Obesity and metabolic syndrome increase the risk of multiple metabolic-related diseases and of malignancy. Obesity is generally characterized as a systemic disorder that impacts multiple organs, including two highly metabolic organs—the liver and adipose tissue. In the liver, a manifestation of metabolic syndrome involves lipid accumulation in hepatocytes, formally known as MASLD. Hepatic steatosis is associated with insulin resistance, dyslipidemia, and both hepatic and extrahepatic cancers. Similarly, adipose tissue in obesity exhibits excessive inflammation, aberrant cytokine production, and abnormal expansion. Here, we investigated both 1) the mechanisms and therapeutic vulnerabilities in MASLD and 2) the interplay between metabolically dysfunctional adipose tissue and tumor growth. While previous studies suggest that targeting de novo lipogenesis may be beneficial in suppressing hepatic steatosis, we find that genetic ablation in the liver of a central lipogenic enzyme, ATP-citrate lyase (ACLY), paradoxically exacerbates lipid accumulation. Conversely, the proposed ACLY inhibitor, Bempedoic Acid (BPA) ameliorates hepatic steatosis, however, in a manner independently of ACLY. BPA and ACLY have opposing roles; BPA increases, and ACLY loss suppresses, PPARa expression and that of its target genes. Moreover, using a mouse model that uncouples features of metabolic syndrome from obesity, we also show that metabolically dysfunctional adipose tissue itself promotes tumor growth independently of obesity. Tumors grown in these mice exhibit immune remodeling in the tumor microenvironment, with a distinct increase in the frequency of PD1+ macrophages, consistent with that seen in diet-induced obesity models. Mechanistically, cancer cell insulin signaling is critical for tumor growth, and genetic deficiency of the insulin receptor nearly ablates tumor growth, even in models of high-fat diet induced obesity with hyperinsulinemia.