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Blocking the IL‑6 pathway to treat immune checkpoint inhibitor‑induced inflammatory arthritis (Review)

  • Authors:
    • Liwen Zhao
    • Chuting Feng
    • Yong-Jing Gao
    • Tianzhen He
  • View Affiliations / Copyright

    Affiliations: Institute of Pain Medicine and Special Environmental Medicine, Co‑innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226019, P.R. China
    Copyright: © Zhao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 250
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    Published online on: July 8, 2025
       https://doi.org/10.3892/mmr.2025.13615
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Abstract

The incorporation of immune checkpoint inhibitors (ICIs) into cancer treatment has revolutionized oncology, providing marked advantages in managing various types of cancer. Nevertheless, the increasing use of ICIs has led to the emergence of immune‑related side effects, including autoimmune diseases such as inflammatory arthritis. IL‑6 signaling is crucial in the development of inflammatory arthritis and is linked to both the benefits and adverse effects of ICIs. The present review summarizes the latest progress in the IL‑6 pathway in inflammatory arthritis and discusses the therapeutic potential of IL‑6 pathway inhibitors for ICI‑induced inflammatory arthritis.
View Figures

Figure 1

Cell signaling pathway mediated by
IL-6 and its receptors. IL-6 and its receptors trigger the
activation of three major intracellular signaling pathways,
including the JAK-STAT3 pathway, the Ras-MAPK pathway and the
PI3K-Akt pathway. The activation of these signaling pathways
resulted in the transcription of downstream target genes,
subsequently leading to the induction of inflammatory responses. gp
130, glycoprotein 130; IL-6R, interleukin 6 receptor; TYK2,
tyrosine kinase 2; JAK, Janus kinase; STAT3, signal transducer and
activator of transcription 3; GRB2, growth factor receptor-bound
protein 2; SOS, son of sevenless; MAPKKK, mitogen-activated protein
kinase kinase kinase; JNK, c-Jun N-terminal kinase; AP-1, activator
protein-1; RAS, rat sarcoma; RAF, rapidly accelerated fibrosarcoma;
MEK1/2, MAPK kinase 1/2; ERK1/2, extracellular signal-regulated
kinase1/2; PI3K, phosphoinositide 3-kinase; Akt, protein kinase B;
Blimp1, B-lymphocyte-induced maturation protein 1; RORγt, retinoic
acid receptor-related orphan receptor γt.

Figure 2

Underlying mechanism for treating
ICI-induced IA by targeting IL-6. Tumor cells upregulate PD-L1 and
CD80 to evade immune surveillance. Then, ICIs such as anti-CTLA-4
and anti-PD1 reverse this, activating immune response against tumor
cells. However, ICIs can also excessively enhance the immune
system, resulting in the emergence of irAEs, including autoimmune
diseases such as inflammatory arthritis. The IL-6 receptor
antagonists were demonstrated to be effectiveness against
ICI-induced IA, which was due to their inhibition of the PD-1/PD-L1
mediated T-cell suppression and the differentiation of Th17/B
cells. ICI-induced IA, ICI-induced inflammatory arthritis; ICIs,
immune checkpoint inhibitors; PD-L1, programmed death ligand 1;
PD-1, programmed cell death protein 1; irAEs, immune-related
adverse events; CTLA-4, cytotoxic T lymphocyte-associated
antigen-4; ACPA, anti-citrullinated peptide antibody; APC,
antigen-presenting cell.
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Copy and paste a formatted citation
Spandidos Publications style
Zhao L, Feng C, Gao Y and He T: Blocking the IL‑6 pathway to treat immune checkpoint inhibitor‑induced inflammatory arthritis (Review). Mol Med Rep 32: 250, 2025.
APA
Zhao, L., Feng, C., Gao, Y., & He, T. (2025). Blocking the IL‑6 pathway to treat immune checkpoint inhibitor‑induced inflammatory arthritis (Review). Molecular Medicine Reports, 32, 250. https://doi.org/10.3892/mmr.2025.13615
MLA
Zhao, L., Feng, C., Gao, Y., He, T."Blocking the IL‑6 pathway to treat immune checkpoint inhibitor‑induced inflammatory arthritis (Review)". Molecular Medicine Reports 32.3 (2025): 250.
Chicago
Zhao, L., Feng, C., Gao, Y., He, T."Blocking the IL‑6 pathway to treat immune checkpoint inhibitor‑induced inflammatory arthritis (Review)". Molecular Medicine Reports 32, no. 3 (2025): 250. https://doi.org/10.3892/mmr.2025.13615
Copy and paste a formatted citation
x
Spandidos Publications style
Zhao L, Feng C, Gao Y and He T: Blocking the IL‑6 pathway to treat immune checkpoint inhibitor‑induced inflammatory arthritis (Review). Mol Med Rep 32: 250, 2025.
APA
Zhao, L., Feng, C., Gao, Y., & He, T. (2025). Blocking the IL‑6 pathway to treat immune checkpoint inhibitor‑induced inflammatory arthritis (Review). Molecular Medicine Reports, 32, 250. https://doi.org/10.3892/mmr.2025.13615
MLA
Zhao, L., Feng, C., Gao, Y., He, T."Blocking the IL‑6 pathway to treat immune checkpoint inhibitor‑induced inflammatory arthritis (Review)". Molecular Medicine Reports 32.3 (2025): 250.
Chicago
Zhao, L., Feng, C., Gao, Y., He, T."Blocking the IL‑6 pathway to treat immune checkpoint inhibitor‑induced inflammatory arthritis (Review)". Molecular Medicine Reports 32, no. 3 (2025): 250. https://doi.org/10.3892/mmr.2025.13615
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