Interleukin 6 induces M2 macrophage differentiation by STAT3 activation that correlates with gastric cancer progression
Open accessAbstract
Interleukin 6 (IL-6) was abundant in the tumor microenvironment and played potential roles in tumor progression. In our study, the expression of IL-6 in tumor tissues from 36 gastric cancer (GC) patients was significantly higher than in non-tumor tissues. Moreover, the number of CD163+CD206+ M2 macrophages that infiltrated in tumor tissues was significantly greater than those infiltrated in non-tumor tissues. The frequencies of M2 macrophages were positively correlated with the IL-6 expression in GC tumors. We also found that IL-6 could induce normal macrophages to differentiate into M2 macrophages with higher IL-10 and TGF-β expression, and lower IL-12 expression, via activating STAT3 phosphorylation. Accordingly, knocking down STAT3 using small interfering RNA decreased the expression of M2 macrophages-related cytokines (IL-10 and TGF-β). Furthermore, supernatants from IL-6-induced M2 macrophages promote GC cell proliferation and migration. Moreover, IL-6 production and CD163+CD206+ M2 macrophage infiltration in tumors were associated with disease progression and reduced GC patient survival. In conclusion, our data indicate that IL-6 induces M2 macrophage differentiation (IL-10 high TGF-β high IL-12 p35low ) by activating STAT3 phosphorylation, and the IL-6-induced M2 macrophages exert a pro-tumor function by promoting GC cell proliferation and migration.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
IL-6 and IL-10 are abundant in tumor microenvironments originated from myeloid cells, fibroblasts and tumor cells, and they further induce M2 macrophage differentiation through STAT3.
“IL-6 and IL-10 are abundant in tumor microenvironments originated from myeloid cells, fibroblasts and tumor cells, and they further induce M2 macrophage differentiation through STAT3 (215, 216).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [216]
The section ‘IL-6 induces M2 macrophage differentiation via STAT3 phosphorylation’ shows that IL-6 induces M2 differentiation through STAT3 activation. The Discussion also says IL-10 can promote M2 differentiation, but does not establish that IL-10 does so through STAT3. Our copy reports elevated IL-6 in gastric tumors; it does not establish that both cytokines are abundant across tumor microenvironments or identify myeloid cells, fibroblasts, and tumor cells as their sources. No page numbers are available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Exploring the full spectrum of macrophage activation
Mosser, D. M., & Edwards, J. P. (2008) · Nature Reviews Immunology · doi:10.1038/nri2448 · Cited by 9,144 · see citing works
The chemokine system in diverse forms of macrophage activation and polarization
MANTOVANI, A., SICA, A., SOZZANI, S., ALLAVENA, P., VECCHI, A., & LOCATI, M. (2004) · Trends in Immunology · doi:10.1016/j.it.2004.09.015 · Cited by 6,534 · see citing works
Alternative activation of macrophages
Gordon, S. (2003) · Nature Reviews Immunology · doi:10.1038/nri978 · Cited by 6,189 · see citing works
Adipokines in inflammation and metabolic disease
Ouchi, N., Parker, J. L., Lugus, J. J., & Walsh, K. (2011) · Nature Reviews Immunology · doi:10.1038/nri2921 · Cited by 4,625 · see citing works
Alternative activation of macrophages: mechanism and functions
Gordon, S., & Martinez, F. O. (2010) · Immunity · doi:10.1016/j.immuni.2010.05.007 · Cited by 4,197 · see citing works
The many faces of macrophage activation
Mosser, D. M. (2003) · Journal of Leukocyte Biology · doi:10.1189/jlb.0602325 · Cited by 1,902 · see citing works
Kraakman, M. J., Kammoun, H. L., Allen, T. L., Deswaerte, V., Henstridge, D. C., Estevez, E., Matthews, V. B., Neill, B., White, D. A., Murphy, A. J., et al. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.02.006 · Cited by 257 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Macrophages in immunoregulation and therapeutics
Chen, S., Saeed, A. F. U. H., Liu, Q., Jiang, Q., Xu, H., Xiao, G. G., Rao, L., & Duo, Y. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01452-1 · Cited by 2,348 · see citing works
“IFN-γ ligand binding to its receptor induces Janus kinase 1/2-mediated tyrosine phosphorylation and subsequent dimerization and activation of STAT1, which binds as a homodimer to the promoter of M1 signature genes.184 Activation of STAT3 by IL-10 and IL-6 stimulation can induce M2-associated markers expression such as…”
BackgroundIL-6 in inflammation, autoimmunity and cancer
Hirano, T. (2021) · International Immunology · doi:10.1093/intimm/dxaa078 · Cited by 1,453 · see citing works
“IL-6 and IL-10 are abundant in tumor microenvironments originated from myeloid cells, fibroblasts and tumor cells, and they further induce M2 macrophage differentiation through STAT3 (215, 216).”
