Leukocyte-intrinsic ER stress responses contribute to chemotherapy-induced peripheral neuropathy
Chemotherapy-induced peripheral neuropathy (CIPN) is the most prevalent and limiting side effect of paclitaxel treatment in patients with cancer. CIPN affects sensory neurons through neuroinflammatory mechanisms, but how immune cells sense and interpret systemic paclitaxel exposure during treatment is unclear. Here, we found that paclitaxel administration activated the endoplasmic reticulum (ER) stress sensor inositol-requiring enzyme 1α (IRE1α) in circulating and dorsal root ganglion-resident myeloid cells, engendering an inflammatory milieu that promotes CIPN. Mechanistically, paclitaxel induced the overproduction of mitochondria-derived reactive oxygen species (ROS) that provoked ER stress and IRE1α hyperactivation in macrophages. This process reprogrammed macrophages toward an inflammatory state characterized by IRE1α-dependent production of TNF-α, IL-1β, PGE<sub>2</sub>, IL-6, IL-5, GM-CSF, MCP-1, and MIP-2. Ablation of IRE1α in leukocytes, or treatment with a selective IRE1α pharmacological inhibitor, prevented dorsal root ganglion neuroinflammation and CIPN-related pain behaviors in mice. Furthermore, the development and severity of CIPN in patients with gynecological cancer were associated with the status of IRE1α activation in their circulating leukocytes. Our study uncovers leukocyte-intrinsic IRE1α as a key mediator of CIPN and suggests that targeting its dysregulated activation could help mitigate CIPN in patients with cancer who are receiving paclitaxel.
Authors
- Fang‐Chi Hsu (ORCID: https://orcid.org/0000-0002-3310-184X)
- Anderson O. Cox (ORCID: https://orcid.org/0000-0001-5491-1019)
- Glenn Jay Lesser (ORCID: https://orcid.org/0009-0003-5471-8907)
- E. Alfonso Romero‐Sandoval (ORCID: https://orcid.org/0000-0002-3859-8023)
- Byuri Angela Cho (ORCID: https://orcid.org/0000-0002-1802-7709)
- Takao Iwawaki (ORCID: https://orcid.org/0000-0001-8753-1979)
- Samuel S. Lentz (ORCID: https://orcid.org/0000-0001-6397-6383)
- Roy E. Strowd (ORCID: https://orcid.org/0000-0001-6651-5267)
- David I. Shalowitz (ORCID: https://orcid.org/0000-0002-5189-4687)
- Lance David Miller (ORCID: https://orcid.org/0000-0003-3799-2528)
- Sarah D. Pennypacker (ORCID: https://orcid.org/0000-0002-4777-747X)
- James W. Morgan (ORCID: https://orcid.org/0000-0002-4772-1388)
- Michael Limia (ORCID: https://orcid.org/0009-0003-0740-3769)
- Alexander Emmanuelli (ORCID: https://orcid.org/0000-0002-7937-7681)
- Yusuke Shiozawa (ORCID: https://orcid.org/0000-0001-9814-9230)
- Oriana Gelblung
- Jeong Park (ORCID: https://orcid.org/0000-0002-7012-4784)
- Miriam M. Fonseca (ORCID: https://orcid.org/0000-0003-0738-2577)
- Taylor Brooks (ORCID: https://orcid.org/0009-0007-4352-9296)
- Juan R. Cubillos‐Ruiz (ORCID: https://orcid.org/0000-0002-4267-4893)
- Deepika Awasthi (ORCID: https://orcid.org/0000-0001-7125-9405)
- Cristina M. Furdui (ORCID: https://orcid.org/0000-0003-3771-7999)
- Xuewei Zhu (ORCID: https://orcid.org/0000-0002-8606-0930)
- Wesley Hsu (ORCID: https://orcid.org/0000-0001-7492-4837)
- Luis Carlos Tovias-Sanchez
- Lindsay Macnamara (ORCID: https://orcid.org/0000-0002-0819-8109)
- Alejandro Pluma-Pluma (ORCID: https://orcid.org/0000-0003-4829-9948)
- Michael Kelly (ORCID: https://orcid.org/0000-0003-4552-7546)
- Chen Tan (ORCID: https://orcid.org/0000-0003-0521-8044)
- Ryan Martinez
- M. Eber
Institutions
- Atrium Health Wake Forest Baptist (US)
- Kanazawa Medical University (JP)
- Cornell University (US)
- West Michigan Cancer Center (US)
- Weill Cornell Medicine (US)
- Wake Forest University (US)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Science Translational Medicine
- Published
- 2025-10-29
- DOI
- https://doi.org/10.1126/scitranslmed.ady5288
- Citations
- 4
- Primary Topic
- Cancer Treatment and Pharmacology
- Type
- article
- Field-Weighted Citation Impact
- 4.18