巨噬细胞在胰腺癌中的作用及其作为治疗靶点的潜力
The Role of Macrophages in Pancreatic Cancer and Their Potential as Therapeutic Targets
DOI: 10.12677/acm.2025.15102892, PDF,   
作者: 龚 锐*：南昌医学院临床医学院，江西 南昌；钟金康：新疆医科大学第五临床医学院，新疆 乌鲁木齐
关键词: 胰腺癌；巨噬细胞；肿瘤微环境；抗肿瘤活性；Pancreas Cancer； Macrophage； Tumor Microenvironment； Antitumor Activity
摘要: 胰腺癌是一种高度恶性、预后极差的消化系统肿瘤，其复杂的免疫微环境在疾病进展中发挥关键作用。巨噬细胞作为肿瘤微环境的重要组成部分，既可通过促炎反应抑制肿瘤，也可在特定条件下由M1极化为M2型，促进肿瘤生长、血管生成及免疫逃逸。近年来的研究发现，胰腺癌组织中巨噬细胞浸润程度与患者生存率显著相关，提示其在疾病进展与耐药形成中的潜在价值。本文结合近年来的基础与临床研究，探讨巨噬细胞在胰腺癌发生发展过程中的双重作用及其可能的分子机制，并分析针对巨噬细胞的治疗策略，包括抑制M2极化、阻断巨噬细胞募集及增强其抗肿瘤活性等。深入理解巨噬细胞与胰腺癌之间的相互作用，有望为精准免疫治疗提供新思路。
Abstract: Pancreatic cancer is a highly malignant digestive system tumor with an extremely poor prognosis, and its complex immune microenvironment plays a critical role in disease progression. As a key component of the tumor microenvironment, macrophages can inhibit tumors through pro-inflammatory responses but may also polarize from the M1 to the M2 phenotype under specific conditions, thereby promoting tumor growth, angiogenesis, and immune escape. Recent studies have shown that the extent of macrophage infiltration in pancreatic cancer tissue is significantly correlated with patient survival, suggesting its potential role in disease progression and drug resistance development. This article integrates recent basic and clinical research to explore the dual role of macrophages in the initiation and progression of pancreatic cancer and their possible molecular mechanisms. It also analyzes macrophage-targeted therapeutic strategies, including inhibiting M2 polarization, blocking macrophage recruitment, and enhancing their anti-tumor activity. A deeper understanding of the interaction between macrophages and pancreatic cancer may provide new insights for precision immunotherapy.
文章引用：龚锐, 钟金康. 巨噬细胞在胰腺癌中的作用及其作为治疗靶点的潜力[J]. 临床医学进展, 2025, 15(10): 1349-1356. https://doi.org/10.12677/acm.2025.15102892

参考文献

[1] Watanabe, S., Alexander, M., Misharin, A.V. and Budinger, G.R.S. (2019) The Role of Macrophages in the Resolution of Inflammation. Journal of Clinical Investigation, 129, 2619-2628. [Google Scholar] [CrossRef] [PubMed]
[2] Hao, N., Lü, M., Fan, Y., Cao, Y., Zhang, Z. and Yang, S. (2012) Macrophages in Tumor Microenvironments and the Progression of Tumors. Clinical and Developmental Immunology, 2012, Article ID: 948098. [Google Scholar] [CrossRef] [PubMed]
[3] Smithy, J.W. and O’Reilly, E.M. (2021) Pancreas Cancer: Therapeutic Trials in Metastatic Disease. Journal of Surgical Oncology, 123, 1475-1488. [Google Scholar] [CrossRef] [PubMed]
[4] Morrison, A.H., Byrne, K.T. and Vonderheide, R.H. (2018) Immunotherapy and Prevention of Pancreatic Cancer. Trends in Cancer, 4, 418-428. [Google Scholar] [CrossRef] [PubMed]
[5] Bear, A.S., Vonderheide, R.H. and O’Hara, M.H. (2020) Challenges and Opportunities for Pancreatic Cancer Immunotherapy. Cancer Cell, 38, 788-802. [Google Scholar] [CrossRef] [PubMed]
[6] Tempero, M.A., Malafa, M.P., Al-Hawary, M., Behrman, S.W., Benson, A.B., Cardin, D.B., et al. (2021) Pancreatic Adenocarcinoma, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. Journal of the National Comprehensive Cancer Network, 19, 439-457. [Google Scholar] [CrossRef] [PubMed]