BackgroundWeng, Y.-S., Tseng, H., Chen, Y.-A., Shen, P.-C., Haq, A. T. A., Chen, L.-M., Tung, Y., & Hsu, H.-L. (2019) · Molecular Cancer · doi:10.1186/s12943-019-0988-0 · Cited by 393 · see citing works
“The IL-6-STAT3-Twist circuit stimulates the EMT process and M2 macrophage polarization [28].”
BackgroundTumor-associated macrophages: an effective player of the tumor microenvironment
Basak, U., Sarkar, T., Mukherjee, S., Chakraborty, S., Dutta, A., Dutta, S., Nayak, D., Kaushik, S., Das, T., & Sa, G. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1295257 · Cited by 346 · see citing works
Tumor-Associated Macrophage Subsets: Shaping Polarization and Targeting
Zhang, Q., & Sioud, M. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24087493 · Cited by 306 · see citing works
“Most often, high levels of TAMs in the TME are associated with cancer progression, metastatic spread, poor treatment efficacy, and shorter survival in several cancer types such as lung cancer [2,3], breast cancer [4–7], hepatocellular carcinoma (HCC) [8], gastric cancer [9], and melanoma [10].”
BackgroundInfluentialUnraveling the complexity of STAT3 in cancer: molecular understanding and drug discovery
Hu, Y., Dong, Z., & Liu, K. (2024) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-024-02949-5 · Cited by 288 · see citing works
“Recently, studies have found that IL-6 promotes normal macrophages to differentiate into M2 macrophages mediated by STAT3 and therefore supports tumor proliferation in gastric cancer [121].”
BackgroundAdvances in the role of STAT3 in macrophage polarization
Xia, T., Zhang, M., Lei, W., Yang, R., Fu, S.-P., Fan, Z., Yang, Y., & Zhang, T. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1160719 · Cited by 289 · see citing works
Crosstalk of Inflammatory Cytokines within the Breast Tumor Microenvironment
Habanjar, O., Bingula, R., Decombat, C., Diab‐Assaf, M., Caldefie‐Chezet, F., & Delort, L. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24044002 · Cited by 272 · see citing works
“IL-6 Monocytes, macrophages, TAM [71,72], T cells, B cells, fibroblasts, CAFs [73,74], endothelial cells, and adipocytes [75–77] some cancer cells [78,79], myeloid-derived suppressor cells (MDSC), and CD4+ T cells Activated B, DCs, cells, T cells, CD4+ T, plasma cells, hematopoietic stem cells, cancer cells, macrophag…”
BackgroundEmerging role of tumor cell plasticity in modifying therapeutic response
Qin, S., Jiang, J., Lü, Y., Nice, E. C., Huang, C., Zhang, J., & He, W. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00313-5 · Cited by 274 · see citing works
Yang, S., Liu, Q., & Liao, Q. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.607209 · Cited by 202 · see citing works
Griess, B., Mir, S. U. R., Datta, K., & Teoh-Fitzgerald, M. L. T. (2019) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2019.12.018 · Cited by 200 · see citing works
Meteorin-like facilitates skeletal muscle repair through a Stat3/IGF-1 mechanism
Baht, G., Bareja, A., Lee, D. E., Rao, R. R., Huang, R., Huebner, J., Bartlett, D. B., Hart, C., Gibson, J. R., Lanza, I., et al. (2020) · Nature Metabolism · doi:10.1038/s42255-020-0184-y · Cited by 168 · see citing works
STAT3 pathway in cancers: Past, present, and future
Wang, H., Man, Q., Huo, F., Gao, X., Lin, H., Li, S.-R., Wang, J., Su, F., Cai, L., Shi, Y., et al. (2022) · MedComm · doi:10.1002/mco2.124 · Cited by 172 · see citing works
Jin, Y. T., Kang, Y., Wang, M., Wu, B., Su, B., Yin, H., Tang, Y., Li, Q., Wei, W., Mei, Q., et al. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-00872-9 · Cited by 169 · see citing works
“IL6/JAK2/STAT3 signaling mediates M2 polarization of microglia IL6 has been shown to activate the JAK/STAT signaling pathway, critically contributing to TAM polarization.(28,29) Given that A549F3 and co-cultured cells exhibited upregulated IL6, we speculated that IL6/JAK/STAT signaling might be involved in microglia M…”
BackgroundTan, Y., Sun, R., Liu, L., Yang, D.-J., Xiang, Q., Li, L., Tang, J., Qiu, Z., Peng, W.-Y., Wang, Y.-Y., et al. (2021) · Theranostics · doi:10.7150/thno.58322 · Cited by 158 · see citing works
“IL-6 is abundant in TME and has been shown to induce differentiation of M2 macrophages [42].”
