CD300LD (CD300 molecule like family member d) is a transmembrane signaling receptor predominantly expressed on neutrophils that functions as a critical regulator of immune responses in both tumor and infectious disease contexts. In cancer immunity, CD300LD is specifically upregulated on polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) and is essential for their recruitment into tumors and suppression of T cell activation via the STAT3-S100A8/A9 axis 1. CD300LD knockout inhibits multiple tumor types in a PMN-MDSC-dependent manner and synergizes with anti-PD1 therapy, while CD300LD upregulation correlates with poor patient survival in human cancers 1. CD300LD blockade also overcomes vaccine resistance in advanced tumors by inhibiting PMN-MDSC-mediated immunosuppression 2. Conversely, in infectious disease, CD300LD promotes protective immunity: it associates with the Fc receptor common gamma-chain and enhances neutrophil bacterial phagocytosis through Rac2 activation 3. CD300LD expression is decreased in septic patients and mice, and restoration via agonist antibody or cell transfer reduces bacterial loads and organ injury in sepsis 3. Additionally, CD300LD functions as a functional receptor for murine norovirus infection 4, and is upregulated in multi-drug-resistant tuberculosis 5. This dual functionality makes CD300LD an important target for cancer immunotherapy while potentially requiring preservation for antimicrobial immunity.