960. DOI: 10.12114/j.issn.1007-9572.2024.0195.

参考文献 120

[1]	LEE A Y L, DUBOIS C L, SARAI K, et al. Cell of origin affects tumour development and phenotype in pancreatic ductal adenocarcinoma[J]. Gut，2019，68(3)：487-498. DOI：10.1136/gutjnl-2017-314426.
[2]	MIZRAHI J D, SURANA R, VALLE J W, et al. Pancreatic cancer[J]. Lancet，2020，395(10242)：2008-2020. DOI：10.1016/s0140-6736(20)30974-0.
[3]	STROBEL O, NEOPTOLEMOS J, JÄGER D, et al. Optimizing the outcomes of pancreatic cancer surgery[J]. Nat Rev Clin Oncol，2019，16(1)：11-26. DOI：10.1038/s41571-018-0112-1.
[4]	CONROY T, PFEIFFER P, VILGRAIN V, et al. Pancreatic cancer：ESMO Clinical Practice Guideline for diagnosis，treatment and follow-up[J]. Ann Oncol，2023，34(11)：987-1002. DOI：10.1016/j.annonc.2023.08.009.
[5]	GOBBI P G, BERGONZI M, COMELLI M, et al. The prognostic role of time to diagnosis and presenting symptoms in patients with pancreatic cancer[J]. Cancer Epidemiol，2013，37(2)：186-190. DOI：10.1016/j.canep.2012.12.002.
[6]	VAN CUTSEM E, TEMPERO M A, SIGAL D, et al. Randomized phaseⅢ trial of pegvorhyaluronidase Alfa with nab-paclitaxel plus gemcitabine for patients with hyaluronan-high metastatic pancreatic adenocarcinoma[J]. J Clin Oncol，2020，38(27)：3185-3194. DOI：10.1200/JCO.20.00590.
[7]	TEMPERO M, OH D Y, TABERNERO J, et al. Ibrutinib in combination with nab-paclitaxel and gemcitabine for first-line treatment of patients with metastatic pancreatic adenocarcinoma：phaseⅢ RESOLVE study[J]. Ann Oncol，2021，32(5)：600-608. DOI：10.1016/j.annonc.2021.01.070.
[8]	HECHT J R, LONARDI S, BENDELL J, et al. Randomized phase Ⅲ study of FOLFOX alone or with pegilodecakin as second-line therapy in patients with metastatic pancreatic cancer that progressed after gemcitabine（SEQUOIA）[J]. J Clin Oncol，2021，39(10)：1108-1118. DOI：10.1200/JCO.20.02232.
[9]	HUBER M, BREHM C U, GRESS T M, et al. The immune microenvironment in pancreatic cancer[J]. Int J Mol Sci，2020，21(19)：7307. DOI：10.3390/ijms21197307.
[10]	DOUGAN S K. The pancreatic cancer microenvironment[J]. Cancer J，2017，23(6)：321-325. DOI：10.1097/PPO.0000000000000288.
[11]	CHAKKERA M, FOOTE J B, FARRAN B, et al. Breaking the stromal barrier in pancreatic cancer：advances and challenges[J]. Biochim Biophys Acta Rev Cancer，2024，1879(1)：189065. DOI：10.1016/j.bbcan.2023.189065.
[12]	ZHAO T S, XIAO D, JIN F J, et al. ESE3-positive PSCs drive pancreatic cancer fibrosis，chemoresistance and poor prognosis via tumour-stromal IL-1β/NF-κB/ESE3 signalling axis[J]. Br J Cancer，2022，127(8)：1461-1472. DOI：10.1038/s41416-022-01927-y.
[13]	NAKASHIMA H, NAKAMURA M, YAMAGUCHI H, et al. Nuclear factor-kappaB contributes to hedgehog signaling pathway activation through sonic hedgehog induction in pancreatic cancer[J]. Cancer Res，2006，66(14)：7041-7049. DOI：10.1158/0008-5472.CAN-05-4588.
[14]	KONG W J, LIU Z S, SUN M N, et al. Synergistic autophagy blockade and VDR signaling activation enhance stellate cell reprogramming in pancreatic ductal adenocarcinoma[J]. Cancer Lett，2022，539：215718. DOI：10.1016/j.canlet.2022.215718.
[15]	MALIK S, WESTCOTT J M, BREKKEN R A, et al. CXCL12 in pancreatic cancer：its function and potential as a therapeutic drug target[J]. Cancers，2021，14(1)：86. DOI：10.3390/cancers14010086.
[16]	TANG D, YUAN Z X, XUE X F, et al. High expression of Galectin-1 in pancreatic stellate cells plays a role in the development and maintenance of an immunosuppressive microenvironment in pancreatic cancer[J]. Int J Cancer，2012，130(10)：2337-2348. DOI：10.1002/ijc.26290.
[17]	LUNARDI S, LIM S Y, MUSCHEL R J, et al. IP-10/CXCL10 attracts regulatory T cells：implication for pancreatic cancer[J]. Oncoimmunology，2015，4(9)：e1027473. DOI：10.1080/2162402X.2015.1027473.
