切换至 "中华医学电子期刊资源库"

中华结直肠疾病电子杂志 ›› 2025, Vol. 14 ›› Issue (06) : 546 -551. doi: 10.3877/cma.j.issn.2095-3224.2025.06.009

综述

肿瘤相关中性粒细胞在结直肠癌中的双重调控作用及临床意义
宋柯瑾, 李文星()   
  1. 030001 太原,山西医科大学第二医院普通外科
  • 收稿日期:2025-08-20 出版日期:2025-12-25
  • 通信作者: 李文星
  • 基金资助:
    山西省基础研究计划(自由探索类)面上项目(No. 202503021211284)

The dual role of tumor-associated neutrophils in colorectal cancer and their clinical implications

Kejin Song, Wenxing Li()   

  1. Department of General Surgery, the Second Hospital of Shanxi Medical University, Taiyuan 030001, China
  • Received:2025-08-20 Published:2025-12-25
  • Corresponding author: Wenxing Li
引用本文:

宋柯瑾, 李文星. 肿瘤相关中性粒细胞在结直肠癌中的双重调控作用及临床意义[J/OL]. 中华结直肠疾病电子杂志, 2025, 14(06): 546-551.

Kejin Song, Wenxing Li. The dual role of tumor-associated neutrophils in colorectal cancer and their clinical implications[J/OL]. Chinese Journal of Colorectal Diseases(Electronic Edition), 2025, 14(06): 546-551.

结直肠癌的发生与肿瘤微环境(TME)的免疫调控密切相关。在这一复杂的环境中,中性粒细胞作为先天免疫系统的重要组成成分,展示了显著的异质性和功能可塑性。近年来的研究表明,肿瘤相关中性粒细胞(TANs)通过释放细胞因子、蛋白酶和活性氧(ROS),以及形成中性粒细胞胞外陷阱(NETs),在结直肠癌的炎症驱动、血管生成、免疫抑制和转移微环境的形成中发挥了双重作用。其具体功能并非简单的"非此即彼",而是由TME中复杂的信号网络动态塑造的一个功能连续谱。笔者对TANs在结直肠癌发生与发展中的分子调控网络、临床相关性及其治疗潜力进行了系统综述。同时分析未来的研究应聚焦于探讨TANs的不同亚群特征、功能转化机制,以及如何通过靶向干预改善结直肠癌患者的预后,以期为临床防治结直肠癌提供新的策略和参考。

The pathogenesis of colorectal cancer is closely linked to immune regulation within the tumor microenvironment (TME). In this complex setting, neutrophils, as key components of the innate immune system, exhibit remarkable heterogeneity and functional plasticity. Recent studies have demonstrated that tumor-associated neutrophils (TANs) play a dual role in inflammation-driven tumorigenesis, angiogenesis, immune suppression, and the formation of a metastatic microenvironment in colorectal cancer, primarily through the release of cytokines, proteases, and reactive oxygen species (ROS), as well as the formation of neutrophil extracellular traps (NETs). Their specific functions are not a simple "either-or" dichotomy but rather represent a functional continuum dynamically shaped by intricate signaling networks within the TME. This article provides a systematic review of the molecular regulatory networks, clinical relevance, and therapeutic potential of TANs in the initiation and progression of colorectal cancer. Furthermore, we conclude that future research should focus on elucidating the characteristics of different TAN subsets, the mechanisms underlying their functional polarization, and how targeted interventions can improve the prognosis of colorectal cancer patients, thereby offering novel strategies and references for the clinical prevention and treatment of this disease.

