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 and liver tissues, were 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 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 attenuated hepatic inflammatory signatures and mitigated tumor and/or chemoradiotherapy-associated behavioral fatigue 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.