[18]	MACE T A, AMEEN Z, COLLINS A, et al. Pancreatic cancer-associated stellate cells promote differentiation of myeloid-derived suppressor cells in a STAT3-dependent manner[J]. Cancer Res，2013，73(10)：3007-3018. DOI：10.1158/0008-5472.CAN-12-4601.
[19]	WANG R Z, HONG K Z, ZHANG Q Y, et al. A nanodrug simultaneously inhibits pancreatic stellate cell activation and regulatory T cell infiltration to promote the immunotherapy of pancreatic cancer[J]. Acta Biomater，2023，169：451-463. DOI：10.1016/j.actbio.2023.08.007.
[20]	GYORI D, LIM E L, GRANT F M, et al. Compensation between CSF1R+ macrophages and Foxp3+ Treg cells drives resistance to tumor immunotherapy[J]. JCI Insight，2018，3(11)：e120631. DOI：10.1172/jci.insight.120631.
[21]	LI C X, JIANG P, WEI S H, et al. Regulatory T cells in tumor microenvironment：new mechanisms，potential therapeutic strategies and future prospects[J]. Mol Cancer，2020，19(1)：116. DOI：10.1186/s12943-020-01234-1.
[22]	SEIFERT A M, EYMER A, HEIDUK M, et al. PD-1 expression by lymph node and intratumoral regulatory T cells is associated with lymph node metastasis in pancreatic cancer[J]. Cancers，2020，12(10)：2756. DOI：10.3390/cancers12102756.
[23]	KRYCZEK I, WEI S, ZOU L H, et al. Cutting edge：induction of B7-H4 on APCs through IL-10：novel suppressive mode for regulatory T cells[J]. J Immunol，2006，177(1)：40-44. DOI：10.4049/jimmunol.177.1.40.
[24]	ZHANG Y Q, LAZARUS J, STEELE N G, et al. Regulatory T-cell depletion alters the tumor microenvironment and accelerates pancreatic carcinogenesis[J]. Cancer Discov，2020，10(3)：422-439. DOI：10.1158/2159-8290.CD-19-0958.
[25]	VONDERHEIDE R H, BEAR A S. Tumor-derived myeloid cell chemoattractants and T cell exclusion in pancreatic cancer[J]. Front Immunol，2020，11：605619. DOI：10.3389/fimmu.2020.605619.
[26]	WU Y Z, YI M, NIU M K, et al. Myeloid-derived suppressor cells：an emerging target for anticancer immunotherapy[J]. Mol Cancer，2022，21(1)：184. DOI：10.1186/s12943-022-01657-y.
[27]	THYAGARAJAN A, ALSHEHRI M S A, MILLER K L R, et al. Myeloid-derived suppressor cells and pancreatic cancer：implications in novel therapeutic approaches[J]. Cancers，2019，11(11)：1627. DOI：10.3390/cancers11111627.
[28]	KUMAR V, PATEL S, TCYGANOV E, et al. The nature of myeloid-derived suppressor cells in the tumor microenvironment[J]. Trends Immunol，2016，37(3)：208-220. DOI：10.1016/j.it.2016.01.004.
[29]	SHARMA V, SACHDEVA N, GUPTA V, et al. IL-6 is associated with expansion of myeloid-derived suppressor cells and enhanced immunosuppression in pancreatic adenocarcinoma patients[J]. Scand J Immunol，2021，94(6)：e13107. DOI：10.1111/sji.13107.
[30]	STROMNES I M, BROCKENBROUGH J S, IZERADJENE K, et al. Targeted depletion of an MDSC subset unmasks pancreatic ductal adenocarcinoma to adaptive immunity[J]. Gut，2014，63(11)：1769-1781. DOI：10.1136/gutjnl-2013-306271.
[31]	GARGETT T, CHRISTO S N, HERCUS T R, et al. GM-CSF signalling blockade and chemotherapeutic agents act in concert to inhibit the function of myeloid-derived suppressor cells in vitro[J]. Clin Transl Immunology，2016，5(12)：e119. DOI：10.1038/cti.2016.80.
[32]	CASSETTA L, POLLARD J W. Tumor-associated macrophages[J]. Curr Biol，2020，30(6)：R246-R248. DOI：10.1016/j.cub.2020.01.031.
[33]	WANG X F, LUO G T, ZHANG K D, et al. Correction：hypoxic tumor-derived exosomal miR-301a mediates M2 macrophage polarization via PTEN/PI3Kγ to promote pancreatic cancer metastasis[J]. Cancer Res，2020，80(4)：922. DOI：10.1158/0008-5472.CAN-19-3872.
[34]	SHI C J, WASHINGTON M K, CHATURVEDI R, et al. Fibrogenesis in pancreatic cancer is a dynamic process regulated by macrophage-stellate cell interaction[J]. Lab Invest，2014，94(4)：409-421. DOI：10.1038/labinvest.2014.10.