[1]
Borregaard N. Neutrophils, from marrow to microbes[J]. Immunity, 2010, 33(5): 657-670.
[2]
Koenderman L,Vrisekoop N. Neutrophils in cancer: from biology to therapy[J]. Cell Mol Immunol, 2025, 22(1): 4-23.
[3]
Liu Y, Liang J, Zhang Y, et al. Drug resistance and tumor immune microenvironment: an overview of current understandings (Review)[J]. Int J Oncol, 2024, 65(4): 96.
[4]
Barry ST, Gabrilovich DI, Sansom OJ, et al. Therapeutic targeting of tumour myeloid cells[J]. Nat Rev Cancer, 2023, 23(4): 216-237.
[5]
Siegel RL, Wagle NS, Cercek A, et al. Colorectal cancer statistics, 2023[J]. CA Cancer J Clin, 2023, 73(3): 233-254.
[6]
Maier-Begandt D, Alonso-Gonzalez N, Klotz L, et al. Neutrophils-biology and diversity[J]. Nephrol Dial Transplant, 2024, 39(10): 1551-1564.
[7]
Aroca-Crevillén A, Vicanolo T, Ovadia S, et al. Neutrophils in physiology and pathology[J]. Annu Rev Pathol, 2024(19): 227-259.
[8]
Hedrick CC, Malanchi I. Neutrophils in cancer: heterogeneous and multifaceted[J]. Nat Rev Immunol, 2022, 22(3): 173-187.
[9]
Zhang M, Qin H, Wu Y, et al. Complex role of neutrophils in the tumor microenvironment: an avenue for novel immunotherapies[J]. Cancer Biol Med, 2024, 21(10): 849-863.
[10]
Fridlender ZG, Sun J, Kim S, et al. Polarization of tumor-associated neutrophil phenotype by TGF-beta: "N1" versus "N2" TAN[J]. Cancer Cell, 2009, 16(3): 183-194.
[11]
Liu S, Wu W, Du Y, et al. The evolution and heterogeneity of neutrophils in cancers: origins, subsets, functions, orchestrations and clinical applications[J]. Mol Cancer, 2023, 22(1): 148.
[12]
Xue R, Zhang Q, Cao Q, et al. Liver tumour immune microenvironment subtypes and neutrophil heterogeneity[J]. Nature, 2022, 612(7938): 141-147.
[13]
Wang N, Wang Q, Chi J, et al. Carcinoembryonic antigen cell adhesion molecule 1 inhibits the antitumor effect of neutrophils in tongue squamous cell carcinoma[J]. Cancer Sci, 2019, 110(2): 519-529.
[14]
Andzinski L, Kasnitz N, Stahnke S, et al. Type I IFNs induce anti-tumor polarization of tumor associated neutrophils in mice and human[J]. Int J Cancer, 2016, 138(8): 1982-1993.
[15]
Coffelt SB, Wellenstein MD, de Visser KE. Neutrophils in cancer: neutral no more[J]. Nat Rev Cancer, 2016, 16(7): 431-446.
[16]
Hu B, Friedman G, Elinav E, et al. Transmissible inflammation-induced colorectal cancer in inflammasome-deficient mice[J]. Oncoimmunology, 2018, 8(10): e981995.
[17]
Nøst TH, Alcala K, Urbarova I, et al. Systemic inflammation markers and cancer incidence in the UK Biobank[J]. Eur J Epidemiol, 2021, 36(8): 841-848.
[18]
Zheng W, Wu J, Peng Y, et al. Tumor-associated neutrophils in colorectal cancer development, progression and immunotherapy[J]. Cancers (Basel), 2022, 14(19): 4755.
[19]