BackgroundPlasminogen activator inhibitor-1 promotes the recruitment and polarization of macrophages in cancer
Kubala, M., Punj, V., Placencio-Hickok, V. R., Fang, H., Fernandez, G. E., Sposto, R., & DeClerck, Y. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.10.082 · Cited by 152 · see citing works
Tumor Associated Macrophages: Origin, Recruitment, Phenotypic Diversity, and Targeting
Hourani, T., Holden, J., Li, W., Lenzo, J., Hadjigol, S., & O'Brien-Simpson, N. M. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.788365 · Cited by 151 · see citing works
Transforming Growth Factor-β: A Multifunctional Regulator of Cancer Immunity
Xue, V., Chung, J., Córdoba, C. G., Cheung, A., Kang, W., Lam, E., Leung, K., To, K. F., Lan, H., & Tang, P. (2020) · Cancers · doi:10.3390/cancers12113099 · Cited by 131 · see citing works
“IL-6 Gastric cancer Increase M2 differentiation, lead to the proliferation and migration of tumour cells Human [91] IL-10 STAT3”
BackgroundSTAT3, a master regulator of anti-tumor immune response
Rébé, C., & Ghiringhelli, F. (2019) · Cancers · doi:10.3390/cancers11091280 · Cited by 129 · see citing works
Yin, Z., Zhou, Y., Ma, T.-T., Chen, S., Shi, N., Zou, Y.-P., Hou, B., & Zhang, C. (2020) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.15125 · Cited by 116 · see citing works
Mi, X., Xu, R.-Y., Hong, S., Xu, T., Zhang, W.-F., & Liu, M. (2020) · Molecular Therapy: Nucleic Acids · doi:10.1016/j.omtn.2020.09.035 · Cited by 115 · see citing works
“Recently, associations between M2 macrophages and gastric cancer development have been found.(21) Nevertheless, the role of M2 macrophage-derived exosomes in EC remains to be examined.”
BackgroundSTAT3 Pathway in Gastric Cancer: Signaling, Therapeutic Targeting and Future Prospects
Ashrafizadeh, M., Zarrabi, A., Orouei, S., Zarrin, V., Moghadam, E. R., Zabolian, A., Mohammadi, S., Hushmandi, K., Gharehaghajlou, Y., Makvandi, P., et al. (2020) · Biology · doi:10.3390/biology9060126 · Cited by 108 · see citing works
“This axis leads to a remarkable increase in the progression and malignancy of GC cells [274].”
BackgroundMu, G.-G., Zhu, Y.-J., Dong, Z.-H., Shi, L., Deng, Y.-C., & Li, H. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.727306 · Cited by 97
Zhang, B., Liu, J., Mo, Y., Zhang, K., Huang, B., & Shang, D. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1476904 · Cited by 76 · see citing works
Contribution of STAT3 to the pathogenesis of COVID-19
Jafarzadeh, A., Nemati, M., & Jafarzadeh, S. (2021) · Microbial Pathogenesis · doi:10.1016/j.micpath.2021.104836 · Cited by 108 · see citing works
The Vicious Cross-Talk between Tumor Cells with an EMT Phenotype and Cells of the Immune System
Romeo, E. L., Caserta, C. A., Rumio, C., & Marcucci, F. (2019) · Cells · doi:10.3390/cells8050460 · Cited by 108 · see citing works
Sun, Z.-Q., Xu, Y.-X., Shao, B., Dang, P., Hu, S.-Y., Sun, H., Chen, C., Wang, C., Liu, J.-B., Liu, Y., et al. (2024) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2023-008491 · Cited by 75 · see citing works
Profibrotic Activation of Human Macrophages in Systemic Sclerosis
Bhandari, R., Ball, M. S., Martyanov, V., Popovich, D., Schaafsma, E., Han, S., ElTanbouly, M. A., Orzechowski, N. M., Carns, M. A., Arroyo, E., et al. (2020) · Arthritis & Rheumatology · doi:10.1002/art.41243 · Cited by 90 · see citing works
“STAT3 signaling, which is induced by IL6, is a key mediator of macrophage activation in a variety of pathologic conditions (39,40), and is a regulator of macrophage migration (41).”
BackgroundSignal transducer and activator of transcription 3 signaling in tumor immune evasion
Zhang, L., Kuca, K., You, L., Zhao, Y., Musilek, K., Nepovimova, E., Wu, Q., Wu, W., & Adam, V. (2022) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2021.107969 · Cited by 67 · see citing works
Self-citationTumor‑associated macrophages in lung cancer: Friendly or evil? (Review)
Xu, F., Wei, Y., Tang, Z., Liu, B., & Dong, J. (2020) · Molecular Medicine Reports · doi:10.3892/mmr.2020.11518 · Cited by 67 · see citing works
The controversial role of senescence-associated secretory phenotype (SASP) in cancer therapy
Cao, L., Li, K., Li, Q., Tong, Q., Wang, Y., & Huang, L. (2025) · Molecular Cancer · doi:10.1186/s12943-025-02475-8 · Cited by 70 · see citing works
“For example, epithelial cells may secrete IL-33, a family member of IL-1, which could limit tumor growth [176], whereas tumor cells may secrete IL-6 [177], IL-8 [13], and VEGF to promote cell proliferation, angiogenesis, and EMT transition [178, 179].”
