The liver is one the most common metastatic sites, but unfortunately liver metastasis patients show low response to immunotherapy. One of the main immune cells populating liver metastases are macrophages, which play a key role in regulating anti-tumor immune responses. However, we still lack the capacity to modulate macrophage activity, as we do not yet understand their functional diversity and the molecular signals driving their pro-tumoral activity in metastasis. The host lab recently reported a major role for liver-specific cell-cell interactions in the development and functional specialization of hepatic macrophages called Kupffer cells (KCs). My preliminary data indicate that both resident KCs and recruited tumor-associated macrophages (TAMs) expand in liver metastases. Transcriptomic analysis in mouse and human revealed that TAMs recruited in metastases are different from KCs, suggesting a distinct functional specialization. The molecular pathways involved in the reprogramming of KCs and TAMs and their relative contribution to tumor growth remain poorly understood. I will combine cutting-edge spatial multiomic technologies, intravital microscopy, and in vivo CRISPR screens to investigate the role of KCs and TAMs in liver metastasis and to identify the cell-cell interactions driving their functional reprogramming. Finally, I will perform preclinical studies to assess whether we can boost response to immunotherapy by modulating macrophage activity during liver metastasis.