[35]	INCIO J, SUBOJ P, CHIN S M, et al. Metformin reduces desmoplasia in pancreatic cancer by reprogramming stellate cells and tumor-associated macrophages[J]. PLoS One，2015，10(12)：e0141392. DOI：10.1371/journal.pone.0141392.
[36]	LI N, LI Y, LI Z X, et al. Hypoxia inducible factor 1（HIF-1）recruits macrophage to activate pancreatic stellate cells in pancreatic ductal adenocarcinoma[J]. Int J Mol Sci，2016，17(6)：799. DOI：10.3390/ijms17060799.
[37]	BARRY S T, GABRILOVICH D I, SANSOM O J, et al. Therapeutic targeting of tumour myeloid cells[J]. Nat Rev Cancer，2023，23(4)：216-237. DOI：10.1038/s41568-022-00546-2.
[38]	ZHU Y, KNOLHOFF B L, MEYER M A, et al. CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models[J]. Cancer Res，2014，74(18)：5057-5069. DOI：10.1158/0008-5472.CAN-13-3723.
[39]	WANG K, HE H. Pancreatic tumor microenvironment[J]. Adv Exp Med Biol，2020，1296：243-257. DOI：10.1007/978-3-030-59038-3_15.
[40]	HIRTH M, GANDLA J, HÖPER C, et al. CXCL10 and CCL21 promote migration of pancreatic cancer cells toward sensory neurons and neural remodeling in tumors in mice，associated with pain in patients[J]. Gastroenterology，2020，159(2)：665-681.e13. DOI：10.1053/j.gastro.2020.04.037.
[41]	XIANG Z J, HU T, WANG Y, et al. Neutrophil-lymphocyte ratio（NLR）was associated with prognosis and immunomodulatory in patients with pancreatic ductal adenocarcinoma（PDAC）[J]. Biosci Rep，2020，40(6)：BSR20201190. DOI：10.1042/BSR20201190.
[42]	BRANDAU S, DUMITRU C A, LANG S. Protumor and antitumor functions of neutrophil granulocytes[J]. Semin Immunopathol，2013，35(2)：163-176. DOI：10.1007/s00281-012-0344-6.
[43]	MOLLINEDO F. Neutrophil degranulation，plasticity，and cancer metastasis[J]. Trends Immunol，2019，40(3)：228-242. DOI：10.1016/j.it.2019.01.006.
[44]	MANTOVANI A, MARCHESI F, JAILLON S, et al. Tumor-associated myeloid cells：diversity and therapeutic targeting[J]. Cell Mol Immunol，2021，18(3)：566-578. DOI：10.1038/s41423-020-00613-4.
[45]	CUI C, CHAKRABORTY K, TANG X A, et al. Neutrophil elastase selectively kills cancer cells and attenuates tumorigenesis[J]. Cell，2021，184(12)：3163-3177.e21. DOI：10.1016/j.cell.2021.04.016.
[46]	XUE R D, ZHANG Q M, CAO Q, et al. Liver tumour immune microenvironment subtypes and neutrophil heterogeneity[J]. Nature，2022，612(7938)：141-147. DOI：10.1038/s41586-022-05400-x.
[47]	JAILLON S, PONZETTA A, MITRI D D, et al. Neutrophil diversity and plasticity in tumour progression and therapy[J]. Nat Rev Cancer，2020，20(9)：485-503. DOI：10.1038/s41568-020-0281-y.
[48]	CHEN Y, MCANDREWS K M, KALLURI R. Clinical and therapeutic relevance of cancer-associated fibroblasts[J]. Nat Rev Clin Oncol，2021，18(12)：792-804. DOI：10.1038/s41571-021-00546-5.
[49]	MUCCIOLO G, ARAOS HENRÍQUEZ J, JIHAD M, et al. EGFR-activated myofibroblasts promote metastasis of pancreatic cancer[J]. Cancer Cell，2024，42(1)：101-118.e11. DOI：10.1016/j.ccell.2023.12.002.
[50]	FRANCESCONE R, CRAWFORD H C, VENDRAMINI-COSTA D B. Rethinking the roles of cancer-associated fibroblasts in pancreatic cancer[J]. Cell Mol Gastroenterol Hepatol，2024，17(5)：737-743. DOI：10.1016/j.jcmgh.2024.01.022.
[51]	ELYADA E, BOLISETTY M, LAISE P, et al. Cross-species single-cell analysis of pancreatic ductal adenocarcinoma reveals antigen-presenting cancer-associated fibroblasts[J]. Cancer Discov，2019，9(8)：1102-1123. DOI：10.1158/2159-8290.CD-19-0094.
[52]	XU W C, LIU J Z, ZHANG J L, et al. Tumor microenvironment crosstalk between tumors and the nervous system in pancreatic cancer：molecular mechanisms and clinical perspectives[J]. Biochim Biophys Acta Rev Cancer，2024，1879(1)：189032. DOI：10.1016/j.bbcan.2023.189032.
