TREM2 protects from atherosclerosis by limiting necrotic core formation. Atherosclerosis is a chronic disease of the vascular wall driven by lipid accumulation and inflammation in the intimal layer of arteries, leading to complications such as myocardial infarction and stroke. TREM2, a lipid-sensing receptor, is highly expressed in macrophage foam cells in atherosclerosis. This study shows that TREM2 deficiency increases necrotic core formation, while TREM2 agonism decreases it. TREM2 is essential for macrophage efferocytosis and the survival of lipid-laden macrophages, maintaining the balance between foam cell death and clearance, thus controlling plaque necrosis. Atherosclerosis begins when low-density lipoproteins (LDLs) accumulate in the intima of arteries, become modified, and promote monocyte recruitment, which differentiates into macrophages. Macrophages take up modified lipoproteins and become foam cells, playing a key role in clearing cellular debris and apoptotic cells through efferocytosis. Impaired efferocytosis and foam cell death promote necrotic core formation, a feature of unstable atherosclerotic lesions. Using mouse models, the study found that TREM2 deficiency increased necrotic core formation in early atherosclerosis, while TREM2 agonism reduced it. TREM2 deficiency reduced macrophage efferocytosis and increased necrotic core size. TREM2 activation with the agonistic antibody 4D9 inhibited necrotic core formation. Single-cell RNA sequencing revealed that TREM2 affects gene expression in foamy macrophages, influencing lipid uptake, survival, and efferocytosis. In vitro experiments showed that TREM2 promotes macrophage foam cell survival and efferocytosis. TREM2 deficiency reduced oxLDL uptake and macrophage survival, while TREM2 activation increased these processes. TREM2 also enhances anti-inflammatory gene expression and efferocytosis, which are crucial for plaque stability. The study concludes that TREM2 limits atherosclerotic plaque necrosis by enhancing macrophage survival, lipid handling, and efferocytosis. TREM2 may be a therapeutic target for cardiometabolic diseases, as it reduces plaque necrosis and promotes lesion stabilization. The findings highlight the importance of TREM2 in maintaining vascular homeostasis and preventing atherosclerosis progression.TREM2 protects from atherosclerosis by limiting necrotic core formation. Atherosclerosis is a chronic disease of the vascular wall driven by lipid accumulation and inflammation in the intimal layer of arteries, leading to complications such as myocardial infarction and stroke. TREM2, a lipid-sensing receptor, is highly expressed in macrophage foam cells in atherosclerosis. This study shows that TREM2 deficiency increases necrotic core formation, while TREM2 agonism decreases it. TREM2 is essential for macrophage efferocytosis and the survival of lipid-laden macrophages, maintaining the balance between foam cell death and clearance, thus controlling plaque necrosis. Atherosclerosis begins when low-density lipoproteins (LDLs) accumulate in the intima of arteries, become modified, and promote monocyte recruitment, which differentiates into macrophages. Macrophages take up modified lipoproteins and become foam cells, playing a key role in clearing cellular debris and apoptotic cells through efferocytosis. Impaired efferocytosis and foam cell death promote necrotic core formation, a feature of unstable atherosclerotic lesions. Using mouse models, the study found that TREM2 deficiency increased necrotic core formation in early atherosclerosis, while TREM2 agonism reduced it. TREM2 deficiency reduced macrophage efferocytosis and increased necrotic core size. TREM2 activation with the agonistic antibody 4D9 inhibited necrotic core formation. Single-cell RNA sequencing revealed that TREM2 affects gene expression in foamy macrophages, influencing lipid uptake, survival, and efferocytosis. In vitro experiments showed that TREM2 promotes macrophage foam cell survival and efferocytosis. TREM2 deficiency reduced oxLDL uptake and macrophage survival, while TREM2 activation increased these processes. TREM2 also enhances anti-inflammatory gene expression and efferocytosis, which are crucial for plaque stability. The study concludes that TREM2 limits atherosclerotic plaque necrosis by enhancing macrophage survival, lipid handling, and efferocytosis. TREM2 may be a therapeutic target for cardiometabolic diseases, as it reduces plaque necrosis and promotes lesion stabilization. The findings highlight the importance of TREM2 in maintaining vascular homeostasis and preventing atherosclerosis progression.