LMO7 Suppresses Tumor‐Associated Macrophage Phagocytosis of Tumor Cells Through Degradation of LRP1

Abstract Tumor‐associated macrophages (TAMs) are one of the most abundant immune cells in solid tumors and play a critical role in tumor progression. This study found that the expression of LIM domain‐only protein 7 (LMO7) in TAMs is associated with poor patient survival. LMO7 deficiency significantly inhibited tumor growth and increased the accumulation of antitumor TAMs and CD8 + T cells. Specifically, single‐cell RNA sequencing (scRNA‐seq) reveals that LMO7‐deficient TAMs undergo an antitumor reprogramming, characterized by upregulated expression of pro‐inflammatory and phagocytosis‐related genes. Notably, LMO7 deficiency enhances immune‐mediated tumor confinement by regulating the phagocytic activity of TAMs. Mechanistically, LMO7 inhibits TAM phagocytosis by promoting the lysine 48‐linked polyubiquitination at lysine 45 of the β chain of the phagocytic receptor low‐density lipoprotein receptor‐related protein 1 (LRP1), leading to degradation via the ubiquitin‐proteasome system. Furthermore, combined targeting of LMO7 deficiency and SIRPα blockade demonstrates synergistic antitumor efficacy. Collectively, these findings demonstrate the critical role of LMO7 in orchestrating TAM phagocytosis and suggest that LMO7 inhibition is a promising drug target to enhance cancer immunotherapy.