AMPK suppresses multiple cell death pathways to sustain tumor-associated macrophage proportion and promotes tumor progression

Tumor-associated macrophages (TAMs) are a major immune cell population in the tumor microenvironment (TME). This part depends on their capacity to resist cell death by adapting to the harsh tumor microenvironment, characterized by nutrient deprivation and the accumulation of metabolic waste, through metabolic reprogramming. This enables TAMs to not only utilize excess metabolites and metabolic waste in the tumor microenvironment as energy sources, but also to cope with metabolic stress by upregulating cysteine uptake and activating hypoxia-inducible factors, thereby maintaining their survival and function. However, the core genes that suppress TAM death in response to the metabolic dynamics of the tumor microenvironment during tumor progression remain unknown. In this study, we used proteomics analysis combined with experimental validation found that the degree of TAM apoptosis decreased while the level of AMPK activation increased during tumor progression. Notably, myeloid-specific knockout of AMPK significantly inhibits tumor growth, reduces TAM proportion in the tumor, and weakens its pro-tumor phenotype. Bulk RNA sequencing data analysis further revealed that specific knockout of AMPK in TAMs triggers multiple forms of cell death, including apoptosis, ferroptosis, and necroptosis. Further experimental validation confirmed that AMPK knockout not only induces apoptosis and ferroptosis in TAMs but may also trigger disulfidptosis. Mechanistic research suggested that AMPK might regulate cysteine uptake and the pentose phosphate pathway to inhibit ferroptosis and disulfidptosis in TAMs. In conclusion, this study identifies AMPK as a key regulator that responds to the metabolic dynamics of the TME and inhibits various forms of cell death in TAMs, providing new theoretical insights for TAM-targeted metabolic therapies.