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The significant role of interleukin-6 and its signaling pathway in the immunopathogenesis and treatment of breast cancer
Open accessAbstract
Despite remarkable improvements in cancer treatment approaches, breast cancer is still the main cause of cancer-related death in women. Its principal cause is the resistance of the cancer cells against conventional anticancer therapeutics, mainly in advanced disease stages. It has been shown that chronic inflammation in the tumor microenvironment facilitates tumor growth and induces resistance toward chemo- and radiotherapy. Overexpression of interleukin-6 (IL-6) cytokine in the tumor microenvironment has been demonstrated in numerous tumors including breast cancer. Tumor cells and tumor-associated fibroblasts are the major sources of IL-6 secretion in the tumor microenvironment. Several studies have demonstrated the immunopathogenic function of IL-6 and its signaling in the tumor growth, metastasis, and therapeutic resistance in the breast cancer. Therefore, it seems that targeting IL-6 and/or its receptor in combination with other potent anticancer therapies may be a potent therapeutic approach for breast cancer therapy.
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“IL-6 is also a key factor in inflammation, autoimmunity and cancer, with its effect mainly exerted through the IL-6–signal transducer and activator of transcription 3 (STAT3) pathway (18–26, 61–65).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [22]
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Ravi, K., Zhang, Y., Sakala, L., Manoharan, T. J. M., Pockaj, B. A., LaBaer, J., Park, J. G., & Nikkhah, M. (2025) · Advanced Science · doi:10.1002/advs.202413457 · Cited by 22
Interleukin-6 related signaling pathways as the intersection between chronic diseases and sepsis
Yang, J., Yang, L., Wang, Y., Huai, L. F., Shi, B., Zhang, D., Xu, W., & Cui, D. (2025) · Molecular Medicine · doi:10.1186/s10020-025-01089-6 · Cited by 28
Vecchi, L., Mota, S., Zóia, M. A. P., Martins, I. C., de Souza, J. B., Santos, T., Beserra, A. D. O., de Andrade, V. P., Goulart, L., & Araújo, T. (2022) · Cells · doi:10.3390/cells11101705 · Cited by 26
“IL-6 modulates the proliferation and differentiation of malignant cells [32] and its expression is frequently increased in different tumors including prostate cancer [33] and BC [34].”
BackgroundSalimifard, S., Kiani, F., Eshaghi, F., Izadi, S., Shahdadnejad, K., Masjedi, A., Heydari, M., Ahmadi, A., Hojjat-Farsangi, M., Hassannia, H., et al. (2020) · Life Science · doi:10.1016/j.lfs.2020.118423 · Cited by 26
Self-citationRetractedNguyen, T. T. K., Woo, S., Seo, S., Banstola, A., Kim, H., Duwa, R., Vu, A. T., Hong, I.-S., Kwon, T. K., & Yook, S. (2024) · Biomaterials · doi:10.1016/j.biomaterials.2024.122733 · Cited by 25
ERK5 modulates IL-6 secretion and contributes to tumor-induced immune suppression
Riegel, K., Yurugi, H., Schlöder, J., Jonuleit, H., Kaulich, M., Kirschner, F., Arnold-Schild, D., Tenzer, S., Schild, H., & Rajalingam, K. (2021) · Cell Death and Disease · doi:10.1038/s41419-021-04257-8 · Cited by 31
“Not only cancer cells themselves are considered primary sources of IL-6, but also tumor-associated macrophages (TAMs), MDSCs, and cancerassociated fibroblasts (CAFs) [13, 14].”
BackgroundSmac mimetics as novel promising modulators of apoptosis in the treatment of breast cancer
Nikkhoo, A., Rostami, N., Hojjat-Farsangi, M., Azizi, G., Yousefi, B., Ghalamfarsa, G., & Jadidi-Niaragh, F. (2018) · Journal of Cellular Biochemistry · doi:10.1002/jcb.28205 · Cited by 25
Self-citationThe Molecular and Genetic Interactions between Obesity and Breast Cancer Risk
Ajabnoor, G. (2023) · Medicina · doi:10.3390/medicina59071338 · Cited by 25
STAT3 as a therapeutic target in the metformin-related treatment.
