Jingkun Qin, Xinyu Hu, Lei Wang, Ying Cai, Ziming Hu, Xiuxiu Xu, Zhigang Nian, Zhenbang Liu, Xiaoyu Ding, Yan Jiang, Yuanhao Lin, Ke Ruan, Binqing Fu, Zhigang Tian, Yonggang Zhou, Haiming Wei
Lipid metabolic reprogramming can facilitate immune escape by promoting a suppressive phenotype in tumor-infiltrating immune cells, although this process remains poorly understood. Here, we identify the lipoprotein, Lipocalin-2 (LCN2), as an essential factor driving natural killer (NK) cell dysfunction and immunosuppressive phenotype. Spatial metabolomics with crystal structure analysis demonstrates that LCN2 binding to phosphatidylserine (PS) and PS enrichment is required for tumor-associated lipid reprogramming. Increased LCN2-PS binding limits IL-15-mediated JAK-STAT pathway activation in NK cells, while inhibiting tumor-infiltrating neutrophil maintenance of anti-tumor potential in NK cells via suppression of IFN-I response. Structure-based drug screening identifies semapimod as an LCN2 inhibitor that blocks interaction with PS, disrupting the LCN2-PS immunosuppressive axis and inducing tumor control. Overall, this study uncovers a lipid metabolic reprogramming mechanism that mediates innate immune evasion and proposes a tumor treatment strategy through enhanced innate immune surveillance.