Claudins Interact With Lilrb Immune Inhibitory Receptors to Promote Myeloid Immunosuppression in Cancer

Authors

• Xiaoye Liu
• Ryan Huang
• Zhiqiang Ku
• Jingjing Xie
• Heyu Chen
• Yubo He
• Qi Lou
• Chengcheng Zhang
• Xing Yang
• Cheryl Lewis
• Jade Homsi
• Ankit Gupta
• Lei Dong
• Kenian Chen
• Annabel Tu
• Liming Du
• Hailong Yu
• Qing Hu
• Meng Fang
• Bufan Li
• A E M Adan Khan
• Caroline Simith
• Samuel John
• Lin Xu
• Ningyan Zhang
• Zhiqiang An
• Cheng Cheng Zhang

Language

English

Publication Date

4-3-2026

Journal

Science Immunology

DOI

10.1126/sciimmunol.adt7832

PMID

41931598

PMCID

PMC13282697

PubMedCentral® Posted Date

6-21-2026

PubMedCentral® Full Text Version

Author MSS

Abstract

The mechanisms underlying tumor cell-myeloid cell interactions in the tumor microenvironment (TME) remain unclear, and predictive biomarkers for patient response to myeloid checkpoint blockade are lacking. This study identified specific binding between tight junction claudins (CLDNs) and leukocyte immunoglobulin-like receptor subfamily B2 (LILRB2) and LILRB5. In multiple human cancer cohorts, the spatial proximity of LILRB2-positive macrophages to CLDN-expressing cancer cells correlated with clinical outcomes, highlighting this spatial relationship as a potential biomarker. In syngeneic LILRB2-transgenic and humanized mouse models, CLDN18.2-LILRB2 interactions triggered bidirectional signaling, enhanced the immunosuppressive activity of myeloid cells, and accelerated tumor progression. These effects were reversed by LILRB2 blockade. The CLDN-LILRB2 axis sustained immunosuppression by regulating NF-κB and STAT signaling pathways. Our findings reveal a mechanism of myeloid cell regulation by tight junction proteins in the TME, offering a rationale for targeting this pathway in cancer therapy.

Keywords

Animals, Humans, Receptors, Immunologic, Claudins, Mice, Tumor Microenvironment, Myeloid Cells, Neoplasms, Membrane Glycoproteins, Signal Transduction, Immune Tolerance, Cell Line, Tumor, Mice, Transgenic

Comments

This article has been corrected. See Sci Immunol. 2026 Jun 26;11(120):eaej3848.

Published Open-Access

yes

Recommended Citation

Liu, Xiaoye; Huang, Ryan; Ku, Zhiqiang; et al., "Claudins Interact With Lilrb Immune Inhibitory Receptors to Promote Myeloid Immunosuppression in Cancer" (2026). The Brown Foundation: Institute of Molecular Medicine. 86.
https://digitalcommons.library.tmc.edu/molecular_med/86