Macrophages are highly heterogeneous immune cells that fulfill tissue-specific functions. Tissue-derived signals play a critical role in determining macrophage heterogeneity. However, these signals remain largely unknown. The BMP receptor activin receptor–like kinase 1 (ALK1) is well known for its role in blood vessel formation; however, its role within the immune system has never been revealed to our knowledge. Here, we found that BMP9/BMP10/ALK1 signaling controlled the identity and self-renewal of Kupffer cells (KCs) through a Smad4-dependent pathway. In contrast, ALK1 was dispensable for the maintenance of macrophages located in the lung, kidney, spleen, and brain. Following ALK1 deletion, KCs were lost over time and were replaced by monocyte-derived macrophages. These hepatic macrophages showed significantly reduced expression of the complement receptor VSIG4 and alterations in immune zonation and morphology, which is important for the tissue-specialized function of KCs. Furthermore, we found that this signaling pathway was important for KC-mediated Listeria monocytogenes capture, as the loss of ALK1 and Smad4 led to a failure of bacterial capture and overwhelming disseminated infections. Thus, ALK1 signaling instructs a tissue-specific phenotype that allows KCs to protect the host from systemic bacterial dissemination.

Tumor-associated macrophages (TAMs) represent a predominant immune cell population within the tumor microenvironment (TME). To adapt to the metabolically hostile conditions of the TME, characterized by nutrient deprivation and accumulation of metabolic waste products, TAMs undergo metabolic reprogramming to evade cell death. These adaptations enable TAMs to utilize alternative metabolites as energy sources and mitigate metabolic stress through enhanced cystine uptake and activation of hypoxia-inducible factor pathways, thereby supporting their survival and function. However, the key molecular regulators that prevent TAMs death in response to dynamic metabolic changes during tumor progression remain poorly understood. Through integrated multi-omics analyses and experimental validation, we observed that increased AMPK activation during tumor progression is associated with transcriptomic and proteomic features indicative of reduced susceptibility of TAMs to multiple forms of cell death. Conditional deletion of AMPK in TAMs reprogrammed the expression of cell death-related genes and was associated with increased apoptosis, ferroptosis, and notably, disulfidptosis. Clinical correlation analyses revealed that AMPK activity in TAMs was inversely associated with the expression of disulfidptosis-, ferroptosis-, and apoptosis-related gene signatures. Furthermore, tumors characterized by concurrent enrichment of AMPK signaling and TAMs infiltration exhibited lower disulfidptosis, ferroptosis, and apoptosis signature scores, which were associated with a more malignant phenotype. Collectively, our findings suggest that AMPK activity is associated with TAM survival and tumor progression and with reduced susceptibility to multiple forms of cell death, including disulfidptosis. These findings provide evidence linking AMPK activity to metabolic adaptation and cell death resistance in TAMs and suggest its potential as a therapeutic target for cancer intervention.