Pathologically Activated Neutrophils Induce Contact-Dependent Suppression of Cytotoxic T Cells

The immunosuppressive tumor microenvironment remains a major obstacle to successful immunotherapy. Pathologically activated neutrophils, alternatively termed polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), drive tumor immune evasion principally through induction of CD8+ T cell tolerance. While direct intercellular contact between neutrophils and CD8+ T cells is essential for immunosuppressive activity, the mechanisms mediating this interaction need for deeper understanding. Here, we identify CD300ld, an immune inhibitory receptor on neutrophils, mediates neutrophil-driven contact-dependent suppression of cytotoxic CD8+ T cells via binding to phosphatidylserine (PS). Mice with mutant CD300ld, which lack PS-binding capacity, exhibit reduced immunosuppressive activity, phenocopying CD300ld knockout mice in multiple tumor models. Blockade of the PS-CD300ld interaction by neutralizing antibodies demonstrate therapeutic efficacy against established tumors and synergize with anti-PD-1 therapy. Clinical analyses reveal elevated CD300LD expression inversely associates with intertumoral PShigh CD8+ T cell infiltration and predicts poor responses to checkpoint blockade therapy. Our findings establish CD300ld-PS mediated T cell contact as a critical mechanism of neutrophil-driven immune evasion, revealing a targetable checkpoint pathway to overcome tumor immune resistance and improve immunotherapy outcomes.