Metastasis arises from cancer cell-intrinsic adaptations and permissive tumor microenvironments (TME) that are distinct across different organs. Deciphering the mechanisms underpinning organotropism could provide novel preventive and therapeutic strategies for patients with cancer. Rogava and colleagues identified Pip4k2c as a driver of liver metastasis, acting by sensitizing cancer cells to insulin-dependent PI3K/AKT signaling, which could be reversed by dual pharmacologic inhibition of PI3K and SGLT2 or a ketogenic diet. The study highlights the importance of tumor microenvironment communication in the context of systemic physiology and points toward potential combination therapies.
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