From Fat Providers to Cancer Therapy: Adipocytes as Unexpected Allies

Adipocytes from white adipose tissue support cancer progression by supplying fatty acids (FA) to tumor cells, whereas cold-activated brown adipose tissue has been shown to inhibit tumor growth by disrupting cancer cell metabolism. In a groundbreaking study published in Nature Biotechnology, Nguyen and colleagues developed adipose manipulation transplantation (AMT), a strategy that genetically reprograms white adipocytes to outcompete tumors for key nutrients. Using CRISPR activation technology, researchers enhanced adipocyte glucose and FA consumption by inducing a stable browning phenotype. In vitro, browned adipocytes reduced glycolysis and FA oxidation in cancer cells, inhibiting their proliferation. Implantation of engineered adipose organoids adjacent to tumors suppressed tumor growth, reduced angiogenesis, and altered metabolic gene expression in xenograft models. AMT also prevented tumor development in genetic mouse models of cancer, suggesting a role in cancer prevention. Finally, modified human mammary adipocytes inhibited the growth of patient-derived breast cancer organoids. This therapy, based on autologous fat transplantation, could offer a reversible and patient-specific approach. Challenges remain, including metabolic plasticity in cancer cells and the fragility of mature adipocytes in cell culture. AMT represents a paradigm shift in cancer therapy, leveraging adipocytes as metabolic competitors rather than tumor facilitators, opening new avenues for metabolism-targeted cancer treatments.