Pe, K. C., Saetung, R., Yodsurang, V., Chaotham, C., Suppipat, K., Chanvorachote, P., & Tawinwung, S. (2022) · PLoS ONE · doi:10.1371/journal.pone.0273044 · Cited by 62 · see citing works
“Furthermore, primary macrophages secrete IL-6, which in turn increase IL-6 secretion from cancer cells [46], where IL-6 is shown to perpetuate this vicious cycle by generating more aggressive M2 macrophage polarization by activating Stat3 phosphorylation [44,47].”
BackgroundDing, J.-L., Yang, C.-G., Cheng, Y.-X., Wang, J.-Y., Zhang, S., Yan, S.-S., He, F., Yin, T., & Yang, J. (2020) · International Immunopharmacology · doi:10.1016/j.intimp.2020.106788 · Cited by 59
Tumor associated macrophage and microbe: The potential targets of tumor vaccine delivery
Jiang, J., Mei, J., Yi, S., Feng, C., Ma, Y., Liu, Y., Liu, Y., & Chen, C. (2021) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2021.114046 · Cited by 66 · see citing works
Alves, A., Diel, L., Ramos, G., Pinto, A. F. M., Bernardi, L., Yates, J., & Lamers, M. (2020) · Oral Oncology · doi:10.1016/j.oraloncology.2020.105038 · Cited by 58 · see citing works
Tumor hijacks macrophages and microbiota through extracellular vesicles
Jiang, J., Mei, J., Ma, Y., Jiang, S., Zhang, J., Yi, S., Feng, C., Liu, Y., & Liu, Y. (2022) · Exploration · doi:10.1002/exp.20210144 · Cited by 83 · see citing works
Baumeier, C., Escher, F., Aleshcheva, G., Pietsch, H., & Schultheiß, H. (2021) · Basic Research in Cardiology · doi:10.1007/s00395-020-00840-w · Cited by 60 · see citing works
Chen, X., Dou, J., Fu, Z., Qiu, Y., Zou, L., Huang, D., & Tan, X. (2022) · Journal of Applied Oral Science · doi:10.1590/1678-7757-2022-0316 · Cited by 65 · see citing works
Zhou, T.-Y., Zhou, Y.-L., Qian, M.-J., Fang, Y.-Z., Ye, S., Xin, W.-X., Yang, X.-C., & Wu, H.-H. (2018) · Journal of Pharmacological Sciences · doi:10.1016/j.jphs.2018.07.013 · Cited by 54 · see citing works
Liao, X.-X., Wang, W., Yu, B., & Tan, S.-Y. (2022) · Cancer Cell International · doi:10.1186/s12935-022-02622-x · Cited by 52 · see citing works
“In gastric cancer, IL-6 induces the differentiation of M2 macrophages and promotes the secretion of tumor-promoting cytokines, such as IL-10 and TGF-β, by M2 macrophages, thus facilitating tumor growth and tumor metastasis [18, 41].”
BackgroundTargeting the STAT3 oncogenic pathway: Cancer immunotherapy and drug repurposing
Dong, Y., Chen, J., Chen, Y., & Liu, S. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.115513 · Cited by 54 · see citing works
The Role of TAMs in Tumor Microenvironment and New Research Progress
Feng, Y.-W., Ye, Z.-Q., Song, F., He, Y., & Liu, J. (2022) · Stem Cells International · doi:10.1155/2022/5775696 · Cited by 50 · see citing works
“Macrophages are induced by TGF-β to differentiate into M2-type expression, namely, TAMs [72], which simultaneously inhibit the proliferation of CD4+ T cells and prevent T cells from attacking tumor cells; at the same time, it secretes growth factors to nourish tumor cells and promote tumor tissue angiogenesis [69].”
BackgroundRetractedBaj, J., Brzozowska, K., Forma, A., Maani, A., Sitarz, E., & Portincasa, P. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21072544 · Cited by 50 · see citing works
Sobieh, B. H., EL-Mesallamy, H. O., & Kassem, D. H. (2023) · Heliyon · doi:10.1016/j.heliyon.2023.e15700 · Cited by 49 · see citing works
Lescoat, A., Ballerie, A., Augagneur, Y., Morzadec, C., Vernhet, L., Fardel, O., Jego, P., Jouneau, S., & Lecureur, V. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19030894 · Cited by 49
Zhang, Y., Meng, W., Yue, P., & Li, X. (2020) · Journal of experimental & clinical cancer research : CR · doi:10.1186/s13046-020-01626-7 · Cited by 47 · see citing works
RetractedZhang, Y., & Zhang, X. (2018) · International Journal of Surgery · doi:10.1016/j.ijsu.2018.05.018 · Cited by 47
Macrophages in tumor cell migration and metastasis
Friedman, M., Karagiannis, G. S., Condeelis, J. S., Oktay, M. H., & Entenberg, D. R. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1494462 · Cited by 44 · see citing works
Numajiri, H., Kuzumi, A., Fukasawa, T., Ebata, S., Yoshizaki-Ogawa, A., Asano, Y., Kazoe, Y., Mawatari, K., Kitamori, T., Yoshizaki, A., et al. (2021) · Arthritis & Rheumatology · doi:10.1002/art.41798 · Cited by 45 · see citing works
“Indeed, previous studies have shown that IL6 induces profibrotic macrophage differentiation (41,42).”