Yuan J, Ma J, Zhang F, et al. Neutrophil-derived serine proteases induce FOXA2-mediated autophagy dysfunction and exacerbate colitis-associated carcinogenesis via protease activated receptor 2[J]. Autophagy, 2025, 21(10): 2130-2147.
[20]
Butin-Israeli V, Bui TM, Wiesolek HL, et al. Neutrophil-induced genomic instability impedes resolution of inflammation and wound healing[J]. J Clin Invest, 2019, 129(2): 712-726.
[21]
Xia T, Guo J, Zhang B, et al. Bisphenol a promotes the progression of colon cancer through dual-targeting of NADPH oxidase and mitochondrial electron-transport chain to produce ros and activating HIF-1α/VEGF/PI3K/AKT axis[J]. Front Endocrinol (Lausanne), 2022(13): 933051.
[22]
Lee YS, Choi I, Ning Y, et al. Interleukin-8 and its receptor CXCR2 in the tumour microenvironment promote colon cancer growth, progression and metastasis[J]. Br J Cancer, 2012, 106(11): 1833-1841.
[23]
Rodriguez PC, Quiceno DG, Zabaleta J, et al. Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T-cell receptor expression and antigen-specific T-cell responses[J]. Cancer Res, 2004, 64(16): 5839-5849.
[24]
Germann M, Zangger N, Sauvain MO, et al. Neutrophils suppress tumor-infiltrating T cells in colon cancer via matrix metalloproteinase-mediated activation of TGFβ[J]. EMBO Mol Med, 2020, 12(1): e10681.
[25]
Cui C, Chakraborty K, Tang XA, et al. Neutrophil elastase selectively kills cancer cells and attenuates tumorigenesis[J]. Cell, 2021, 184(12): 3163-3177.
[26]
Tadie JM, Bae HB, Jiang S, et al. HMGB1 promotes neutrophil extracellular trap formation through interactions with Toll-like receptor 4[J]. Am J Physiol Lung Cell Mol Physiol, 2013, 304(5): L342-349.
[27]
Stehr AM, Wang G, Demmler R, et al. Neutrophil extracellular traps drive epithelial-mesenchymal transition of human colon cancer[J]. J Pathol, 2022, 256(4): 455-467.
[28]
Gonzalez H, Hagerling C, Werb Z. Roles of the immune system in cancer: from tumor initiation to metastatic progression[J]. Genes Dev, 2018, 32(19-20): 1267-1284.
[29]
Kochumon S, Al-Sayyar A, Jacob T, et al. TGF-β and TNF-α interaction promotes the expression of MMP-9 through H3K36 dimethylation: implications in breast cancer metastasis[J]. Front Immunol, 2024(15): 1430187.
[30]
Denis Musquer M, Jouand N, Pere M, et al. High-density of FcγRIIIA+ (CD16+) tumor-associated neutrophils in metastases improves the therapeutic response of cetuximab in metastatic colorectal cancer patients, independently of the HLA-E/CD94-NKG2A Axis[J]. Front Oncol, 2021(11): 684478.
[31]
Liu Z, Liu B, Feng Y, et al. Dual-targeted self-adjuvant heterocyclic lipidoid@polyester hybrid nanovaccines for boosting cancer immunotherapy[J]. ACS Nano, 2024, 18(24): 15557-15575.
[32]
Korbecki J, Kojder K, Simińska D, et al. CC chemokines in a tumor: a review of pro-cancer and anti-cancer properties of the ligands of receptors CCR1, CCR2, CCR3, and CCR4[J]. Int J Mol Sci, 2020, 21(21): 8412.
[33]