[53]	BELFIORI G, CRIPPA S, FRANCESCA A, et al. Long-term survivors after upfront resection for pancreatic ductal adenocarcinoma：an actual 5-year analysis of disease-specific and post-recurrence survival[J]. Ann Surg Oncol，2021，28(13)：8249-8260. DOI：10.1245/s10434-021-10401-7.
[54]	BERNARD V, SEMAAN A, HUANG J, et al. Single-cell transcriptomics of pancreatic cancer precursors demonstrates epithelial and microenvironmental heterogeneity as an early event in neoplastic progression[J]. Clin Cancer Res，2019，25(7)：2194-2205. DOI：10.1158/1078-0432.CCR-18-1955.
[55]	Cancer Genome Atlas Research Network. Electronic address：andrew_aguirre@dfci.harvard.edu；Cancer Genome Atlas Research Network. Integrated genomic characterization of pancreatic ductal adenocarcinoma[J]. Cancer Cell，2017，32(2)：185-203.e13. DOI：10.1016/j.ccell.2017.07.007.
[56]	WITKIEWICZ A K, MCMILLAN E A, BALAJI U, et al. Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets[J]. Nat Commun，2015，6：6744. DOI：10.1038/ncomms7744.
[57]	MCINTYRE C A, LAWRENCE S A, RICHARDS A L, et al. Alterations in driver genes are predictive of survival in patients with resected pancreatic ductal adenocarcinoma[J]. Cancer，2020，126(17)：3939-3949. DOI：10.1002/cncr.33038.
[58]	OU S I, JÄNNE P A, LEAL T A, et al. First-in-human phase I/IB dose-finding study of adagrasib（MRTX849）in patients with advanced KRASG12C solid tumors（KRYSTAL-1）[J]. J Clin Oncol，2022，40(23)：2530-2538. DOI：10.1200/JCO.21.02752.
[59]	BEKAII-SAAB T S, YAEGER R, SPIRA A I, et al. Adagrasib in advanced solid tumors harboring a KRASG12C mutation[J]. J Clin Oncol，2023，41(25)：4097-4106. DOI：10.1200/JCO.23.00434.
[60]	HALLIN J, ENGSTROM L D, HARGIS L, et al. The KRASG12C inhibitor MRTX849 provides insight toward therapeutic susceptibility of KRAS-mutant cancers in mouse models and patients[J]. Cancer Discov，2020，10(1)：54-71. DOI：10.1158/2159-8290.CD-19-1167.
[61]	LANMAN B A, ALLEN J R, ALLEN J G, et al. Discovery of a covalent inhibitor of KRASG12C（AMG 510）for the treatment of solid tumors[J]. J Med Chem，2020，63(1)：52-65. DOI：10.1021/acs.jmedchem.9b01180.
[62]	STRICKLER J H, SATAKE H, GEORGE T J, et al. Sotorasib in KRAS p.G12C-mutated advanced pancreatic cancer[J]. N Engl J Med，2023，388(1)：33-43. DOI：10.1056/NEJMoa2208470.
[63]	LI S Q, BALMAIN A, COUNTER C M. A model for RAS mutation patterns in cancers：finding the sweet spot[J]. Nat Rev Cancer，2018，18(12)：767-777. DOI：10.1038/s41568-018-0076-6.
[64]	WANG X L, ALLEN S, BLAKE J F, et al. Identification of MRTX1133，a noncovalent，potent，and selective KRASG12D inhibitor[J]. J Med Chem，2022，65(4)：3123-3133. DOI：10.1021/acs.jmedchem.1c01688.
[65]	KEMP S B, CHENG N, MARKOSYAN N, et al. Efficacy of a small-molecule inhibitor of KrasG12D in immunocompetent models of pancreatic cancer[J]. Cancer Discov，2023，13(2)：298-311. DOI：10.1158/2159-8290.CD-22-1066.
[66]	HALLIN J, BOWCUT V, CALINISAN A, et al. Anti-tumor efficacy of a potent and selective non-covalent KRASG12D inhibitor[J]. Nat Med，2022，28(10)：2171-2182. DOI：10.1038/s41591-022-02007-7.
[67]	PANT S, WAINBERG Z A, WEEKES C D, et al. Lymph-node-targeted，mKRAS-specific amphiphile vaccine in pancreatic and colorectal cancer：the phase 1 AMPLIFY-201 trial[J]. Nat Med，2024，30(2)：531-542. DOI：10.1038/s41591-023-02760-3.
[68]	KAMERKAR S, LEBLEU V S, SUGIMOTO H, et al. Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer[J]. Nature，2017，546(7659)：498-503. DOI：10.1038/nature22341.
[69]	PHILIP P A, AZAR I, XIU J, et al. Molecular characterization of KRAS wild-type tumors in patients with pancreatic adenocarcinoma[J]. Clin Cancer Res，2022，28(12)：2704-2714. DOI：10.1158/1078-0432.CCR-21-3581.
