Cutting calories lowers IGF‑1 levels, which then reduces a protein called HIF‑1α in neutrophils. This change stops neutrophils from storing fats, cutting the fuel tumors get and boosting the body’s anti‑cancer immunity. In mice, removing neutrophils wipes out the cancer‑fighting benefit of calorie restriction, showing neutrophils are key.

Caloric restriction (CR) induces tumor resistance in mammals, but its mechanisms remain poorly understood. Here, we found that CR altered the proportions and gene expression profiles of tumor-infiltrating neutrophils (TINs). Depletion of neutrophils largely abrogated CR-induced tumor inhibition across multiple murine cancer models, underscoring their critical role in CR's broad anti-tumor effect. CR-induced gene expression changes in TINs were associated primarily with lipid-related processes, notably downregulating hypoxia-inducible lipid droplet-associated (HILPDA). This downregulation reduced lipid accumulation in TINs, limiting tumor growth and enhancing anti-tumor immunity by decreasing lipid transfer to tumor and immune effector cells. Upstream, CR reduced hypoxia-inducible factor 1 (HIF-1α) mRNA expression in circulating neutrophils by decreasing insulin-like growth factor 1 (IGF-1), thereby limiting HILPDA expression in TINs. Patients with lung cancer who had low baseline neutrophil HIF-1α mRNA exhibited improved responses to combined immunotherapy. These findings identify a novel neutrophil- and lipid-centered mechanism for CR-induced tumor inhibition, suggesting the IGF-1/HIF-1α/HILPDA axis as a therapeutic target.