Calnexin-TREM1 engagement improves tumor antigen presentation and enhances the activation of anti-tumor T cells

Tumor-associated macrophages (TAMs) are associated with immunosuppression, but accumulating studies indicate they can support antitumor responses when reprogrammed. Here we identify TREM1, a myeloid immunoreceptor traditionally linked to inflammation, as a positive regulator of tumor antigen presentation. We also show that Calnexin is an agonistic ligand for TREM1 in the tumor microenvironment (TME). Using a recombinant Calnexin-based ligand called Tetra-CNX, we demonstrate that engagement of TREM1 reprograms TAMs into antigen-presenting cells that support cytotoxic and helper T cell responses, in part through a SYK-dependent program that enhances antigen processing and promotes MHC-I- and MHC-II–mediated T cell priming. This pathway is associated with a reduction in exhausted CD8⁺ T cells within the TME, suggesting improved anti-tumor T cell function. Our findings reposition TREM1 as a noncanonical modulator of adaptive immunity and highlight the therapeutic potential of engineered ligand-based strategies to restore myeloid cell function and enhance tumor-specific T cell responses.