[7] Carvalho, T.M.A., Di Molfetta, D., Greco, M.R., Koltai, T., Alfarouk, K.O., Reshkin, S.J., et al. (2021) Tumor Microenvironment Features and Chemoresistance in Pancreatic Ductal Adenocarcinoma: Insights into Targeting Physicochemical Barriers and Metabolism as Therapeutic Approaches. Cancers, 13, Article 6135. [Google Scholar] [CrossRef] [PubMed]
[8] Sherman, M.H. and Beatty, G.L. (2023) Tumor Microenvironment in Pancreatic Cancer Pathogenesis and Therapeutic Resistance. Annual Review of Pathology: Mechanisms of Disease, 18, 123-148. [Google Scholar] [CrossRef] [PubMed]
[9] Wang, K. and He, H. (2020) Pancreatic Tumor Microenvironment. In: Birbrair, A., Ed., Tumor Microenvironments in Organs, Springer, 243-257. [Google Scholar] [CrossRef] [PubMed]
[10] Mantovani, A., Marchesi, F., Malesci, A., Laghi, L. and Allavena, P. (2017) Tumour-Associated Macrophages as Treatment Targets in Oncology. Nature Reviews Clinical Oncology, 14, 399-416. [Google Scholar] [CrossRef] [PubMed]
[11] Zhu, Y., Knolhoff, B.L., Meyer, M.A., Nywening, T.M., West, B.L., Luo, J., et al. (2014) CSF1/CSF1R Blockade Reprograms Tumor-Infiltrating Macrophages and Improves Response to T-Cell Checkpoint Immunotherapy in Pancreatic Cancer Models. Cancer Research, 74, 5057-5069. [Google Scholar] [CrossRef] [PubMed]
[12] Pu, Y. and Ji, Q. (2022) Tumor-Associated Macrophages Regulate PD-1/PD-L1 Immunosuppression. Frontiers in Immunology, 13, Article 874589. [Google Scholar] [CrossRef] [PubMed]
[13] Kurahara, H., Takao, S., Maemura, K., et al. (2011) M2-Polarized Tumor-Associated Macrophage Infiltration of Regional Lymph Nodes Is Associated with Nodal Lymphangiogenesis and Metastasis in Pancreatic Cancer. Pancreas, 40, 884-891.
[14] Qian, B. and Pollard, J.W. (2010) Macrophage Diversity Enhances Tumor Progression and Metastasis. Cell, 141, 39-51. [Google Scholar] [CrossRef] [PubMed]
[15] Zhang, Q., He, Y., Luo, N., Patel, S.J., Han, Y., Gao, R., et al. (2019) Landscape and Dynamics of Single Immune Cells in Hepatocellular Carcinoma. Cell, 179, 829-845.e20. [Google Scholar] [CrossRef] [PubMed]
[16] Li, M., He, L., Zhu, J., Zhang, P. and Liang, S. (2022) Targeting Tumor-Associated Macrophages for Cancer Treatment. Cell & Bioscience, 12, Article No. 85. [Google Scholar] [CrossRef] [PubMed]
[17] Wood, L.D., Canto, M.I., Jaffee, E.M. and Simeone, D.M. (2022) Pancreatic Cancer: Pathogenesis, Screening, Diagnosis, and Treatment. Gastroenterology, 163, 386-402.e1. [Google Scholar] [CrossRef] [PubMed]
[18] Yang, S., Liu, Q. and Liao, Q. (2021) Tumor-associated Macrophages in Pancreatic Ductal Adenocarcinoma: Origin, Polarization, Function, and Reprogramming. Frontiers in Cell and Developmental Biology, 8, Article 607209. [Google Scholar] [CrossRef] [PubMed]
[19] Guan, F., Wang, R., Yi, Z., Luo, P., Liu, W., Xie, Y., et al. (2025) Tissue Macrophages: Origin, Heterogenity, Biological Functions, Diseases and Therapeutic Targets. Signal Transduction and Targeted Therapy, 10, Article No. 93. [Google Scholar] [CrossRef] [PubMed]
[20] Cruz, A.F., et al. (2020) Macrophages in the Pancreas: Villains by Circumstances, Not Necessarily by Actions. Immunity, Inflammation and Disease, 8, 807-824.