[70]	VARGHESE A M, SINGH I, SINGH R, et al. Early-onset pancreas cancer：clinical descriptors，genomics，and outcomes[J]. J Natl Cancer Inst，2021，113(9)：1194-1202. DOI：10.1093/jnci/djab038.
[71]	QIN S K, LI J, BAI Y X, et al. Nimotuzumab plus gemcitabine for K-ras wild-type locally advanced or metastatic pancreatic cancer[J]. J Clin Oncol，2023，41(33)：5163-5173. DOI：10.1200/JCO.22.02630.
[72]	BISHOP D T, DEMENAIS F, GOLDSTEIN A M, et al. Geographical variation in the penetrance of CDKN2A mutations for melanoma[J]. J Natl Cancer Inst，2002，94(12)：894-903. DOI：10.1093/jnci/94.12.894.
[73]	KLEIN M E, KOVATCHEVA M, DAVIS L E, et al. CDK4/6 inhibitors：the mechanism of action may not be as simple as once thought[J]. Cancer Cell，2018，34(1)：9-20. DOI：10.1016/j.ccell.2018.03.023.
[74]	QIAN Z R, RUBINSON D A, NOWAK J A, et al. Association of alterations in main driver genes with outcomes of patients with resected pancreatic ductal adenocarcinoma[J]. JAMA Oncol，2018，4(3)：e173420. DOI：10.1001/jamaoncol.2017.3420.
[75]	PANAGIOTOU E, GOMATOU G, TRONTZAS I P, et al. Cyclin-dependent kinase（CDK）inhibitors in solid tumors：a review of clinical trials[J]. Clin Transl Oncol，2022，24(2)：161-192. DOI：10.1007/s12094-021-02688-5.
[76]	CHOU A, FROIO D, NAGRIAL A M, et al. Tailored first-line and second-line CDK4-targeting treatment combinations in mouse models of pancreatic cancer[J]. Gut，2018，67(12)：2142-2155. DOI：10.1136/gutjnl-2017-315144.
[77]	GOODWIN C M, WATERS A M, KLOMP J E, et al. Combination therapies with CDK4/6 inhibitors to treat KRAS-mutant pancreatic cancer[J]. Cancer Res，2023，83(1)：141-157. DOI：10.1158/0008-5472.CAN-22-0391.
[78]	GOGGINS M, OVERBEEK K A, BRAND R, et al. Management of patients with increased risk for familial pancreatic cancer：updated recommendations from the International Cancer of the Pancreas Screening（CAPS）Consortium[J]. Gut，2020，69(1)：7-17. DOI：10.1136/gutjnl-2019-319352.
[79]	BLANDINO G, AGOSTINO S D. New therapeutic strategies to treat human cancers expressing mutant p53 proteins[J]. J Exp Clin Cancer Res，2018，37(1)：30. DOI：10.1186/s13046-018-0705-7.
[80]	BYKOV V J N, ERIKSSON S E, BIANCHI, et al. Targeting mutant p53 for efficient cancer therapy[J]. Nat Rev Cancer，2018，18(2)：89-102. DOI：10.1038/nrc.2017.109.
[81]	LINDEMANN A, PATEL A A, SILVER N L, et al. COTI-2，A novel thiosemicarbazone derivative，exhibits antitumor activity in HNSCC through p53-dependent and-independent mechanisms[J]. Clin Cancer Res，2019，25(18)：5650-5662. DOI：10.1158/1078-0432.CCR-19-0096.
[82]	TODORIC J, ANTONUCCI L, CARO G D, et al. Stress-activated NRF2-MDM2 cascade controls neoplastic progression in pancreas[J]. Cancer Cell，2017，32(6)：824-839.e8. DOI：10.1016/j.ccell.2017.10.011.
[83]	RINGSHAUSEN I, O'SHEA C C, FINCH A J, et al. Mdm² is critically and continuously required to suppress lethal p53 activity in vivo[J]. Cancer Cell，2006，10(6)：501-514. DOI：10.1016/j.ccr.2006.10.010.
[84]	WANG W, QIN J J, VORUGANTI S, et al. Discovery and characterization of dual inhibitors of MDM2 and NFAT1 for pancreatic cancer therapy[J]. Cancer Res，2018，78(19)：5656-5667. DOI：10.1158/0008-5472.CAN-17-3939.
[85]	WANG W, QIN J J, VORUGANTI S, et al. Identification of a new class of MDM2 inhibitor that inhibits growth of orthotopic pancreatic tumors in mice[J]. Gastroenterology，2014，147(4)：893-902.e2. DOI：10.1053/j.gastro.2014.07.001.
[86]	KONOPLEVA M, MARTINELLI G, DAVER N, et al. MDM2 inhibition：an important step forward in cancer therapy[J]. Leukemia，2020，34(11)：2858-2874. DOI：10.1038/s41375-020-0949-z.
[87]	HAHN S A, SCHUTTE M, HOQUE A T, et al. DPC4，a candidate tumor suppressor gene at human chromosome 18q21.1[J]. Science，1996，271(5247)：350-353. DOI：10.1126/science.271.5247.350.