BackgroundRole of exosomes in the immune microenvironment of ovarian cancer (Review)
Xiao, L., Liu, Y., Zheng, S., Zhang, T., Wu, J., Sun, Y., Zhang, J., & Liu, G. (2021) · Oncology Letters · doi:10.3892/ol.2021.12638 · Cited by 40 · see citing works
Resveratrol enhanced chemosensitivity by reversing macrophage polarization in breast cancer
Cheuk, I.-W., Chen, J., Siu, M., Ho, J., Lam, S., Shin, V., & Kwong, A. (2021) · Clinical and Translational Oncology · doi:10.1007/s12094-021-02731-5 · Cited by 44
Chen, R., Lu, X., Li, Z., Sun, Y., He, Z., & Li, X.-M. (2020) · OncoTargets and Therapy · doi:10.2147/ott.s249046 · Cited by 44
Jiang, B., Zhu, S.-H., Xiao, S., & Xue, M. (2019) · Inflammation · doi:10.1007/s10753-019-01004-2 · Cited by 43 · see citing works
Yang, H., Xu, H.-L., Wang, Z.-Y., Li, X., Wang, P., Cao, X.-L., Xu, Z.-Y., Lv, D., Rong, Y.-C., Chen, M., et al. (2023) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2023.110573 · Cited by 42 · see citing works
The Prognostic Value of CD206 in Solid Malignancies: A Systematic Review and Meta-Analysis
Debacker, J., Gondry, O., Lahoutte, T., Keyaerts, M., & Huvenne, W. (2021) · Cancers · doi:10.3390/cancers13143422 · Cited by 39 · see citing works
CAA-derived IL-6 induced M2 macrophage polarization by activating STAT3
Zhao, C.-R., Zeng, N., Zhou, X.-M., Tan, Y.-F., Wang, Y.-C., Zhang, J., Wu, Y.-P., & Zhang, Q. (2023) · BMC Cancer · doi:10.1186/s12885-023-10826-1 · Cited by 38
“In the immune system, IL-6 has a dual effect: a pro-inflammatory or an anti-inflammatory factor, mainly depending on the local immune microenvironment [17, 27].”
BackgroundMoonlighting Proteins Are Important Players in Cancer Immunology
Adamo, A., Frusteri, C., Pallotta, M. T., Pirali, T., Sartoris, S., & Ugel, S. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2020.613069 · Cited by 41 · see citing works
“Tgase2 inhibitors have shown to prevent tubule formation and such phenotype can be restored by exogenous TGF-b1.”
BackgroundInfluentialPrognostic Biomarkers in Evolving Melanoma Immunotherapy
Reschke, R., Enk, A. H., & Hassel, J. C. (2024) · American Journal of Clinical Dermatology · doi:10.1007/s40257-024-00910-y · Cited by 36 · see citing works
“Additionally, epithelial cells can produce interleukin-6, which promotes an M2 macrophage phenotype [46, 47].”
Carbon Dots Crosslinked Egg White Hydrogel for Tissue Engineering
Wu, J., Lei, J., Li, M.-X., Zhang, A., Li, Y., Liang, X., de Souza, S. C., Yuan, Z., Wang, C.-M., Chen, G.-K., et al. (2024) · Advancement of science · doi:10.1002/advs.202404702 · Cited by 34 · see citing works
El‐Asrar, A. M. A., Ahmad, A., Allegaert, E., Siddiquei, M. M., Gikandi, P. W., Hertogh, G. D., & Opdenakker, G. (2019) · Ocular Immunology and Inflammation · doi:10.1080/09273948.2019.1616772 · Cited by 38 · see citing works
“STAT3 and its downstream genes promote cancer growth, survival, angiogenesis and metastasis.(66) Similarly, signaling pathways mediated by STAT3 play a primary role in diabetic retinopathy progression.”
BackgroundThe lactylation-macrophage interplay: implications for gastrointestinal disease therapeutics
Che, X., Zhang, Y., Chen, X., Xie, G., Li, J., Xu, C., Zhang, C., Zhu, Y., & Yang, X. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1608115 · Cited by 25 · see citing works
Targeting crosstalk of STAT3 between tumor-associated M2 macrophages and Tregs in colorectal cancer
Huang, L.-L., Zhao, Y., Shan, M., Wang, S., Chen, J., Liu, Z., & Xu, Q. (2023) · Cancer Biology & Therapy · doi:10.1080/15384047.2023.2226418 · Cited by 31 · see citing works
Self-citationRole of IL-37 in Cardiovascular Disease Inflammation.
