Researchers Uncover How Tumors Hijack The Immune System via Adhesion Proteins

The mechanisms underlying interactions between tumor cells and myeloid cells within the tumor microenvironment (TME) remain unclear, and predictive biomarkers for patient responses to myeloid checkpoint blockade therapy are lacking.

Recently, a team led by Chengcheng Zhang at the University of Texas Southwestern Medical Center published a study online in Science Immunology titled “Claudins interact with LILRB immune inhibitory receptors to promote myeloid immunosuppression in cancer.”

The study identifies a specific interaction between tight junction proteins known as claudins (CLDNs) and leukocyte immunoglobulin-like receptor subfamily B members LILRB2 and LILRB5. Across multiple human cancer cohorts, the spatial proximity between LILRB2-positive macrophages and CLDN-expressing cancer cells correlates with clinical outcomes, highlighting the potential of this spatial relationship as a biomarker.

In syngeneic LILRB2 transgenic and humanized mouse models, the interaction between CLDN18.2 and LILRB2 triggers bidirectional signaling that enhances the immunosuppressive activity of myeloid cells and accelerates tumor progression. These effects can be reversed by blocking LILRB2. The CLDN-LILRB2 axis maintains immunosuppression by regulating NF-κB and STAT signaling pathways. This study reveals a regulatory role of tight junction proteins in modulating myeloid cells within the tumor microenvironment and provides a theoretical basis for targeting this pathway in cancer therapy.

T cell–based immune checkpoint blockade therapies are effective in some cancer patients, suggesting the existence of additional immune evasion mechanisms within the TME. Myeloid cells are often the most abundant immune cell population in the TME, where systemic and local signals can drive large numbers of these cells toward an immunosuppressive phenotype.

These include monocytic and polymorphonuclear myeloid-derived suppressor cells (M-MDSCs and PMN-MDSCs), as well as specific subsets of macrophages, neutrophils, and dendritic cells. Therefore, targeting or reprogramming immunosuppressive myeloid cells represents a promising therapeutic strategy.

Leukocyte immunoglobulin-like receptor subfamily B (LILRB) proteins are a class of type I transmembrane receptors containing immunoreceptor tyrosine-based inhibitory motifs (ITIMs) and are expressed in hematopoietic cells. Upon ligand binding, LILRBs recruit Src homology 2 domain-containing phosphatases such as SHP-1, SHP-2, or SH2-containing inositol phosphatase (SHIP) to suppress immune activation. LILRBs are primate-specific, and their murine homologs, paired immunoglobulin-like receptor B (PirB) and glycoprotein 49B1 (gp49B1), differ in expression patterns and ligand recognition, limiting the utility of knockout mouse models for studying LILRB biology.

Figure 1. The scheme of the interaction of CLDNs and LILRB2 regulates the immunosuppressive myeloid cells and cancer cell proliferation to promote cancer development. (LIU, Xiaoye, et al., 2026)

Blocking signaling mediated by LILRB1, LILRB2, LILRB3, LILRB4, or leukocyte-associated immunoglobulin-like receptor 1 (LAIR1) in normal or malignant human immune cells enhances antitumor immune activation, establishing LILRBs as myeloid immune checkpoints. Several clinical trials have been initiated to evaluate the safety and efficacy of LILRB-based therapeutics. However, how LILRBs interact with cells in the tumor microenvironment to regulate tumor development remains unclear, and the characteristics of cancer patients who may benefit from LILRB2 blockade therapy are not yet defined.

Claudins (CLDNs) specifically bind to LILRB2 and LILRB5, including aberrantly expressed CLDN18.2 found in gastric, pancreatic, and biliary cancers. In healthy individuals, CLDNs are expressed on epithelial and endothelial cells, but their expression is dysregulated in cancer cells. The receptors for CLDNs had previously not been clearly identified.

This study demonstrates that CLDN18.2 activates LILRB2 signaling to sustain the immunosuppressive function of myeloid cells and promote tumor progression. LILRB2 mediates CLDN18.2-induced signaling in MIA PaCa-2 cells. The physical proximity between LILRB2-positive macrophages and CLDN-positive cancer cells is associated with poor therapeutic outcomes across five human cancer cohorts, revealing a clinically relevant CLDN-LILRB axis that regulates tumor progression.