Zhang, W.-R., Li, D., Li, B., Chu, X., & Kong, B. (2023) · International Immunopharmacology · doi:10.1016/j.intimp.2023.109770 · Cited by 25
Bellenghi, M., Talarico, G., Botti, L., Puglisi, R., Tabolacci, C., Portararo, P., Piva, A., Pontecorvi, G., Carè, A., Colombo, M., et al. (2022) · Oncogene · doi:10.1038/s41388-022-02401-y · Cited by 24
The Signal Transducer IL6ST (gp130) as a Predictive and Prognostic Biomarker in Breast Cancer
Martínez-Pérez, C., Leung, J., Kay, C., Meehan, J., Gray, M., Dixon, J. M., & Turnbull, A. (2021) · Journal of Personalized Medicine · doi:10.3390/jpm11070618 · Cited by 25
Tumour brain: Pretreatment cognitive and affective disorders caused by peripheral cancers
Mampay, M., Flint, M. S., & Sheridan, G. K. (2021) · British Journal of Pharmacology · doi:10.1111/bph.15571 · Cited by 28
“increased serum levels of IL-6 have been demonstrated in various cancers (Masjedi et al., 2018).”
BackgroundTumor exposed-lymphatic endothelial cells promote primary tumor growth via IL6
van de Velde, M., Ebroin, M., Durré, T., Joiret, M., Gillot, L., Blacher, S., Geris, L., Kridelka, F., & Noel, A. (2020) · Cancer Letters · doi:10.1016/j.canlet.2020.10.020 · Cited by 24
“IL6 is one of the major inflammatory interleukins that has been linked to cancer progression [35,40,41].”
BackgroundZhu, C., Ding, X., Chen, M., Feng, J., Zou, J., & Zhang, L. (2025) · Biomolecules · doi:10.3390/biom15060893 · Cited by 23
CircTMC5 promotes gastric cancer progression and metastasis by targeting miR-361-3p/RABL6
Xu, P., Xu, X.-L., Wu, X., Zhang, L.-X., Meng, L., Chen, Z.-M., Han, W.-X., Yao, J., & Xu, A. (2021) · Gastric Cancer · doi:10.1007/s10120-021-01220-6 · Cited by 23
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Interlinking pathways: a narrative review on the role of IL-6 in cancer and atherosclerosis
Cau, R., & Saba, L. (2024) · Cardiovascular Diagnosis and Therapy · doi:10.21037/cdt-24-344 · Cited by 27
“IL-6 is involved in various aspects of cancer development, including cell proliferation, survival, angiogenesis, and metastasis, and has been linked to a poor prognosis in several cancer types (8,31,39-44) ( Table 3 ).”
Alshaman, R., Alattar, A., El-Sayed, R. M., Gardouh, A. R., Elshaer, R. E., Elkazaz, A., Eladl, M., El-Sherbiny, M., Farag, N., Hamdan, A., et al. (2022) · Nanomaterials · doi:10.3390/nano12050857 · Cited by 22
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Advances in tumor-associated macrophage-mediated chemotherapeutic resistance in glioma
Liu, X., & Yu, Q. (2025) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2025.1676338 · Cited by 21
Ironing Out the Mechanism of gp130 Signaling
Osman, E. E. A., & Neamati, N. (2024) · Pharmacological Reviews · doi:10.1124/pharmrev.124.001245 · Cited by 21
Pro-Tumorigenic and Thrombotic Activities of Platelets in Lung Cancer
Anderson, R., Rapoport, B. L., Steel, H. C., & Theron, A. J. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241511927 · Cited by 22
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“Interestingly, IL6 is known to promote tumor growth by upregulating antiapoptotic and angiogenic proteins in tumor cells [75], and elevated IL10 may inhibit tumor growth by suppressing IL6 production.”
BackgroundInfluentialChang, P., Wu, H.-K., Chen, Y.-H., Hsu, Y., Cheng, M.-T., Yu, C.-H., & Chen, S.-K. (2022) · Molecular Biology Reports · doi:10.1007/s11033-022-07243-1 · Cited by 21
“It has been reported that IL-6 enhances proliferation through IL-6R/JAK/STAT3 signaling [33, 34].”
BackgroundThe IL6-like Cytokine Family: Role and Biomarker Potential in Breast Cancer
Martínez-Pérez, C., Kay, C., Meehan, J., Gray, M., Dixon, J. M., & Turnbull, A. (2021) · Journal of Personalized Medicine · doi:10.3390/jpm11111073 · Cited by 28
“While emerging drugs targeting IL6-like cytokines and their signalling have been reviewed recently [19,79,87,88,295,296], in this section we will summarise the main therapeutic approaches and highlight those agents with current or emerging applications in BC.”
