Tumor cells have substantially increased lipid biogenesis, which is primarily regulated by the activation of sterol regulatory element-binding protein (SREBP). However, whether SREBP regulation can be targeted for cancer treatment remains unclear. Here, it is demonstrated that treating tumor cells with a peptide that replicates the amino acid sequence in Insig1/2 loop 1, which is the region where Insig1/2 interacts with AKT-phosphorylated phosphoenolpyruvate carboxykinase 1 (PCK1), inhibits the IGF1-induced interaction between PCK1 and Insig1/2. Consequently, this treatment abrogates PCK1-mediated phosphorylation of Insig1 at S207 and Insig2 at S151, reduces the nuclear accumulation of SREBP1, and decreases SREBP1 activity-dependent expression of lipid synthesis genes, lipid accumulation, and tumor cell proliferation. Intravenous administration of engineered liposomal nanoparticles (LNP)-encapsulated Insig1/2 loop 1 peptide effectively suppresses tumor growth and extends mouse survival without apparent adverse effects. The peptide treatment, when combined with the receptor tyrosine kinase inhibitor lenvatinib or the anti-obesity medication semaglutide, results in additive tumor inhibition. These findings highlight the potential of LNP-Insig1/2 loop 1 peptide administration to inhibit SREBP activity-traditionally regarded as untargetable-for the treatment of human cancer.