[88]	BIANKIN A V, MOREY A L, LEE C S, et al. DPC4/Smad4 expression and outcome in pancreatic ductal adenocarcinoma[J]. J Clin Oncol，2002，20(23)：4531-4542. DOI：10.1200/JCO.2002.12.063.
[89]	WANG F, XIA X J, YANG C Y, et al. SMAD4 gene mutation renders pancreatic cancer resistance to radiotherapy through promotion of autophagy[J]. Clin Cancer Res，2018，24(13)：3176-3185. DOI：10.1158/1078-0432.CCR-17-3435.
[90]	HONG E, PARK S, OOSHIMA A, et al. Inhibition of TGF-β signalling in combination with nal-IRI plus 5-Fluorouracil/Leucovorin suppresses invasion and prolongs survival in pancreatic tumour mouse models[J]. Sci Rep，2020，10(1)：2935. DOI：10.1038/s41598-020-59893-5.
[91]	DEY P, BADDOUR J, MULLER F, et al. Genomic deletion of malic enzyme 2 confers collateral lethality in pancreatic cancer[J]. Nature，2017，542(7639)：119-123. DOI：10.1038/nature21052.
[92]	QI C S, GONG J F, LI J, et al. Claudin18.2-specific CAR T cells in gastrointestinal cancers：phase 1 trial interim results[J]. Nat Med，2022，28(6)：1189-1198. DOI：10.1038/s41591-022-01800-8.
[93]	SHITARA K, LORDICK F, BANG Y J, et al. Zolbetuximab plus mFOLFOX6 in patients with CLDN18.2-positive，HER2-negative，untreated，locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma（SPOTLIGHT）：a multicentre，randomised，double-blind，phase 3 trial[J]. Lancet，2023，401(10389)：1655-1668. DOI：10.1016/S0140-6736(23)00620-7.
[94]	SHAH M A, SHITARA K, AJANI J A, et al. Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma：the randomized，phase 3 GLOW trial[J]. Nat Med，2023，29(8)：2133-2141. DOI：10.1038/s41591-023-02465-7.
[95]	BAUM R P, SINGH A, SCHUCHARDT C, et al. 177Lu-3BP-227 for neurotensin receptor 1-targeted therapy of metastatic pancreatic adenocarcinoma：first clinical results[J]. J Nucl Med，2018，59(5)：809-814. DOI：10.2967/jnumed.117.193847.
[96]	HURTADO DE MENDOZA T, MOSE E S, BOTTA G P, et al. Tumor-penetrating therapy for β5 integrin-rich pancreas cancer[J]. Nat Commun，2021，12(1)：1541. DOI：10.1038/s41467-021-21858-1.
[97]	DEAN A, GILL S, MCGREGOR M, et al. Dual αV-integrin and neuropilin-1 targeting peptide CEND-1 plus nab-paclitaxel and gemcitabine for the treatment of metastatic pancreatic ductal adenocarcinoma：a first-in-human，open-label，multicentre，phase 1 study[J]. Lancet Gastroenterol Hepatol，2022，7(10)：943-951. DOI：10.1016/S2468-1253(22)00167-4.
[98]	KARAMITOPOULOU E, ANDREOU A, PAHUD DE MORTANGES A, et al. PD-1/PD-L1-associated immunoarchitectural patterns stratify pancreatic cancer patients into prognostic/predictive subgroups[J]. Cancer Immunol Res，2021，9(12)：1439-1450. DOI：10.1158/2326-6066.CIR-21-0144.
[99]	MCGUIGAN A J, COLEMAN H G, MCCAIN R S, et al. Immune cell infiltrates as prognostic biomarkers in pancreatic ductal adenocarcinoma：a systematic review and meta-analysis[J]. J Pathol Clin Res，2021，7(2)：99-112. DOI：10.1002/cjp2.192.
[100]	LUCHINI C, BROSENS L A A, WOOD L D, et al. Comprehensive characterisation of pancreatic ductal adenocarcinoma with microsatellite instability：histology，molecular pathology and clinical implications[J]. Gut，2021，70(1)：148-156. DOI：10.1136/gutjnl-2020-320726.
[101]	TERRERO G, DATTA J, DENNISON J, et al. Ipilimumab/nivolumab therapy in patients with metastatic pancreatic or biliary cancer with homologous recombination deficiency pathogenic germline variants[J]. JAMA Oncol，2022，8(6)：1-3.
[102]	O'REILLY E M, OH D Y, DHANI N, et al. Durvalumab with or without tremelimumab for patients with metastatic pancreatic ductal adenocarcinoma：a phase 2 randomized clinical trial[J]. JAMA Oncol，2019，5(10)：1431-1438.
