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Collagens are a primary component of the extracellular matrix and are functional ligands for the inhibitory immune receptor leukocyte associated immunoglobulin-like receptor-1 (LAIR-1). Leukocyte associated immunoglobulin-like receptor-2 (LAIR-2) is a secreted protein that can act as a decoy receptor by binding collagen with higher affinity than LAIR-1. We propose that collagens promote immune evasion by interacting with LAIR-1 and that LAIR-2 could release LAIR-1 mediated immune suppression. Analysis of public datasets shows high LAIR-2 expression being associated with a favorable outcome in certain tumors. We designed a dimeric LAIR-2 with a functional IgG1 Fc tail, NC410, and showed that NC410 reduces tumor growth and increases T cell expansion and effector function in humanized tumor models. Immunohistochemical analysis of human tumors shows that NC410 binds to collagen-rich areas where LAIR-1+immune cells are localized. Our findings show that NC410 might be a powerful new strategy for cancer immunotherapy for immune-excluded tumors.