Yang, Z., Kang, L.-P., Wang, Y., Xiang, J., Wu, Q., Xu, C., Zhou, Y.-Q., Chen, S.-Y., Fang, H.-C., Liu, J., et al. (2019) · Canadian Journal of Cardiology · doi:10.1016/j.cjca.2019.04.007 · Cited by 31
Wang, Z., Yang, K., Lei, Z., Wen, D.-W., Lin, P., & Wang, J.-B. (2021) · Cell Cycle · doi:10.1080/15384101.2020.1867788 · Cited by 30
“Based on previous research, IL-6 induces macrophage to differentiate into M2 for inhibiting inflammation [33,34].”
MethodTiong, T.-Y., Chan, M., Wang, C., Yadav, V. K., Pikatan, N. W., Fong, I.-H., Yeh, C.-T., Kuo, K.-T., & Huang, W.-C. (2023) · Life Science · doi:10.1016/j.lfs.2023.121945 · Cited by 28
Wei, R.-Y., Song, J.-Q., Pan, H., Liu, X.-W., & Gao, J.-P. (2024) · Oncoimmunology · doi:10.1080/2162402x.2024.2352179 · Cited by 27 · see citing works
“Given the crucial role of adjuvant therapy in patients with advanced GC, 2 we examined the correlation between CPT1C + CAFs infiltration and treatment efficacy.”
BackgroundInfluentialCancer invasion and anaerobic bacteria: new insights into mechanisms
Hurst, R., Brewer, D. S., Gihawi, A., Wain, J. R., & Cooper, C. S. (2024) · Journal of Medical Microbiology · doi:10.1099/jmm.0.001817 · Cited by 28 · see citing works
Griffiths, J. I., Cosgrove, P. A., Medina, E. F., Nath, A., Chen, J., Adler, F. R., Chang, J. T., Khan, Q. J., & Bild, A. H. (2025) · Nature Communications · doi:10.1038/s41467-025-56279-x · Cited by 26 · see citing works
Recent advances in potential targets for myocardial ischemia reperfusion injury: Role of macrophages
Zhuang, Q., Li, M., Hu, D., & Li, J. (2024) · Molecular Immunology · doi:10.1016/j.molimm.2024.02.007 · Cited by 28 · see citing works
Niu, X., Zhu, Z., & Bao, J. (2020) · Cancer Cell International · doi:10.1186/s12935-021-01813-2 · Cited by 26 · see citing works
“The decreased level of albumin correlated with the production of pro-inflammatory cytokines, such as interleukin-6, a cytokine associated with progression of cancers [32].”
BackgroundMartin, D., Rödel, F., Balermpas, P., Winkelmann, R., Fokas, E., & Rödel, C. (2019) · Frontiers in Oncology · doi:10.3389/fonc.2019.01200 · Cited by 26
“Interleukin 6 upregulates tumor-promoting M2 macrophages via either STAT3 phosphorylation (40) or direct inhibition of apoptosis and stimulation of proliferation, also mainly mediated by STAT3 (41).”
BackgroundBurger, B., Kühl, C. M. C., Candreva, T., Cardoso, R. D. S., Silva, J. R., Castelucci, B. G., Consonni, S. R., Fisk, H. L., Calder, P. C., Vinolo, M. A. R., et al. (2019) · Scientific Reports · doi:10.1038/s41598-019-45508-1 · Cited by 29 · see citing works
The Complex Role of Thrombin in Cancer and Metastasis: Focus on Interactions with the Immune System
Aleksandrowicz, K., Hempel, D., Polityńska, B., Wojtukiewicz, A. M., Honn, K. V., Tang, D. G., & Wojtukiewicz, M. Z. (2023) · Seminars in Thrombosis and Hemostasis · doi:10.1055/s-0043-1776875 · Cited by 26 · see citing works
“26,33 M2 macrophages, through the secretion of aginase-1, IL-10, and TGF-β , reduce the immunogenicity of the tumor.”
BackgroundReicherz, A., Eltit, F., Scotland, K. B., Almutairi, K., Bell, R. H., Mojtahedzadeh, B., Cox, M. E., Chew, B., & Lange, D. (2023) · Scientific Reports · doi:10.1038/s41598-023-31885-1 · Cited by 25 · see citing works
“Urothelium 47 (10) 67 (25) 47 (22) 41 (5) 44 (5) 0.”
Jiménez-Uribe, A., Valencia-Martínez, H., Carballo-Uicab, G., Vallejo-Castillo, L., Medina-Rivero, E., Chacón-Salinas, R., Pavón, L., Velasco-Velázquez, M., Mellado-Sánchez, G., Estrada-Parra, S., et al. (2019) · Journal of Immunological Research · doi:10.1155/2019/2198508 · Cited by 25 · see citing works
“As an immunomodulatory cytokine, IL-6 has been related to tissue remodeling and macrophage polarization to M2 profile [40, 41].”
