Guo, W.; Leon, D.; Nicholson, B.; Que, J.; Miao, Y. P.

Macrophages are pivotal mediators of wound healing, yet the cellular programs they employ can be hijacked by cancers to drive tumorigenesis. Although similar macrophage programs support both physiological tissue regeneration and pathological cell growth, the molecular and functional difference between wound-associated macrophages (WAMs) and tumor-associated macrophages (TAMs) remain poorly defined. Here, we perform comparative single-cell RNA sequencing to delineate the dynamic cell states of macrophages during skin wound healing and the progression of cutaneous squamous cell carcinoma. Our analyses reveal that aberrantly regulated lipid metabolism is a distinct feature of TAMs. Critically, our genetic manipulations allow us to identify SOX2High tumor-initiating stem cells as key orchestrators that modulate the lipid metabolism of TAMs and shape their cell states. These findings suggest that disrupting the metabolic crosstalk between tumor-initiating stem cells and TAMs represents a promising strategy to normalize myeloid cell function and enhance cancer immunotherapy efficacy.