Vol.:(0123456789) Medical Oncology (2024) 41:182 https://doi.org/10.1007/s12032-024-02422-5 REVIEW ARTICLE Interleukin‑6 serves as a critical factor in various cancer progression and therapy Asma’a H. Mohamed 1  · Abdulrahman T. Ahmed 2  · Waleed Al Abdulmonem 3  · Dmitry Olegovich Bokov 4,5  · Alaa Shafie 6  · Hussein Riyadh Abdul Kareem Al‑Hetty 7  · Chou‑Yi Hsu 8  · Mohammed Alissa 9  · Shahid Nazir 10  · Mohammad Chand Jamali 11  · Mustafa Mudhafar 12,13 Received: 24 April 2024 / Accepted: 6 June 2024 © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2024 Abstract Interleukin-6 (IL-6), a pro-inflammatory cytokine, plays a crucial role in host immune defense and acute stress responses. Moreover, it modulates various cellular processes, including proliferation, apoptosis, angiogenesis, and differentiation. These effects are facilitated by various signaling pathways, particularly the signal transducer and activator of transcription 3 (STAT3) and Janus kinase 2 (JAK2). However, excessive IL-6 production and dysregulated signaling are associated with various cancers, promoting tumorigenesis by influencing all cancer hallmarks, such as apoptosis, survival, proliferation, angiogenesis, invasiveness, metastasis, and notably, metabolism. Emerging evidence indicates that selective inhibition of the IL-6 signaling pathway yields therapeutic benefits across diverse malignancies, such as multiple myeloma, prostate, colorectal, renal, ovarian, and lung cancers. Targeting key components of IL-6 signaling, such as IL-6Rs, gp130, STAT3, and JAK via monoclonal antibodies (mAbs) or small molecules, is a heavily researched approach in preclinical cancer stud- ies. The purpose of this study is to offer an overview of the role of IL-6 and its signaling pathway in various cancer types. Furthermore, we discussed current preclinical and clinical studies focusing on targeting IL-6 signaling as a therapeutic strategy for various types of cancer. Keywords IL-6 · Cancer · Inflammatory cytokines · Targeted therapy · STAT3 Abbreviations IL-6 Interleukin-6 NF-kB Nuclear factor-kappa B mAbs Monoclonal antibodies BSF-2 B cell stimulatory factor-2 mIL-6R Transmembrane IL-6R JAK Janus kinase STAT3 Signal transducer and activator of transcrip- tion 3 SOCS3 Suppressor of cytokine signaling p38-MAPK Ras/activate p38 mitogen-activated protein kinases PI3K Phosphoinositol-3 kinase PkB Protein kinase B PIP2 Phosphatidylinositol-4,5-bisphosphate PIP3 Phosphatidylinositol-3,4,5-trisphosphate TAM Tumor‐associated macrophage TAECs Tumor‐associated endothelial cells DCs Dendritic cells MDSCs Myeloid-derived suppressor cells CRC Colorectal cancer HCC Hepatocellular carcinoma MM Multiple myeloma CRP C-reactive protein MSCs Mesenchymal stem cells DCIS Ductal carcinoma in situ EMT Epithelial–mesenchymal transition NSCLC Non-small cell lung cancer AML Acute myeloid leukemia Significant Statement: Despite progress in cancer treatment, it remains the primary global cause of mortality. Persistent inflammation in the TME drives tumor progression, metastasis, and resistance to treatment. IL-6 is a crucial pro-inflammatory cytokine that influences cancer cell behavior, yet its excessive production worsens malignancy. Both stromal and tumor cells within the TME produce IL-6. Targeting IL-6/IL-6 receptor signaling holds therapeutic potential across various cancers like prostate, colorectal, and lung cancers. In this regard, the importance of IL-6's role in cancer development was underlined in this study. Extended author information available on the last page of the article