The metabolic basis of cancer-related fatigue

Although we are all familiar with the sensation of fatigue, there are still profound divergences on what it represents and its mechanisms. Fatigue can take various forms depending on the condition in which it develops. Cancer-related fatigue is considered a symptom of exhaustion that is often present at the time of diagnosis, increases in intensity during cancer therapy, and does not always recede after completion of treatment. It is usually attributed to the inflammation induced by damage-associated molecular patterns released by tumor cells during cancer progression and in response to its treatment. In this review, we argue that it is necessary to go beyond the symptoms of fatigue to understand its nature and mechanisms. We propose to consider fatigue as a psychobiological process that regulates the behavioral activities an organism engages in to satisfy its needs, according to its physical ability to do so and to the capacity of its intermediary metabolism to exploit the resources procured by these activities. This last aspect is critical as it implies that these metabolic aspects need to be considered to understand fatigue. Based on the findings we have accumulated over several years of studying fatigue in diverse murine models of cancer, we show that energy metabolism plays a key role in the development and persistence of this condition. Cancer-related fatigue is dependent on the energy requirements of the tumor and the negative impact of cancer therapy on the mitochondrial function of the host. When inflammation is present, it adds to the organism's energy expenses. The organism needs to adjust its metabolism to the different forms of cellular stress it experiences thanks to specialized communication factors known as mitokines that act locally and at a distance from the cells in which they are produced. They induce the subjective, behavioral, and metabolic components of fatigue by acting in the brain. Therefore, the targeting of mitokines and their brain receptors offers a window of opportunity to treat fatigue when it is no longer adaptive but an obstacle to the quality of life of cancer survivors.