Tosti N, Cremonesi E, Governa V, et al. Infiltration by IL22-producing T cells promotes neutrophil recruitment and predicts favorable clinical outcome in human colorectal cancer[J]. Cancer Immunol Res, 2020, 8(11): 1452-1462.
[34]
Vadillo E, Mantilla A, Aguilar-Flores C, et al. The invasive margin of early-stage human colon tumors is infiltrated with neutrophils of an antitumoral phenotype[J]. J Leukoc Biol, 2023, 114(6): 672-683.
[35]
Cao TM, King MR. Supercharged eGFP-TRAIL decorated NETs to ensnare and kill disseminated tumor cells[J]. Cell Mol Bioeng, 2020, 13(4): 359-367.
[36]
Andzinski L, Kasnitz N, Stahnke S, et al. Type I IFNs induce anti-tumor polarization of tumor associated neutrophils in mice and human[J]. Int J Cancer, 2016, 138(8): 1982-1993.
[37]
Hsu BE, Tabariès S, Johnson RM, et al. Immature low-density neutrophils exhibit metabolic flexibility that facilitates breast cancer liver metastasis[J]. Cell Rep, 2019, 27(13): 3902-3915.
[38]
Yin C, Okugawa Y, Yamamoto A, et al. Prognostic significance of CD8+ tumor-infiltrating lymphocytes and CD66b+ tumor-associated neutrophils in the invasive margins of stages Ⅰ-Ⅲ colorectal cancer[J]. Oncol Lett, 2022, 24(1): 212.
[39]
Yang L, Liu Q, Zhang X, et al. DNA of neutrophil extracellular traps promotes cancer metastasis via CCDC25[J]. Nature, 2020, 583(7814): 133-138.
[40]
Zhang L, Li Z, Skrzypczynska KM, et al. Single-cell analyses inform mechanisms of myeloid-targeted therapies in colon cancer[J]. Cell, 2020, 181(2): 442-459.e29.
[41]
Khan U, Chowdhury S, Billah MM, et al. Neutrophil extracellular traps in colorectal cancer progression and metastasis[J]. Int J Mol Sci, 2021, 22(14): 7260.
[42]
Chen J, Zhu T, Jiang G, et al. Target delivery of a PD-1-TREM2 scFv by CAR-T cells enhances anti-tumor efficacy in colorectal cancer[J]. Mol Cancer, 2023, 22(1): 131.
[43]
Sun L, Liu R, Wu ZJ, et al. Galectin-7 Induction by EHMT2 inhibition enhances immunity in microsatellite stability colorectal cancer[J]. Gastroenterology, 2024, 166(3): 466-482.
[44]
Zhou J, Li L, Pu Y, et al. Astragaloside Ⅳ inhibits colorectal cancer metastasis by reducing extracellular vesicles release and suppressing M2-type TAMs activation[J]. Heliyon, 2024, 10(10): e31450.
[45]
Maity P, Ganguly S, Deb PK. Therapeutic potential of adenosine receptor modulators in cancer treatment[J]. RSC Adv, 2025, 15(26): 20418-20445.
[46]
Xia Y, He J, Zhang H, et al. AAV-mediated gene transfer of DNase I in the liver of mice with colorectal cancer reduces liver metastasis and restores local innate and adaptive immune response[J]. Mol Oncol, 2020, 14(11): 2920-2935.
[47]
Hsu AY, Huang Q, Liu F, et al. Neutrophil death-more than meets the eye[J]. Exp Hematol, 2025: 104857.
[48]
Zhu W, Yang S, Meng D, et al. Targeting NADPH oxidase and integrin α5β1 to inhibit neutrophil extracellular traps-mediated metastasis in colorectal cancer[J]. Int J Mol Sci, 2023, 24(21): 16001.
