Leukocyte immunoglobulin-like receptor A3 inhibits the activity of immunosuppressive myeloid cells

Abstract Myeloid checkpoint blockade as monotherapy often yields limited benefit, suggesting that multiple inhibitory pathways cooperatively sustain myeloid immunosuppression in the tumor microenvironment (TME). However, strategies to concurrently target multiple myeloid checkpoints remain challenging. Leukocyte immunoglobulin-like receptor A3 (LILRA3) is a soluble LILRA/B family member with unclear immunoregulatory function. Here, we show that LILRA3 is significantly reduced in the serum and tumor tissues of cancer patients, and its systemic levels positively correlate with cytotoxic T cell infiltration and improved survival. LILRA3 suppresses immunosuppressive myeloid cells, enhances pro-inflammatory cytokine production, and inhibits M2 macrophage polarization, thereby indirectly promoting T cell proliferation. Mechanistically, LILRA3 binds to LILRB4 and multiple endogenous LILRB ligands, blocking downstream inhibitory signaling. LILRA3 restrains tumor growth in myeloid-specific LILRB2- and LILRB4-transgenic mice and in humanized mouse models. These findings identify LILRA3 as a natural multi-LILRB signaling antagonist that counteracts myeloid-driven immunosuppression and highlight its potential as a therapeutic immune modulator.