Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71:209–49.
Biller LH, Schrag D. Diagnosis and treatment of metastatic colorectal cancer: a review. JAMA. 2021;325:669–85.
Cervantes A, Adam R, Roselló S, Arnold D, Normanno N, Taïeb J, et al. Metastatic colorectal cancer: ESMO clinical practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023;34:10–32.
Bruni D, Angell HK, Galon J. The immune contexture and Immunoscore in cancer prognosis and therapeutic efficacy. Nat Rev Cancer. 2020;20:662–80.
Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, et al. Neutrophil extracellular traps kill bacteria. Science. 2004;303:1532–5.
Herre M, Cedervall J, Mackman N, Olsson A-K. Neutrophil extracellular traps in the pathology of cancer and other inflammatory diseases. Physiol Rev. 2023;103:277–312.
Papayannopoulos V. Neutrophil extracellular traps in immunity and disease. Nat Rev Immunol. 2018;18:134–47.
Wang Y, Li M, Stadler S, Correll S, Li P, Wang D, et al. Histone hypercitrullination mediates chromatin decondensation and neutrophil extracellular trap formation. J Cell Biol. 2009;184:205–13.
de Visser KE, Joyce JA. The evolving tumor microenvironment: From cancer initiation to metastatic outgrowth. Cancer Cell. 2023;41:374–403.
Arelaki S, Arampatzioglou A, Kambas K, Papagoras C, Miltiades P, Angelidou I, et al. Gradient infiltration of neutrophil extracellular traps in colon cancer and evidence for their involvement in tumour growth. PLoS ONE. 2016;11. https://doi.org/10.1371/JOURNAL.PONE.0154484.
Hedrick CC, Malanchi I. Neutrophils in cancer: heterogeneous and multifaceted. Nat Rev Immunol. 2022;22:173–87.
Rayes RF, Mouhanna JG, Nicolau I, Bourdeau F, Giannias B, Rousseau S, et al. Primary tumors induce neutrophil extracellular traps with targetable metastasis-promoting effects. JCI Insight. 2019;4. https://doi.org/10.1172/JCI.INSIGHT.128008.
Yang L, Liu L, Zhang R, Hong J, Wang Y, Wang J, et al. IL-8 mediates a positive loop connecting increased neutrophil extracellular traps (NETs) and colorectal cancer liver metastasis. J Cancer. 2020;11:4384.
Yang L, Liu Q, Zhang X, Liu X, Zhou B, Chen J, et al. DNA of neutrophil extracellular traps promotes cancer metastasis via CCDC25. Nature. 2020;583:133–8.
Bonnekoh H, Scheffel J, Wu J, Hoffmann S, Maurer M, Krause K. Skin and systemic inflammation in Schnitzler’s syndrome are associated with neutrophil extracellular trap formation. Front Immunol. 2019;10:546.
Tuomisto AE, Mäkinen MJ, Väyrynen JP. Systemic inflammation in colorectal cancer: underlying factors, effects, and prognostic significance. World J Gastroenterol. 2019;25:4383–404.
Cristinziano L, Modestino L, Antonelli A, Marone G, Simon H-U, Varricchi G, et al. Neutrophil extracellular traps in cancer. Semin Cancer Biol. 2022;79:91–104.
Jiang M, Zhang R, Huang M, Yang J, Liu Q, Zhao Z, et al. The Prognostic value of tumor-associated neutrophils in colorectal cancer: a systematic review and meta-analysis. Cancer Med. 2025;14:e70614.
Kastinen M, Sirniö P, Elomaa H, Äijälä VK, Karjalainen H, Tapiainen VV, et al. Establishing criteria for tumor necrosis as prognostic indicator in colorectal cancer. Am J Surg Pathol. 2024;48:1284–92.
Elomaa H, Ahtiainen M, Väyrynen SA, Ogino S, Nowak JA, Friman M, et al. Prognostic significance of spatial and density analysis of T lymphocytes in colorectal cancer. Br J Cancer. 2022;127:514–23.
Aro R, Ohtonen P, Rautio T, Saarnio J, Mäkäräinen E, Häivälä R, et al. Perioperative oral nutritional support for patients diagnosed with primary colon adenocarcinoma undergoing radical surgical procedures -Peri-Nutri Trial: study protocol for a randomized controlled trial. BMC Nutr. 2022;8:89.
Assarsson E, Lundberg M, Holmquist G, Björkesten J, Thorsen SB, Ekman D, et al. Homogenous 96-plex PEA immunoassay exhibiting high sensitivity, specificity, and excellent scalability. PLoS ONE. 2014;9:e95192.