[103]	YANG H S, ZHANG X Z, LAO M Y, et al. Targeting ubiquitin-specific protease 8 sensitizes anti-programmed death-ligand 1 immunotherapy of pancreatic cancer[J]. Cell Death Differ，2023，30(2)：560-575. DOI：10.1038/s41418-022-01102-z.
[104]	DUAN Y, ZHANG X Z, YING H G, et al. Targeting MFAP5 in cancer-associated fibroblasts sensitizes pancreatic cancer to PD-L1-based immunochemotherapy via remodeling the matrix[J]. Oncogene，2023，42(25)：2061-2073. DOI：10.1038/s41388-023-02711-9.
[105]	LI P, ROZICH N, WANG J X, et al. Anti-IL-8 antibody activates myeloid cells and potentiates the anti-tumor activity of anti-PD-1 antibody in the humanized pancreatic cancer murine model[J]. Cancer Lett，2022，539：215722. DOI：10.1016/j.canlet.2022.215722.
[106]	LUO W H, YANG G, LUO W T, et al. Novel therapeutic strategies and perspectives for metastatic pancreatic cancer：vaccine therapy is more than just a theory[J]. Cancer Cell Int，2020，20：66. DOI：10.1186/s12935-020-1147-9.
[107]	MIDDLETON G, SILCOCKS P, COX T, et al. Gemcitabine and capecitabine with or without telomerase peptide vaccine GV1001 in patients with locally advanced or metastatic pancreatic cancer（TeloVac）：an open-label，randomised，phase 3 trial[J]. Lancet Oncol，2014，15(8)：829-840.
[108]	JO J H, KIM Y T, CHOI H S, et al. Efficacy of GV1001 with gemcitabine/capecitabine in previously untreated patients with advanced pancreatic ductal adenocarcinoma having high serum eotaxin levels（KG4/2015）：an open-label，randomised，Phase 3 trial[J]. Br J Cancer，2024，130(1)：43-52.
[109]	ŁUKSZA M, SETHNA Z M, ROJAS L A, et al. Neoantigen quality predicts immunoediting in survivors of pancreatic cancer[J]. Nature，2022，606(7913)：389-395. DOI：10.1038/s41586-022-04735-9.
[110]	ROJAS L A, SETHNA Z, SOARES K C, et al. Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer[J]. Nature，2023，618(7963)：144-150.
[111]	JUNE C H, O'CONNOR R S, KAWALEKAR O U, et al. CAR T cell immunotherapy for human cancer[J]. Science，2018，359(6382)：1361-1365. DOI：10.1126/science.aar6711.
[112]	BEATTY G L, O'HARA M H, LACEY S F, et al. Activity of mesothelin-specific chimeric antigen receptor T cells against pancreatic carcinoma metastases in a phase 1 trial[J]. Gastroenterology，2018，155(1)：29-32.
[113]	BAGLEY S J, O'ROURKE D M. Clinical investigation of CAR T cells for solid tumors：lessons learned and future directions[J]. Pharmacol Ther，2020，205：107419.
[114]	MIAO L L, ZHANG J, ZHANG Z C, et al. A bibliometric and knowledge-map analysis of CAR-T cells from 2009 to 2021[J]. Front Immunol，2022，13：840956.
[115]	LIN D N, SHEN Y N, LIANG T B. Oncolytic virotherapy：basic principles，recent advances and future directions[J]. Signal Transduct Target Ther，2023，8(1)：156.
[116]	LIU S Y, LI F, MA Q Q, et al. OX40L-armed oncolytic virus boosts T-cell response and remodels tumor microenvironment for pancreatic cancer treatment[J]. Theranostics，2023，13(12)：4016-4029. DOI：10.7150/thno.83495.
[117]	NELSON A, GEBREMESKEL S, LICHTY B D, et al. Natural killer T cell immunotherapy combined with IL-15-expressing oncolytic virotherapy and PD-1 blockade mediates pancreatic tumor regression[J]. J Immunother Cancer，2022，10(3)：e003923. DOI：10.1136/jitc-2021-003923.
[118]	NEJMAN D, LIVYATAN I, FUKS G, et al. The human tumor microbiome is composed of tumor type-specific intracellular bacteria[J]. Science，2020，368(6494)：973-980.
[119]	RIQUELME E, ZHANG Y, ZHANG L L, et al. Tumor microbiome diversity and composition influence pancreatic cancer outcomes[J]. Cell，2019，178(4)：795-806.e12.
[120]	TEMPERO M A, MALAFA M P, AL-HAWARY M, et al. Pancreatic adenocarcinoma，version 2.2021，NCCN clinical practice guidelines in oncology[J]. J Natl Compr Canc Netw，2021，19(4)：439-457. DOI：10.6004/jnccn.2021.0017.

