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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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“IL6 can act as both a proinflammatory cytokine and an antiinflammatory myokine, and it is associated with many types of cancer development [36].”
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Gołąbek-Grenda, A., Kaczmarek, M., Dondajewska, E., Sakrajda, K., Mackiewicz, A. A., & Dams‐Kozlowska, H. (2021) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2021.9913 · Cited by 7
“IL‐6 has been indicated to serve a significant role in the breast cancer microenvironment (47).”
BackgroundNoori, S., Nourbakhsh, M., Farzaneh, S., & Zarghi, A. (2020) · Anti-Cancer Agents in Medicinal Chemistry · doi:10.2174/1871520620666200807103903 · Cited by 6
Glioblastoma cell-induced immunosuppression causing chemoresistance
Sordillo, P. P., & Sordillo, L. A. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-821567-8.00008-7 · Cited by 5
Li, A., Sun, R., Wu, Y., Zhang, Q., Mao, R., Sun, X.-D., Wang, L., & Ren, X.-Y. (2026) · Frontiers in Sports and Active Living · doi:10.3389/fspor.2026.1768179 · Cited by 5
Sarf, E., Dyachenko, E. I., & Bel'skaya, L. (2024) · Biomedicines · doi:10.3390/biomedicines12061329 · Cited by 5
“A number of studies have shown that breast cancer cell lines produce and secrete cytokines of the IL-6 family [55].”
BackgroundKhanom, M. A. A., Hossen, M. S., Barek, M. A., Ahamed, M. S., Alam, M. S., Bhowmik, K. K., Jafrin, S., Aziz, M. A., & Islam, M. S. (2024) · Health Science Reports · doi:10.1002/hsr2.1875 · Cited by 5
Fang, Y., Zhang, Q.-F., Chen, C.-F., Chen, Z., Zheng, R.-G., She, C., Zhang, R., & Wu, J.-D. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1189635 · Cited by 5
“Interleukin-6 (IL6) is a pro-inflammatory cytokine that is secreted by different cell types and is known to modulate the growth and differentiation of BC (39, 40).”
BackgroundMendelian Randomization Study on Causal Association of IL-6With Breast Cancer.
Zhang, M., Ma, N., & Wang, R.-X. (2023) · Clinical Breast Cancer · doi:10.1016/j.clbc.2023.01.015 · Cited by 5
Ang, K. P., Foong, C. P., & Hamid, R. A. (2022) · Life Sciences · doi:10.1016/j.lfs.2022.121161 · Cited by 5
Zhao, L.-W., Feng, C., Gao, Y.-J., & He, T. (2025) · Molecular Medicine Reports · doi:10.3892/mmr.2025.13615 · Cited by 4
“…tumor growth, such as JAK/STAT3, PI3K/AKT and Ras/MAPK, leading to enhanced cell survival, proliferation, invasion, migration and angiogenesis (81). it further promotes tumor invasion through upregulation of matrix metalloproteinases (MMPs), which degrade extracellular matrix components and…”
IL-6 underlies microenvironment immunosuppression and resistance to therapy in glioblastoma
Young, J. S., Cho, N., Lucas, C.-H. G., Najem, H., Mirchia, K., Chen, W. C., Seo, K., Zakimi, N., Daggubati, V., Casey-Clyde, T., et al. (2025) · bioRxiv · doi:10.1101/2025.03.12.642800 · Cited by 4
Zafar, S., Bai, Y.-H., Muhammad, S. A., Guo, J.-L., Khurram, H., Zafar, S., Muqaddas, I., Shaikh, R. S., & Bai, B. (2025) · PLoS ONE · doi:10.1371/journal.pone.0309049 · Cited by 4
Beta-blocker adjunct therapy as a prospective anti-metastatic with cardio-oncologic regulation
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“Precisely analysing the cancer aetiology, che-moresistance in ovarian cancer and stimulation of EMT in breast cancer cells were driven by elevated IL-6 expression, whereas IL-8 exhibited an omnipresence in almost all cancers through beta-2 adrenergic reception [82, 83].”
Jonas, K., Prinz, F., Ferracin, M., Krajina, K., Deutsch, A. J. A., Madl, T., Rinner, B., Slabý, O., Klec, C., & Pichler, M. (2023) · Non-Coding RNA · doi:10.3390/ncrna10010002 · Cited by 4
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“18,19 IL-6 IL-6 could therefore be considered as a biomarker to identify ACL injury patients with persistent joint inflammation/nonresponders and those responder patients whose joint inflammation resolves after ACLR.”
BackgroundEffect of Poly(methacrylic acid) on the Cytokine Level in an In Vivo Tumor Model
Zhukova, O., Arkhipova, E., Kovaleva, T., Zykova, D., & Dubovskaya, N. A. (2022) · Molecules · doi:10.3390/molecules27144572 · Cited by 4
“Increased levels of IL-6 in the serum and tumor site were demonstrated in several cancers, including breast cancer [12].”
