Purpose <p>This study aimed to evaluate hypothalamic–pituitary–adrenal (HPA) axis activity in lung cancer patients using ¹⁸F-FDG PET/CT and explore its potential as a therapeutic target.</p> Methods <p>Clinical data and ¹⁸F-FDG PET/CT images from 151 lung cancer patients and 94 healthy controls were retrospectively analyzed. Metabolic activity in HPA-associated organs (brain, pituitary, adrenal glands, thyroid, gonads, muscle, fat) was compared. Spearman’s correlation assessed associations, whereas Kaplan–Meier survival and Cox proportional hazards regression analyses evaluated the prognostic impact of HPA axis activity. An A549 lung cancer mouse model was treated with chemotherapy, propranolol or combination therapy. Tumor size, glucose metabolism and motor function were assessed.</p> Results <p>Lung cancer patients exhibited higher SUVmax, SUVmean, and MTV in adrenal glands; higher SUVmax and SUVmean in muscle and fat and higher SUVmean in gonads and pituitary compared to controls (P &lt; 0.05). Hypermetabolism was observed in subthalamic nuclei, thalamus and amygdala, whereas hypometabolism was noted in frontal gyri and insula. Multivariate analysis identified right adrenal SUVmean (P = 0.048), fat SUVmax (P = 0.002) and total lesion glycolysis (TLG) (P = 0.036) as independent prognostic factors. In the mouse model, combination therapy improved body weight and motor function, and reduced glucose metabolism compared to chemotherapy (P &lt; 0.05).</p> Conclusions <p>[¹⁸F]FDG PET/CT imaging demonstrated increased metabolic activity in HPA axis-related organs in lung cancer patients, especially adrenal glands which may worsen prognosis. In preclinical models, the combination of an HPA axis inhibitor (β-blocker) with chemotherapy significantly improved survival in tumor-bearing animals.</p> Clinical trial number <p>Not applicable.</p>