Activation of the cGAS-STING pathway contributes to cancer-related fatigue in a murine model of head and neck cancer.

Cancer-related inflammation and metabolic alterations extend beyond the tumor microenvironment, exerting systemic effects that disrupt energy homeostasis and contribute to reduced physical function and chronic fatigue. The cGAS-STING pathway has emerged as a key regulator of innate immunity and inflammation; however, its role in cancer-associated fatigue remains poorly understood. In this study, we investigated the contribution of cGAS-STING-mediated inflammation to cancer- and/or its treatment-induced fatigue using a mouse model of human papillomavirus-related head and neck cancer. Wheel running activity, along with inflammatory and metabolic changes in tumor, liver tissues, and plasma, was assessed following chemoradiotherapy and pharmacological inhibition of STING in tumor-bearing and tumor-free control mice. The results revealed that tumor growth and chemoradiotherapy activated the cGAS-STING pathway, together with an upregulation of proinflammatory mediators in the plasma and alterations of mitochondrial and metabolic gene expression in the liver. To inhibit STING activation, mice were administered H-151, a specific STING antagonist. This intervention did not alter mitochondrial stress but attenuated hepatic and plasma inflammatory signatures and mitigated tumor- and/or chemoradiotherapy-associated behavioral fatigue, as measured by decreased voluntary wheel running. These findings implicate for the first time the cGAS-STING signaling pathway and metabolic homeostasis in cancer- and cancer therapy-related fatigue.