Claudins interact with LILRB immune inhibitory receptors to promote myeloid immunosuppression in cancer

The mechanisms underlying tumor cell-myeloid cell interactions within 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 B members LILRB2 and LILRB5. In multiple human cancer cohorts, the spatial proximity of LILRB2⁺ macrophages to CLDN-expressing cancer cells correlated with clinical outcomes, nominating this spatial relationship as a potential biomarker. In syngeneic LILRB2-transgenic and humanized mouse models, CLDN18.2–LILRB2 interaction triggered bidirectional signaling, enhanced the immunosuppressive activity of myeloid cells, and accelerated tumor progression. These effects were reversed by LILRB2 blockade. Mechanistically, the CLDN-LILRB2 axis sustained immunosuppression by regulating NF-κB and STAT signaling pathways. Our findings reveal a novel tight junction protein-mediated mechanism of myeloid cell regulation in the TME, offering a rationale for targeting this pathway in cancer therapy.