An, W., Yu, Y., Zhang, Y., Zhang, Z., Yu, Y., & Zhao, X. (2018) · British Journal of Pharmacology · doi:10.1111/bph.14549 · Cited by 30 · see citing works
“STAT3 is considered to be one of the primary signalling molecules for M2 macrophage polarization (Yang et al., 2012; Fu et al., 2017), and this transcription factor is also selectively activated by M2 macrophage-polarizing cytokines, such as IL-10, IL-4 and IL-13 (Sica and Bronte, 2007).”
BackgroundLiu, H., Yang, X.-C., Liu, D.-C., Tong, C., Wen, W., & Chen, R.-H. (2023) · Frontiers in Nutrition · doi:10.3389/fnut.2023.1156006 · Cited by 22 · see citing works
“In addition, serum albumin plays an important role in inhibiting the production of pro-inflammatory cytokines and enhancing cell-mediated immunity (51).”
BackgroundImmunomodulatory role of thrombin in cancer progression
Alexander, E. T., & Gilmour, S. K. (2022) · Molecular Carcinogenesis · doi:10.1002/mc.23398 · Cited by 32 · see citing works
“microenvironment promotes the polarization of immunosuppressive M2 macrophages over that of pro‐inflammatory M1 macrophages.(88,89) Tumor‐associated M2 macrophages not only promote”
BackgroundThe multi-faceted immune modulatory role of S100A4 in cancer and chronic inflammatory disease
Wong, T. K. S., Kang, R., & Yun, K. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1525567 · Cited by 20 · see citing works
Prognostic value of CD163+ macrophages in solid tumor malignancies: A scoping review
Mathiesen, H., Juul‐Madsen, K., Tramm, T., Vorup‐Jensen, T., Møller, H. J., Etzerodt, A., & Andersen, M. N. (2025) · Immunology Letters · doi:10.1016/j.imlet.2025.106970 · Cited by 23 · see citing works
Ganguly, K., Shah, A., Atri, P., Rauth, S., Ponnusamy, M., Kumar, S., & Batra, S. (2022) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2022.03.022 · Cited by 22
Yang, J.-K., & Xing, Z.-Y. (2021) · Experimental biology and medicine · doi:10.1177/15353702211010420 · Cited by 22
Kewcharoenwong, C., Prabowo, S. A., Bancroft, G. J., Fletcher, H. A., & Lertmemongkolchai, G. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02109 · Cited by 26 · see citing works
“IL-6 can induce M2 macrophage differentiation through STAT3 activation and can enhance infiltration of CD163+CD206+macrophages in gastric tumor tissue (54).”
BackgroundHe, F.-F., Bao, D., Su, H., Wang, Y.-M., Lei, C., Zhang, C.-Y., Ye, C., Tang, H., Wan, C., You, C., et al. (2018) · Journal of Cellular Physiology · doi:10.1002/jcp.26546 · Cited by 22
“Not surprisingly, by immunoblotting it is showed that IL6 raises the expression of phosphorylated STAT3 and that is in line with studies from other cell lines (Fu et al., 2017).”
ResultShimizu, D., Kanda, M., & Kodera, Y. (2018) · World Journal of Gastrointestinal Oncology · doi:10.4251/wjgo.v10.i6.124 · Cited by 23 · see citing works
Zhang, X., Zhu, M., Hong, Z., & Chen, C. (2021) · Annals of Translational Medicine · doi:10.21037/atm-21-1256 · Cited by 23 · see citing works
Extracellular vesicles shed from gastric cancer mediate protumor macrophage differentiation
Ito, A., Kagawa, S., Sakamoto, S., Kuwada, K., Kajioka, H., Yoshimoto, M., Kikuchi, S., Kuroda, S., Yoshida, R., Tazawa, H., et al. (2021) · BMC Cancer · doi:10.1186/s12885-021-07816-6 · Cited by 21 · see citing works
“STAT3 is commonly activated in tumor-infiltrating macrophages [48, 49], and STAT3 can bind to the promoter of the CD274 gene required for PD-L1 gene expression in T-cell lymphoma [38, 50].”
BackgroundMak, T.-K., Li, K., Zhao, Z., Wang, K.-X., Zeng, L.-L., He, Q., Lu, W.-Q., Chen, W., He, Y.-L., Li, J., et al. (2024) · Cancer Letters · doi:10.1016/j.canlet.2024.217422 · Cited by 20 · see citing works
Su, P., Yu, T., Zhang, Y.-J., Huang, H., Chen, M.-X., Cao, C., Kang, W.-M., Liu, Y., & Yu, J.-C. (2024) · Cancer Cell International · doi:10.1186/s12935-024-03453-8 · Cited by 20
“IL-6 could induce macrophages differentiation into the pro-tumor M2 phenotype via activating STAT3 phosphorylation and then promote GC cells proliferation and migration [41].”
BackgroundM2 macrophages participate in ILC2 activation induced by Helicobacter pylori infection
Peng, R., Xu, C.-X., Zhang, L.-F., Liu, X., Peng, D., Chen, X., Liu, D., & Li, R. (2024) · Gut microbes · doi:10.1080/19490976.2024.2347025 · Cited by 20
“32,33 Our findings indicated that H. pylori infection could promote the polarization of macrophages to M2.”
