Here, we tested whether Treg cells require the energy homeostasis–maintaining enzyme AMPK to adapt to metabolically aberrant microenvironments caused by malignancy or lung injury, finding that AMPK is dispensable for Treg cell immune-homeostatic function but is necessary for full Treg cell function in B16 melanoma tumors and during influenza virus pneumonia. The gene discussed is PRKAA2; the disease is melanoma.