Sajanti S, Sirniö P, Väyrynen JP, Tuomisto A, Klintrup K, Mäkelä J, et al. VE1 immunohistochemistry accurately detects BRAF V600E mutations in colorectal carcinoma and can be utilized in the detection of poorly differentiated colorectal serrated adenocarcinoma. Virchows Archiv. 2014;464:637–43.
Seppälä TT, Böhm JP, Friman M, Lahtinen L, Väyrynen VMJ, Liipo TKE, et al. Combination of microsatellite instability and BRAF mutation status for subtyping colorectal cancer. Br J Cancer. 2015;112:1966–75.
Bankhead P, Loughrey MB, Fernández JA, Dombrowski Y, McArt DG, Dunne PD, et al. QuPath: Open source software for digital pathology image analysis. Sci Rep. 2017;7:16878.
Pagès F, Mlecnik B, Marliot F, Bindea G, Ou F-S, Bifulco C, et al. International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study. Lancet. 2018;391:2128–39.
Kastinen M, Sirniö P, Elomaa H, Ahtiainen M, Väyrynen SA, Herzig KH, et al. Immunological and prognostic significance of tumour necrosis in colorectal cancer. Br J Cancer. 2023;128:2218–26.
Yang S, Zou X, Li J, Yang H, Zhang A, Zhu Y, et al. Immunoregulation and clinical significance of neutrophils/NETs-ANGPT2 in tumor microenvironment of gastric cancer. Front Immunol. 2022;13. https://doi.org/10.3389/FIMMU.2022.1010434.
Aldabbous L, Abdul-Salam V, Mckinnon T, Duluc L, Pepke-Zaba J, Southwood M, et al. Neutrophil extracellular traps promote angiogenesis: evidence from vascular pathology in pulmonary hypertension. Arterioscler Thromb Vasc Biol. 2016;36:2078–87.
Szukiewicz D. CX3CL1 (Fractalkine)-CX3CR1 axis in inflammation-induced angiogenesis and tumorigenesis. Int J Mol Sci. 2024;25. https://doi.org/10.3390/IJMS25094679.
Manda-Handzlik A, Cieloch A, Kuźmicka W, Mroczek A, Stelmaszczyk-Emmel A, Demkow U, et al. Secretomes of M1 and M2 macrophages decrease the release of neutrophil extracellular traps. Sci Rep. 2023;13. https://doi.org/10.1038/S41598-023-42167-1.
Farrera C, Fadeel B. Macrophage clearance of neutrophil extracellular traps is a silent process. J Immunol. 2013;191:2647–56.
Nakazawa D, Shida H, Kusunoki Y, Miyoshi A, Nishio S, Tomaru U, et al. The responses of macrophages in interaction with neutrophils that undergo NETosis. J Autoimmun. 2016;67:19–28.
Jiao Y, Li Z, Loughran PA, Fan EK, Scott MJ, Li Y, et al. Frontline science: macrophage-derived exosomes promote neutrophil necroptosis following hemorrhagic shock. J Leukoc Biol. 2018;103:175–83.
Chan Y-T, Tan H-Y, Lu Y, Zhang C, Cheng C-S, Wu J, et al. Pancreatic melatonin enhances anti-tumor immunity in pancreatic adenocarcinoma through regulating tumor-associated neutrophils infiltration and NETosis. Acta Pharm Sin B. 2023;13:1554–67.
Schedel F, Mayer-Hain S, Pappelbaum KI, Metze D, Stock M, Goerge T, et al. Evidence and impact of neutrophil extracellular traps in malignant melanoma. Pigment Cell Melanoma Res. 2020;33:63–73.
Li Y, Wu S, Zhao Y, Dinh T, Jiang D, Selfridge JE, et al. Neutrophil extracellular traps induced by chemotherapy inhibit tumor growth in murine models of colorectal cancer. J Clin Investig. 2024;134. https://doi.org/10.1172/JCI175031.
Tohme S, Yazdani HO, Al-Khafaji AB, Chidi AP, Loughran P, Mowen K, et al. Neutrophil extracellular traps promote the development and progression of liver metastases after surgical stress. Cancer Res. 2016;76:1367–80.
Okamoto M, Mizuno R, Kawada K, Itatani Y, Kiyasu Y, Hanada K et al. Neutrophil extracellular traps promote metastases of colorectal cancers through activation of ERK signaling by releasing neutrophil elastase. Int J Mol Sci. 2023;24. https://doi.org/10.3390/IJMS24021118.
Ye H, Wang Y, Yao S, Liu Z, Liang C, Zhu Y, et al. Necrosis score as a prognostic factor in stage I-III colorectal cancer: a retrospective multicenter study. Discover oncology. 2023;14:61.
