Liver metastasis (LM) confers poor survival and therapy resistance across cancer types, but the mechanisms of liver-metastatic organotropism remain unknown. Here, through in vivo CRISPR–Cas9 screens, we found that Pip4k2c loss conferred LM but had no impact on lung metastasis or primary tumor growth. Pip4k2c-deficient cells were hypersensitized to insulin-mediated PI3K/AKT signaling and exploited the insulin-rich liver milieu for organ-specific metastasis. We observed concordant changes in PIP4K2C expression and distinct metabolic changes in 3,511 patient melanomas, including primary tumors, LMs and lung metastases. We found that systemic PI3K inhibition exacerbated LM burden in mice injected with Pip4k2c-deficient cancer cells through host-mediated increase in hepatic insulin levels; however, this circuit could be broken by concurrent administration of an SGLT2 inhibitor or feeding of a ketogenic diet. Thus, this work demonstrates a rare example of metastatic organotropism through co-optation of physiological metabolic cues and proposes therapeutic avenues to counteract these mechanisms.

肝转移（LM）导致各种癌症类型的生存率和治疗耐药性较差，但肝转移的器官趋向性机制仍不清楚。在这里，通过体内 CRISPR-Cas9 筛选，我们发现Pip4k2c缺失导致 LM，但对肺转移或原发肿瘤生长没有影响。Pip4k2c缺陷细胞对胰岛素介导的 PI3K/AKT 信号传导高度敏感，并利用富含胰岛素的肝脏环境进行器官特异性转移。我们在 3,511 名黑色素瘤患者（包括原发肿瘤、LM 和肺转移瘤）中观察到PIP4K2C表达的一致变化和明显的代谢变化。我们发现，注射有Pip4k2c缺陷的癌细胞的小鼠中，全身 PI3K 抑制通过宿主介导的肝胰岛素水平增加而加剧了 LM 负担。然而，这种回路可以通过同时服用 SGLT2 抑制剂或生酮饮食来打破。因此，这项工作展示了通过选择生理代谢线索实现转移性器官向性的罕见例子，并提出了抵消这些机制的治疗途径。