Abstract: Tumor-associated macrophages (TAMs) have become the core hub connecting the local microenvironment and system metabolism through lipid metabolism reprogramming. By enhancing lipid uptake and lipophagy-mediated cholesterol redistribution, TAMs support tumor cell membrane synthesis, signaling activation, and invasive potential. Immune checkpoints upregulation driven by peroxisome proliferator-activated receptor γ, nutrient deprivation, and adenosine production contribute to the formation of an immunosuppressive niche. At the systemic level, tumors orchestrate a bidirectional, lipid-mobilizing network by activating hepatic sterol regulatory element-binding protein-1c and promoting adipose tissue lipolysis, with TAMs serving as key intermediaries in this process. The organ-specific features of TAM lipid metabolism shaped by distinct tumor microenvironments suggest that therapeutic strategies should consider tissue context. Integrating metabolomic biomarkers, dietary interventions, and combination immunotherapies holds promise for achieving precision metabolic immunotherapy.