Teng H-W, Wang T-Y, Lin C-C, Tong Z-J, Cheng H-W, Wang H-T. Interferon gamma induces higher neutrophil extracellular traps leading to tumor-killing activity in microsatellite stable colorectal cancer. Mol Cancer Ther. 2024;23:1043–56.
Farhood B, Najafi M, Mortezaee K. CD8+ cytotoxic T lymphocytes in cancer immunotherapy: a review. J Cell Physiol. 2019;234:8509–21.
Dolcetti R, Viel A, Doglioni C, Russo A, Guidoboni M, Capozzi E, et al. High prevalence of activated intraepithelial cytotoxic T lymphocytes and increased neoplastic cell apoptosis in colorectal carcinomas with microsatellite instability. Am J Pathol. 1999;154:1805–13.
Yoon J, Terada A, Kita H. CD66b regulates adhesion and activation of human eosinophils. J Immunol. 2007;179:8454–62.
Zheng W, Wu J, Peng Y, Sun J, Cheng P, Huang Q. Tumor-associated neutrophils in colorectal cancer development, progression and immunotherapy. Cancers. 2022;14. https://doi.org/10.3390/cancers14194755.
Yin C, Okugawa Y, Yamamoto A, Kitajima T, Shimura T, Kawamura M, et al. Prognostic significance of CD8+ tumor-infiltrating lymphocytes and CD66b+ tumor-associated neutrophils in the invasive margins of stages I-III colorectal cancer. Oncol Lett. 2022;24:212.
Xu X, Ma J, Yu G, Qiu Q, Zhang W, Cao F. Effective predictor of colorectal cancer survival based on exclusive expression pattern among different immune cell infiltration. J Histochem Cytochem. 2021;69:271–86.
Ye L, Zhang T, Kang Z, Guo G, Sun Y, Lin K, et al. Tumor-infiltrating immune cells act as a marker for prognosis in colorectal cancer. Front Immunol. 2019;10:2368.
Governa V, Trella E, Mele V, Tornillo L, Amicarella F, Cremonesi E, et al. The interplay between neutrophils and CD8+ T cells improves survival in human colorectal cancer. Clin Cancer Res. 2017;23:3847–58.
Wikberg ML, Ling A, Li X, Öberg Å, Edin S, Palmqvist R. Neutrophil infiltration is a favorable prognostic factor in early stages of colon cancer. Hum Pathol. 2017;68:193–202.
Galdiero MR, Bianchi P, Grizzi F, Di Caro G, Basso G, Ponzetta A, et al. Occurrence and significance of tumor-associated neutrophils in patients with colorectal cancer. Int J Cancer. 2016;139:446–56.
Edin S, Kaprio T, Hagström J, Larsson P, Mustonen H, Böckelman C, et al. The prognostic importance of CD20+ B lymphocytes in colorectal cancer and the relation to other immune cell subsets. Sci Rep. 2019;9:19997.
Hu X, Li Y-Q, Ma X-J, Zhang L, Cai S-J, Peng J-J. A risk signature with inflammatory and T immune cells infiltration in colorectal cancer predicting distant metastases and efficiency of chemotherapy. Front Oncol. 2019;9:704.
Zhu B, Luo J, Jiang Y, Yu L, Liu M, Fu J. Prognostic significance of nomograms integrating IL-37 expression, neutrophil level, and MMR status in patients with colorectal cancer. Cancer Med. 2018;7:3682–94.
Rao H-L, Chen J-W, Li M, Xiao Y-B, Fu J, Zeng Y-X, et al. Increased intratumoral neutrophil in colorectal carcinomas correlates closely with malignant phenotype and predicts patients’ adverse prognosis. PLoS ONE. 2012;7:e30806.
Väyrynen JP, Lau MC, Haruki K, Väyrynen SA, Dias Costa A, Borowsky J, et al. Prognostic significance of immune cell populations identified by machine learning in colorectal cancer using routine hematoxylin and eosin-stained sections. Clin Cancer Res. 2020;26:4326–38.
Berry RS, Xiong M-J, Greenbaum A, Mortaji P, Nofchissey RA, Schultz F, et al. High levels of tumor-associated neutrophils are associated with improved overall survival in patients with stage II colorectal cancer. PLoS ONE. 2017;12:e0188799.
Jakubowska K, Koda M, Grudzińska M, Kisielewski W, Lomperta K, Famulski W. Neutrophil infiltration combined with necrosis in the primary tumor is a useful prognostic indicator for three-year disease-free survival time in patients with colorectal cancer. Oncol Lett. 2022;23:199.
Rottmann BG, Patel N, Ahmed M, Deng Y, Ciarleglio M, Vyas M, et al. Clinicopathological significance of neutrophil-rich colorectal carcinoma. J Clin Pathol. 2023;76:34–9.
