Lu Y, Zhou XL, Chen F. Letter to the Editor: Spinal IL-33/ST2 blockade for gallbladder carcinoma pain - balancing central analgesia with systemic tumor immune microenvironment risks. World J Gastrointest Oncol 2026; 18(7): 121633 [DOI: 10.4251/wjgo.v18.i7.121633]
Corresponding Author of This Article
Fan Chen, Researcher, The First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Provincial Hospital of Chinese Medicine, No. 548 Binwen Road, Binjiang District, Hangzhou 310006, Zhejiang Province, China. chenfan@zcmu.edu.cn
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Gastroenterology & Hepatology
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letter
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Lu Y, Zhou XL, Chen F. Letter to the Editor: Spinal IL-33/ST2 blockade for gallbladder carcinoma pain - balancing central analgesia with systemic tumor immune microenvironment risks. World J Gastrointest Oncol 2026; 18(7): 121633 [DOI: 10.4251/wjgo.v18.i7.121633]
World J Gastrointest Oncol. Jul 15, 2026; 18(7): 121633 Published online Jul 15, 2026. doi: 10.4251/wjgo.v18.i7.121633
Letter to the Editor: Spinal IL-33/ST2 blockade for gallbladder carcinoma pain - balancing central analgesia with systemic tumor immune microenvironment risks
Fan Chen, Xin-Lei Zhou, Yi Lu
Yi Lu, Xin-Lei Zhou, The Third Clinical Medical School, The Rehabilitation Medical School, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang Province, China
Fan Chen, The First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Provincial Hospital of Chinese Medicine, Hangzhou 310006, Zhejiang Province, China
Co-first authors: Yi Lu and Xin-Lei Zhou.
Author contributions: Lu Y and Zhou XL wrote the original draft, they contributed equally to this article, they are the co-first authors of this manuscript; Chen F reviewed and edited the manuscript; and all authors have read and approved the final manuscript.
AI contribution statement: AI tools (specifically DeepL and ChatGPT) were used solely for linguistic refinement and formatting assistance. I tools were used strictly for language polishing and translation. Crucially, every AI-assisted sentence has been manually reviewed and modified by the author. Furthermore, the final manuscript underwent professional polishing by a certified academic editing agency to ensure quality.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Corresponding author: Fan Chen, Researcher, The First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Provincial Hospital of Chinese Medicine, No. 548 Binwen Road, Binjiang District, Hangzhou 310006, Zhejiang Province, China. chenfan@zcmu.edu.cn
Received: March 30, 2026 Revised: April 17, 2026 Accepted: May 19, 2026 Published online: July 15, 2026 Processing time: 106 Days and 22.5 Hours
Abstract
Recently, Ge et al published a study in the World Journal of Gastrointestinal Oncology elucidated the critical role of the spinal interleukin-33/suppression of tumorigenicity 2 (ST2) signaling pathway in gallbladder carcinoma (GBC)-induced chronic pain, providing a highly promising non-opioid analgesic target for advanced refractory cancer pain. We highly commend their establishment of a clinically relevant orthotopic GBC pain model and their profound insights into central sensitization mechanisms. However, before advancing this promising target to clinical translation, the complex “double-edged sword” effects of systemic targeted delivery within tumor biology and systemic immunology must be critically evaluated. This letter highlights that the immunodeficient nude mouse model utilized in the original study fundamentally masks the risk of compromising CD8+ T cell-mediated intrinsic anti-tumor immunity caused by systemic interleukin-33/ST2 blockade. Furthermore, the potential impact of targeted interventions on local dense stromal remodeling in GBC, along with the unknown activation of tumor-intrinsic ST2 signaling, could lead to unexpected pro-tumorigenic consequences. Therefore, we strongly recommend that future translational studies be conducted in immunocompetent syngeneic mouse models, performing head-to-head comparisons between intrathecal targeted delivery and systemic administration. Additionally, utilizing spatial transcriptomics or multiplex immunohistochemistry to clarify the precise cellular localization of ST2 is essential to bridge the gap between neurobiological analgesic mechanisms and the global tumor immune microenvironment.
Core Tip: This article highlights a critical translational blind spot in targeting the spinal interleukin-33/suppression of tumorigenicity 2 axis for gallbladder carcinoma-induced pain. While local blockade exhibits analgesic efficacy, systemic administration risks impairing CD8+ T cell-mediated intrinsic anti-tumor immunity - a critical risk fundamentally masked by the original study’s use of athymic nude mice. Furthermore, potential tumor-intrinsic suppression of tumorigenicity 2 activation and stromal remodeling necessitate extreme caution. We strongly advocate that future evaluations utilize immunocompetent syngeneic models to compare intrathecal vs systemic delivery, aiming to safely bridge the gap between analgesic mechanisms and the tumor immune microenvironment.