[49]
Frota Reis AV, de Sousa ACC, de Freitas JVB, et al. Effect of PLGA composition on nanoencapsulation, fluorescence stability and cellular internalization of R-phycoerythrin in colorectal cancer cells[J]. Int J Pharm, 2025(682): 125966.
[50]
Bullock AJ, Schlechter BL, Fakih MG, et al. Botensilimab plus balstilimab in relapsed/refractory microsatellite stable metastatic colorectal cancer: a phase 1 trial[J]. Nat Med, 2024, 30(9): 2558-2567.
[51]
Gao Q, Yang L, Ye S, et al. Targeting SIRT2 induces MLH1 deficiency and boosts antitumor immunity in preclinical colorectal cancer models[J]. Sci Transl Med, 2025, 17(807): eadv0766.
[52]
Cheng S, Li Z, Gao R, et al. A pan-cancer single-cell transcriptional atlas of tumor infiltrating myeloid cells[J]. Cell, 2021, 184(3): 792-809.e23.
[53]
Cheong JE, Sun L. Targeting the IDO1/TDO2-KYN-AhR pathway for cancer immunotherapy - challenges and opportunities[J]. Trends Pharmacol Sci, 2018, 39(3): 307-325.
[54]
Lewis HD, Liddle J, Coote JE, et al. Inhibition of PAD4 activity is sufficient to disrupt mouse and human NET formation[J]. Nat Chem Biol, 2015, 11(3): 189-191.
[1] 李雨秋, 莫红楠. 乳腺癌肿瘤微环境特征及免疫治疗新进展[J/OL]. 中华乳腺病杂志(电子版), 2025, 19(06): 331-338.
[2] 严征远, 张恒, 曹能琦, 方兴超, 陈大敏. 单孔+1腹腔镜结直肠癌根治切除术的有效性及安全性临床观察[J/OL]. 中华普外科手术学杂志(电子版), 2025, 19(06): 615-618.
[3] 钱龙, 蔡大明, 王行舟, 艾世超, 胡琼源, 孙锋, 宋鹏, 王峰, 王萌, 陆晓峰, 朱欢欢, 沈晓菲, 管文贤. 局部不可切除胃癌转化治疗(联合免疫治疗)后淋巴结转移的相关危险因素分析[J/OL]. 中华普外科手术学杂志(电子版), 2025, 19(06): 624-627.
[4] 王思竣, 王琼, 李珂雨, 袁新普, 张硕珉, 马睿, 谢天宇, 张朝军. 胃上部癌新辅助化疗联合免疫治疗后实施近端胃切除术的临床疗效分析[J/OL]. 中华普外科手术学杂志(电子版), 2025, 19(06): 637-641.
[5] 俞颖倩, 徐兴祥. 淋巴结转移与非转移对原发性支气管肺癌免疫微环境及免疫治疗的影响[J/OL]. 中华肺部疾病杂志(电子版), 2025, 18(06): 1027-1030.
[6] 李才坤, 张又红, 肖斌彬, 温盼, 刘醒, 刘志栋, 周剑辉, 温春玲, 叶劲, 严恒琛. 三维斑点追踪在肺癌患者免疫治疗后左心房功能损害评价的应用[J/OL]. 中华肺部疾病杂志(电子版), 2025, 18(05): 821-823.
[7] 蔡建珊, 陈进宏. 同时性结直肠癌肝转移手术策略[J/OL]. 中华肝脏外科手术学电子杂志, 2025, 14(06): 813-821.
[8] 许侨东, 马志延, 冯庚壬, 钟海彬, 刘坚锐, 古松钢. 肝肺多发性原发性癌转化治疗后行腹腔镜肝右前叶切除术一例(附视频)[J/OL]. 中华肝脏外科手术学电子杂志, 2025, 14(06): 973-976.
[9] 张宇涵, 吴添庆, 高汶卿, 郑梽楷, 贺珉睿, 周仲国. 不可切除性肝内胆管癌不同治疗方式疗效和安全性的Meta分析[J/OL]. 中华肝脏外科手术学电子杂志, 2025, 14(06): 939-947.
[10] 潘胜淇, 李兴源, 王佳琦, 关竣庭, 丁可, 常泽文, 汤庆超. 三臂与四臂达芬奇机器人手术系统在乙状结肠与中高位直肠癌根治术中应用的近期疗效比较[J/OL]. 中华结直肠疾病电子杂志, 2025, 14(06): 509-515.
[11] 张宇坤, 王春林, 周珉玮, 李震洋, 周易明, 顾晓冬, 项建斌. 放疗诱导微卫星稳定型结直肠癌细胞外泌体成分变化及其增强CD8+T细胞功能的体外研究[J/OL]. 中华结直肠疾病电子杂志, 2025, 14(06): 526-532.
[12] 张金珠, 陈海鹏, 赵志勋, 王锡山. 耗竭性CD8+T细胞表型对结直肠癌免疫检查点阻断剂疗效的影响[J/OL]. 中华结直肠疾病电子杂志, 2025, 14(06): 533-537.
[13] 王思远, 刘馨, 曹永丽, 李明, 张远耀, 魏东. 经自然腔道取标本手术在结直肠肿瘤中无菌与无瘤技术的研究进展[J/OL]. 中华结直肠疾病电子杂志, 2025, 14(06): 538-545.
[14] 王春茂, 韩鸣, 王子彤. 局限期小细胞肺癌新辅助治疗后完全病理学缓解五例[J/OL]. 中华临床医师杂志(电子版), 2025, 19(07): 550-554.
[15] 侯雨函, 姜福金, 王苏贵. 膀胱癌免疫治疗的研究进展[J/OL]. 中华临床医师杂志(电子版), 2025, 19(06): 471-475.
阅读次数
全文


摘要


AI


AI小编
你好!我是《中华医学电子期刊资源库》AI小编,有什么可以帮您的吗?