胰腺癌靶向治疗及免疫治疗的研究新进展

Research Progress of Targeted Therapy and Immunotherapy for Pancreatic Cancer

RichHTML

PDF

可视化

摘要/Abstract

引用本文

使用本文

参考文献 120

相关文章 15

编辑推荐

Metrics

留言

[1]	周连鹏, 李伟峰, 董新刚, 王晓元. 铜稳态调节机制在认知障碍中的作用探析[J]. 中国全科医学, 2025, 28(23): 2941-2949.
[2]	董浩铖, 郝潇, 安东, 李浩翰, 李树仁. 射血分数超常的心力衰竭的研究进展[J]. 中国全科医学, 2025, 28(21): 2692-2696.
[3]	杜琼靓, 林白浪, 郭洪花. 群组育儿保健模式的研究进展及启示[J]. 中国全科医学, 2025, 28(21): 2672-2678.
[4]	褚田雨, 顾艳. 颈动脉钙化特征在评估斑块稳定性及临床事件中的作用[J]. 中国全科医学, 2025, 28(18): 2247-2252.
[5]	朱子一, 何贵新, 秦伟彬, 宋惠, 张利文, 唐伟智, 杨斐斐, 刘凌云, 欧阳彬. 线粒体自噬改善心肌梗死后心肌纤维化及其中医药干预的研究进展[J]. 中国全科医学, 2025, 28(18): 2294-2300.
[6]	谭文彬, 李佳, 刘明玉, 路永欣, 程雅欣. 神经系统疾病及相关治疗药物对骨质疏松症影响的研究进展[J]. 中国全科医学, 2025, 28(17): 2092-2100.
[7]	隋鸿平, 李婷婷, 姜桐桐, 夏云龙, 史铁英. 血管内皮生长因子信号通路抑制剂相关高血压的血压管理研究进展[J]. 中国全科医学, 2025, 28(15): 1932-1936.
[8]	李伊婷, 徒文静, 尹婷婷, 梅紫琦, 张苏闽, 王萌, 徐桂华. 人工智能在炎症性肠病患者营养管理中应用的范围综述[J]. 中国全科医学, 2025, 28(14): 1709-1716.
[9]	竺晶, 谢骥, 胡晓霞. 二肽基肽酶-4抑制剂西格列汀的抗炎及抗氧化应激机制研究[J]. 中国全科医学, 2025, 28(12): 1543-1548.
[10]	鲍志鹏, 李芸霞, 王洁, 汤志杰, 游展鸿, 何英, 孙国珍. 心房颤动患者导管消融围术期症状群及管理策略[J]. 中国全科医学, 2025, 28(12): 1479-1485.
[11]	王宇新, 彭文婉, 周正, 黄海阳, 卢晓敏, 董明国. 胃癌前状态的癌变风险及其发病机制的研究进展[J]. 中国全科医学, 2025, 28(11): 1411-1416.
[12]	马婧馨, 杨荣, 刘力滴, 张亚琳, 宋海齐, 罗健钊, 朱林林, 廖晓阳. 连续性照护定量评估指标及应用研究进展[J]. 中国全科医学, 2025, 28(10): 1179-1184.
[13]	黄晶, 苗依婷, 贺雪梅, 蒋东洋, 梁英. 我国全科医生工作满意度及影响因素的系统综述[J]. 中国全科医学, 2025, 28(10): 1220-1227.
[14]	赵琳琳, 罗琪, 胡清华, 陈小垒, 杜娟, 邵爽. 社区老年人多维衰弱研究进展[J]. 中国全科医学, 2025, 28(10): 1281-1288.
[15]	余悦敏, 莫非非, 李乐思, 潘集阳. 中国青少年失眠的评估工具和影响因素：一项范围综述[J]. 中国全科医学, 2025, 28(10): 1213-1219.