AMPK Suppresses Multiple Forms of Cell Death Including Disulfidptosis in Tumor-Associated Macrophages During Tumor Progression

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.