BackgroundOh, J., Hwa, C., Jang, D., Shin, S., Lee, S.-J., Kim, J., Lee, S. E., Jung, H., Oh, Y., Jang, G., et al. (2022) · Experimental and Molecular Medicine · doi:10.1038/s12276-022-00795-z · Cited by 20 · see citing works
Classic and new mediators for in vitro modelling of human macrophages
Luque-Martin, R., Mander, P. K., Leenen, P. J. M., & de Winther, M. P. J. (2020) · Journal of Leukocyte Biology · doi:10.1002/jlb.1ru0620-018r · Cited by 23 · see citing works
Panipinto, P. M., Singh, A. K., Shaikh, F. S., Siegel, R., Chourasia, M., & Ahmed, S. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222212580 · Cited by 19
“While these results are open to different interpretations, the available literature detailing the role of STAT3 in LPS-induced TNFα and other forms of chemokine production in macrophage cells [38,39] further attest to our argument that takinib elicits its anti-inflammatory effects primarily through suppression of JAK/…”
ResultAnghel, F. M., Matei, S.-C., Olteanu, G., Barna, R. A., & Marian, C. (2025) · Biomedicines · doi:10.3390/biomedicines13123050 · Cited by 23 · see citing works
Pang, H., Dai, L., Chen, L., Chen, X., Chen, Z., Zhang, S.-R., & Sun, H. (2024) · BMC Cancer · doi:10.1186/s12885-024-12349-9 · Cited by 18 · see citing works
“In addition, a low serum albumin has been confirmed to prompt the production of pro-inflammatory cytokines and reduce cell-mediated immunity [35].”
BackgroundLi, J., Bao, Y., Peng, S.-S., Jiang, C., Zhu, L., Zou, S.-H., Xu, J.-J., & Li, Y. (2023) · Current Issues in Molecular Biology · doi:10.3390/cimb45060314 · Cited by 18 · see citing works
“The promoting effect of M2 macrophages on the development of tumors has been confirmed in many reports, including gastric cancer and OSCC [8,9].”
BackgroundChen, F., Xie, C., Ren, K., & Xu, X. (2023) · Nutrition and Cancer · doi:10.1080/01635581.2023.2212426 · Cited by 20 · see citing works
“The decreased level of serum albumin may be mediated by proinflammatory cytokines, such as interleukin-6, which is highly expressed in tumor tissues and is associated with cancer progression (33, 34).”
BackgroundChoi, H., Yang, S.-W., Joo, J., Park, M., Jin, Y.-H., Kim, J.-W., Lee, S.-Y., Lee, S.-V., Yun, T.-J., Cho, M., et al. (2022) · Clinical Immunology · doi:10.1016/j.clim.2022.109215 · Cited by 18 · see citing works
Shan, Z., Yan, Z.-B., Peng, L.-S., Cheng, P., Teng, Y.-S., Mao, F.-Y., Fan, K., Zhuang, Y., & Zhao, Y.-L. (2021) · Journal of Immunological Research · doi:10.1155/2021/6613247 · Cited by 18
“Firstly, we confirmed that tumorinfiltrating neutrophils exhibited an activated phenotype characterized by the increase of molecule CD54, compared with peripheral cohorts [21].”
BackgroundMethodSelf-citationThe role of tumor-associated macrophages in lung cancer
Zhu, R., Huang, J., & Qian, F. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1556209 · Cited by 17 · see citing works
- Authors
- Fu, X.-L., Duan, W., Su, C.-Y., Mao, F.-Y., Lv, Y.-P., Teng, Y.-S., Yu, P.-W., Zhuang, Y., & Zhao, Y.-L.
- Affiliations
- Army Medical University (CN)
- Corresponding author
- Zhuang, Yuan
- Venue
- Cancer Immunology, Immunotherapy
- Published
- 2017-08-21
- Volume
- 66
- Issue
- 12
- Pages
- 1597-1608
- ISSN
- 0340-7004 (ISSN-L)
- 1432-0851
- PMC
- PMC11028627
- OpenAlex
- W2748596787
- Cited by
- 242
- References
- 0
- Citations by year
- 2026: 31 · 2025: 34 · 2024: 32 · 2023: 32 · 2022: 26 · 2021: 37 · 2020: 26 · 2019: 15 · 2018: 9
- FWCI
- 6.19
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Immunology Immunotherapy (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- interleukin-6, M2 macrophages, STAT3 phosphorylation, gastric cancer, tumor microenvironment, IL-10, TGF-beta, IL-12, tumor progression, tumor cell proliferation, tumor cell migration, prognostic factors
- MeSH terms
- Cell Differentiation, Cell Movement, Humans, Macrophages, Recombinant Proteins, Stomach Neoplasms, Transfection, Signal Transduction, Interleukin-6, Disease Progression, Cell Line, Tumor, Cell Proliferation, STAT3 Transcription Factor
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