BackgroundRaissa, R., Riawan, W., Safitri, A., Masruri, M., Beltrán, M., & Aulanniam, A. (2022) · F1000Research · doi:10.12688/f1000research.109557.1 · Cited by 4
“The development of effective therapeutic options requires an understanding of IL-6 survival signaling in malignancies.(49,50) Apoptosis inhibition is a well-studied strategy for cell survival.”
BackgroundEditorial: Understanding the Cytokine Release Syndrome: Toward Improving Cancer Immunotherapy
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Li, L., Yang, C., Wang, Z., Zhou, B., Zhang, Y., Liu, H. B., Sun, S., Chen, M., Hu, X., Jia, F., et al. (2026) · Cell Metabolism · doi:10.1016/j.cmet.2026.04.011 · Cited by 2
Effects of Epigallocatechin-3-O-Gallate on Bone Health
Wróbel, P., Czarczyńska-Goślińska, B., Chornovolenko, K., Liwarska, J., Kubiak, J., Koczorowski, T., Malińska, A., Gośliński, T. A., & Waszyk-Nowaczyk, M. (2025) · Applied Sciences · doi:10.3390/app15158182 · Cited by 3
IL‐6 and Olfactory Dysfunction: Focus on Changes, Effects, and Mechanisms
Song, X.-Y., Mou, Y., Wang, H., Wang, Y., Liu, W.-C., Yang, T., Sun, C.-Y., Ren, C., & Song, X. (2025) · Mediators of Inflammation · doi:10.1155/mi/5891188 · Cited by 5
Dorabadi, D. G., Foruzandeh, Z., Torki, Z., Ebrahimi, A., Hashemi, S., & Alivand, M. (2023) · Informatics in Medicine Unlocked · doi:10.1016/j.imu.2023.101434 · Cited by 3
Blockade of CD155 and Interleukin-6 Suppresses Breast Cancer Cell Growth
Khodakarami, A., Darvishi, S., Hassannia, H., Sadeghi, M., Esmaeeli, S., Hashemi, V., Hojjat-Farsangi, M., & Jadidi-Niaragh, F. (2023) · International Journal of Drug Research in Clinics · doi:10.34172/ijdrc.2023.e10 · Cited by 3
Self-citationLi, Y., Zhou, X., Chen, R., Zhang, X., & Cao, H. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.05.30.542607 · Cited by 3
“…only by STAREG regulate the production of interleukin-6, whose signaling pathway plays a significant role in immunopathogenesis and treatment of breast cancer (Masjedi et al ., 2018); and the KEGG pathway of focal adhesion (hsa04510) is a key factor of breast cancer risk (Sahana et al ., 2021).”
BackgroundShetty, K. S., Jose, A., Bani, M., & Vinod, P. K. U. (2023) · Molecular Genetics and Genomics · doi:10.1007/s00438-023-02022-4 · Cited by 3
“IL6 is involved in all aspects of tumorigenesis by regulating proliferation, apoptosis, metabolism, survival, angiogenesis, and metastasis (Kumari et al. 2016; Masjedi et al. 2018).”
BackgroundSil, S., Bertilla, J., & Rupachandra, S. (2022) · 3 Biotech · doi:10.1007/s13205-022-03421-x · Cited by 4
“It is produced by tumour cells, and this helps the tumour cells to grow, proliferate, survive, invade, metastasise, be angiogenic, and be resistant to drugs (Masjedi et al. 2018).”
BackgroundThe Iron-Inflammation Axis in Early-Stage Triple-Negative Breast Cancer
Duan, F., Zhong, M., Ye, J., Wang, L., Jiang, C., Yuan, Z., Bi, X., & Huang, J. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.784179 · Cited by 3
“Moreover, IL-6 also likely contributes to the dysregulated hepcidin/ ferroportin signaling in breast cancer and mediates further iron homeostasis (Masjedi et al., 2018).”
BackgroundAlder, J., Lacy, K. E., Josephs, D. H., Spicer, J. F., Bax, H. J., Karagiannis, S. N., & Chauhan, J. (2026) · Clinical and Translational Allergy · doi:10.1002/clt2.70170 · Cited by 1
Targeting Interleukin‐6 as a Novel Strategy to Overcome Eribulin Resistance in Breast Cancer
Hattori, A., Nagahashi, M., Komatsu, M., Urano, S., Kuroiwa, M., Matsushita, Y., Katagiri, T., Shimoda, M., & Miyoshi, Y. (2025) · Cancer Medicine · doi:10.1002/cam4.71273 · Cited by 2
Karlsen, J., Giskeødegård, G., Tandstad, T., Salvesen, Ø., Wethal, T., & Reidunsdatter, R. J. (2025) · Advances in Radiation Oncology · doi:10.1016/j.adro.2025.101894 · Cited by 2
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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