Richards CH, Flegg KM, Roxburgh CSD, Going JJ, Mohammed Z, Horgan PG, et al. The relationships between cellular components of the peritumoural inflammatory response, clinicopathological characteristics and survival in patients with primary operable colorectal cancer. Br J Cancer. 2012;106:2010–5.
Khanh DT, Mekata E, Mukaisho K, Sugihara H, Shimizu T, Shiomi H, et al. Prognostic role of CD10+ myeloid cells in association with tumor budding at the invasion front of colorectal cancer. Cancer Sci. 2011;102:1724–33.
Droeser RA, Hirt C, Eppenberger-Castori S, Zlobec I, Viehl CT, Frey DM, et al. High myeloperoxidase positive cell infiltration in colorectal cancer is an independent favorable prognostic factor. PLoS ONE. 2013;8:e64814.
Zhang Y, Guo L, Dai Q, Shang B, Xiao T, Di X, et al. A signature for pan-cancer prognosis based on neutrophil extracellular traps. J Immunother Cancer 2022;10. https://doi.org/10.1136/jitc-2021-004210.
Mao Y, Feng Q, Zheng P, Yang L, Liu T, Xu Y, et al. Low tumor purity is associated with poor prognosis, heavy mutation burden, and intense immune phenotype in colon cancer. Cancer Manag Res. 2018;10:3569–77.
Shaul ME, Fridlender ZG. Tumour-associated neutrophils in patients with cancer. Nat Rev Clin Oncol. 2019;16:601–20.
Antuamwine BB, Bosnjakovic R, Hofmann-Vega F, Wang X, Theodosiou T, Iliopoulos I, et al. N1 versus N2 and PMN-MDSC: a critical appraisal of current concepts on tumor-associated neutrophils and new directions for human oncology. Immunol Rev. 2023;314:250–79.
Bai M, Jin Y, Jin Z, Xie Y, Chen J, Zhong Q, et al. Distinct immunophenotypic profiles and neutrophil heterogeneity in colorectal cancer. Cancer Lett. 2025;616:217570.
Huang X, Nepovimova E, Adam V, Sivak L, Heger Z, Valko M, et al. Neutrophils in cancer immunotherapy: friends or foes? Mol Cancer. 2024;23:107.
Kwak JW, Houghton AM. Targeting neutrophils for cancer therapy. Nat Rev Drug Discov. 2025;24:666–84.
Zhang J, Gu J, Wang X, Ji C, Yu D, Wang M, et al. Engineering and targeting neutrophils for cancer therapy. Adv Mater. 2024;36:e2310318.
Wang Y, Yang K, Li J, Wang C, Li P, Du L. Neutrophil extracellular traps in cancer: from mechanisms to treatments. Clin Transl Med. 2025;15:e70368.
Prajapati DR, Molczyk C, Purohit A, Saxena S, Sturgeon R, Dave BJ, et al. Small molecule antagonist of CXCR2 and CXCR1 inhibits tumor growth, angiogenesis, and metastasis in pancreatic cancer. Cancer Lett. 2023;563:216185.
Armstrong AJ, Geva R, Chung HC, Lemech C, Miller WH, Hansen AR, et al. CXCR2 antagonist navarixin in combination with pembrolizumab in select advanced solid tumors: a phase 2 randomized trial. Investig New Drugs. 2024;42:145–59.
Gao F, Peng H, Gou R, Zhou Y, Ren S, Li F. Exploring neutrophil extracellular traps: mechanisms of immune regulation and future therapeutic potential. Exp Hematol Oncol. 2025;14:80.
Park JH, van Wyk H, McMillan DC, Quinn J, Clark J, Roxburgh CSD, et al. Signal Transduction and Activator of Transcription-3 (STAT3) in patients with colorectal cancer: associations with the phenotypic features of the tumor and host. Clin Cancer Res. 2017;23:1698–709.
Noti L, Galván JA, Dawson H, Lugli A, Kirsch R, Assarzadegan N, et al. A combined spatial score of granzyme B and CD68 surpasses CD8 as an independent prognostic factor in TNM stage II colorectal cancer. BMC Cancer. 2022;22:987.
Lee W, Ko SY, Akasaka H, Weigert M, Lengyel E, Naora H. Neutrophil extracellular traps promote pre-metastatic niche formation in the omentum by expanding innate-like B cells that express IL-10. Cancer Cell. 2025;43:69–85.e11.
Masucci MT, Minopoli M, Del Vecchio S, Carriero MV. The emerging role of neutrophil extracellular traps (NETs) in tumor progression and metastasis. Front Immunol. 2020;11:1749.