Trans-presentation of IL-6Rα by macrophages drives colorectal cancer development

  • Cell Rep. 2026 Jun 19;45(7):117549. doi: 10.1016/j.celrep.2026.117549.
Fanwu Gong  1 ,  Qiming Zhang  1 ,  Jiaojiao Qian  1 ,  Yuanyuan He  1 ,  Kaiming Du  1 ,  Haopeng Fang  1 ,  Qiangsheng Li  1 ,  Yang Yang  1 ,  Hua-Xing Wei  1 ,  Tengchuan Jin  2 ,  Yi Wang  3 ,  Bofeng Li  4
Affiliations
  • 1. State Key Laboratory of Immune Response and Immunotherapy, Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, China.
  • 2. Department of Infectious Diseases, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, University of Science and Technology of China, Hefei, Anhui 230001, P.R. China. Electronic address: [email protected].
  • 3. National Key Laboratory of Immune Response and Immunotherapy, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. Electronic address: [email protected].
  • 4. State Key Laboratory of Immune Response and Immunotherapy, Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, China; Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, Anhui 230001, China. Electronic address: [email protected].
PMID: 42319827 DOI: 10.1016/j.celrep.2026.117549
Abstract

IL-10-signaling-deficiency-induced macrophage hyperactivation drives epithelial barrier disruption and severe colitis, but its role in colitis-associated colorectal Cancer (CAC) remains unclear. Here, we report that macrophage-specific IL-10Rα deletion aggravates AOM-DSS-induced CAC in mice. These IL-10Rα-deficient macrophages exhibited a pro-inflammatory phenotype and secreted excessive IL-6 to stimulate intestinal epithelial cell (IEC) proliferation and tumorigenesis via the IL-6/p-STAT3 pathway. Genetic ablation or neutralization of macrophage-specific IL-6Rα reduced IEC p-STAT3 levels and tumor burden, whereas epithelial IL-6Rα deficiency or sgp130 treatment did not. IEC-BMDM co-culture and imaging flow cytometry identify a previously unrecognized macrophage-derived IL-6 trans-presentation as the dominant driver of IEC proliferation and tumorigenesis, rather than classical/trans-signaling. Targeting macrophage IL-6Rα in combination with PD-L1 blockage exerts complementary effects in CAC. Collectively, our data reveal that macrophage-specific IL-10 signaling protects against CAC by suppressing macrophage-dependent IL-6 trans-presentation, which drives excessive IEC proliferation and tumor development.

Keywords
CP: cancer; CP: immunology; IL-10 signaling; IL-6 trans-presentation; IL-6Rα; STAT3 signaling; cancer immunotherapy; colitis-associated colorectal cancer; colorectal cancer; intestinal epithelial cells; macrophages; tumorigenesis.
Products
Inhibitors & Agonists
Other Products