BackgroundSisto, M., Tamma, R., Ribatti, D., & Lisi, S. (2020) · Archivum Immunologiae et Therapiae Experimentalis · doi:10.1007/s00005-020-00591-5 · Cited by 21
Li, X., & Zhao, C. (2025) · Autoimmunity Reviews · doi:10.1016/j.autrev.2025.103826 · Cited by 21
Molecular insights into the interplay between adiposity, breast cancer and bone metastasis
Soni, S., Torvund, M., & Mandal, C. C. (2021) · Clinical & Experimental Metastasis · doi:10.1007/s10585-021-10076-0 · Cited by 25
Afshari, H., Nourbakhsh, M., Salehi, N., Mahboubi‐Rabbani, M., Zarghi, A., & Noori, S. (2020) · PubMed Central · doi:10.22037/ijpr.2020.112587.13843 · Cited by 20
“First of all MCF-7 breast cancer cells were treated with IL-6 which is an established promoter of breast cancer progression and its inhibition leads to the induction of apoptosis (20).”
BackgroundGuillamón, E., Mut‐Salud, N., Rodríguez‐Sojo, M. J., Ruiz‐Malagón, A. J., Cuberos-Escobar, A., Martinez-Ferez, A., Rodríguez‐Nogales, A., Gálvez, J., & Baños, A. (2023) · Nutrients · doi:10.3390/nu15061363 · Cited by 25
“Some authors correlate IL-6 levels with tumor stage, the metastasis survival rate, or apoptosis in various types of cancer, such as breast [80] or colon [81], while the production of IL-8 has been linked to pro-tumorigenic roles which influence the tumor microenvironment [82].”
BackgroundYe, H., Gao, H., Li, H., Nie, J., Li, T., Lu, M., Wu, M., Liu, J., & Wang, K. (2022) · Phytotherapy Research · doi:10.1002/ptr.7515 · Cited by 20
“The challenge in BC management is that cancer cells become resistant to traditional anticancer therapies, mainly in the later stages of the disease (Masjedi et al., 2018).”
BackgroundZhu, K., Cai, Y., Si, X., Ye, Z., Gao, Y., Liu, C., Wang, R. Y., Ma, Z., Zhu, H., Zhang, L. N., et al. (2022) · Cell Death and Differentiation · doi:10.1038/s41418-022-01000-4 · Cited by 19
Local Biomarkers Involved in the Interplay between Obesity and Breast Cancer
Holm, J. B., Rosendahl, A. H., & Borgquist, S. (2021) · Cancers · doi:10.3390/cancers13246286 · Cited by 20
Metadata
- Authors
- Masjedi, A., Hashemi, V., Hojjat-Farsangi, M., Ghalamfarsa, G., Azizi, G., Yousefi, M., & Jadidi-Niaragh, F.
- Affiliations
- Tabriz University of Medical Sciences (IR)
- University of Maragheh (IR)
- Yasuj University of Medical Sciences (IR)
- Alborz University of Medical Sciences (IR)
- ORCID
- Venue
- Biomedicine & Pharmacotherapy
- Publisher
- Elsevier BV
- Published
- 2018-12
- Volume
- 108
- Pages
- 1415-1424
- ISSN
- 0753-3322 (ISSN-L)
- OpenAlex
- W2894776217
- Cited by
- 303
- References
- 136
- Citations by year
- 2026: 20 · 2025: 33 · 2024: 32 · 2023: 60 · 2022: 67 · 2021: 41 · 2020: 39 · 2019: 9 · 2018: 1
- FWCI
- 2.37
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Biomedicine & Pharmacotherapy (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- National Institute for Medical Research Development
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- interleukin-6, IL-6 signaling, breast cancer, tumor microenvironment, chronic inflammation, cancer-associated fibroblasts, chemoresistance, radioresistance (biology), metastasis, immunopathogenesis, combination therapy
- MeSH terms
- Janus Kinase Inhibitors, Interleukin-6 Inhibitors, Antibodies, Monoclonal, Breast Neoplasms, Female, Humans, Signal Transduction, Interleukin-6, Receptors, Interleukin-6, Tumor Microenvironment, Antibodies, Monoclonal, Humanized
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