[21] Zhu, Y., Herndon, J.M., Sojka, D.K., Kim, K., Knolhoff, B.L., Zuo, C., et al. (2017) Tissue-Resident Macrophages in Pancreatic Ductal Adenocarcinoma Originate from Embryonic Hematopoiesis and Promote Tumor Progression. Immunity, 47, 323-338.e6. [Google Scholar] [CrossRef] [PubMed]
[22] Zhu, S., Yi, M., Wu, Y., Dong, B. and Wu, K. (2021) Roles of Tumor-Associated Macrophages in Tumor Progression: Implications on Therapeutic Strategies. Experimental Hematology & Oncology, 10, Article No. 60. [Google Scholar] [CrossRef] [PubMed]
[23] Yang, C., et al. (2021) Macrophages in Pancreatic Cancer: Pathogenic Mechanisms and Therapeutic Opportunities. Frontiers in Cell and Developmental Biology, 8, Article ID: 607209.
[24] Storz, P. (2023) Roles of Differently Polarized Macrophages in the Initiation and Progression of Pancreatic Cancer. Frontiers in Immunology, 14, [page]. [Google Scholar] [CrossRef] [PubMed]
[25] Liou, G.Y., et al. (2017) Macrophage-Secreted Cytokines Drive Pancreatic Acinar-to-Ductal Metaplasia Through NF-κB and STAT3. Molecular Cancer Research, 15, 480-488.
[26] Mantovani, A., Sozzani, S., Locati, M., Allavena, P. and Sica, A. (2002) Macrophage Polarization: Tumor-Associated Macrophages as a Paradigm for Polarized M2 Mononuclear Phagocytes. Trends in Immunology, 23, 549-555. [Google Scholar] [CrossRef] [PubMed]
[27] Pathria, P., Louis, T.L. and Varner, J.A. (2019) Targeting Tumor-Associated Macrophages in Cancer. Trends in Immunology, 40, 310-327. [Google Scholar] [CrossRef] [PubMed]
[28] Kumar, V., Donthireddy, L., Marvel, D., Condamine, T., Wang, F., Lavilla-Alonso, S., et al. (2017) Cancer-Associated Fibroblasts Neutralize the Anti-Tumor Effect of CSF1 Receptor Blockade by Inducing PMN-MDSC Infiltration of Tumors. Cancer Cell, 32, 654-668.e5. [Google Scholar] [CrossRef] [PubMed]
[29] Raghavan, S., Winter, P.S., Navia, A.W., Williams, H.L., DenAdel, A., Lowder, K.E., et al. (2021) Microenvironment Drives Cell State, Plasticity, and Drug Response in Pancreatic Cancer. Cell, 184, 6119-6137.e26. [Google Scholar] [CrossRef] [PubMed]
[30] Zhang, Y., Zoltan, M., Riquelme, E., et al. (2022) Pancreatic Cancer-Intrinsic Immunomodulatory Programs Promote Tumor Progression, Immune Escape and Immunotherapy Resistance. Cancer Discovery, 12, 1022-1041.
[31] Ho, W.J., Jaffee, E.M. and Zheng, L. (2020) The Tumour Microenvironment in Pancreatic Cancer—Clinical Challenges and Opportunities. Nature Reviews Clinical Oncology, 17, 527-540. [Google Scholar] [CrossRef] [PubMed]
[32] Salmon, H., Franciszkiewicz, K., Damotte, D., Dieu-Nosjean, M., Validire, P., Trautmann, A., et al. (2012) Matrix Architecture Defines the Preferential Localization and Migration of T Cells into the Stroma of Human Lung Tumors. Journal of Clinical Investigation, 122, 899-910. [Google Scholar] [CrossRef] [PubMed]
[33] Zhang, Y., He, J., Li, W., Chen, Y., Zhou, Y., Deng, J., et al. (2024) Targeting Tumor-Associated Macrophages Reprograms the Immune Microenvironment and Enhances Immunotherapy in Pancreatic Cancer. Signal Transduction and Targeted Therapy, 9, Article No. 196.

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