Patient characteristics conceptualized as predisposing factors in cancer-related fatigue include biological sex ^[1][63], genetics ^[2][34], body composition (e.g., body fat and low muscle mass) ^[3][4][5][64,65,66], and viral exposures ^[6][7][67,68]. Additionally, circadian rhythms could play a significant role in the etiology of fatigue through the modulation of arousal and sleep ^[8][54].

Predisposing risk factors for cancer-related fatigue include poor performance status, chemoradiotherapy, female sex, insomnia, neuroticism, pain, and depression ^[9][69]. In cancer-related fatigue, the role of genetic variation remains unclear. Twin studies have shown the heritability of fatigue to be between 6% and 50%, with a higher concordance in monozygotic twins than dizygotic twins. Some preliminary studies have identified sets of inflammation-related genetic polymorphisms that are associated with increased fatigue in cancer patients ^[2][34], but the generality of these effects remains to be determined. Genome-wide association studies (GWAS) in fatigue-related diseases have identified variants in genes involved in cognition and circadian rhythms ^[10][11][12][70,71,72]. Publicly available lists of high-scoring genetic–metabolomic associations known as “genetically influenced metabotypes” include several variants located in or near genes encoding enzymes central to human lipid metabolism, including polyunsaturated fatty acid biosynthesis (e.g., FADS1, ELOVL2) and biosynthesis of phospholipids (e.g., SPT16A) ^[13][73], which have not been explored in cancer-related fatigue. Similarly, “genetically influenced inflammotypes” ^[14][74] can be identified by inflammatory-based genome-wide association studies (iWAS), but also have not yet been explored among cancer patients with fatigue.

Previous viral exposure—for example, to Epstein–Barr virus, human herpesvirus, Lyme disease, or COVID-19—may predispose individuals to fatigue through cell alterations, hyperinflammation, mitochondrial modulation, and autoimmunity, although research in this area is lacking ^[15][16][75,76]. Additionally, anthropometry measurements (e.g., obesity) have been associated with links in apnea, sleep quality, and inflammatory biomarkers.

Factors that may initially precipitate the development of cancer-related fatigue remain unclear, though likely include metabolic dysregulation (alterations in metabolic genes and regulatory pathways), as well as inflammation (overproduction of pro-inflammatory cytokines) and accelerated cellular aging (e.g., the premature shortening of telomeres and altered DNA methylation) due to cancer treatment. For example, chemotherapy is known to accelerate aging ^[17][18][77,78]. Chemotherapy may also damage mitochondria in muscle and deconditioning of muscle that may contribute to perceptions of fatigue ^{[19][20][21][22]}[79,80,81,82].

Multiplicative interactions between precipitating factors may also exist. Studies investigating muscle fatigue in cancer patients show metabolic dysregulation, including energy, lipid, and amino acid metabolism ^{[23][24][25][26]}[83,84,85,86]. Furthermore, evidence supports that chemotherapy may damage mitochondria in muscle that in turn increases fatigue, and the deconditioning of muscle further contributes to perceptions of fatigue. In particular, studies have focused on tryptophan catabolism ^[27][28][29][87,88,89]. An essential amino acid, tryptophan drives de novo synthesis of serotonin and niacin. Serotonin modulates behavioral and neuropsychological processes and niacin produces NAD, a co-factor crucial for energy homeostasis that is linked with aging and circadian regulation (SIRT1). Trials modifying tryptophan have demonstrated reductions in physical and mental fatigue following endurance exercise ^[30][90]. Furthermore, metabolic disturbances related to chronic fatigue syndrome have included alterations in 20 metabolic pathways including sphingolipids, phospholipids, purine, cholesterol, microbial metabolites, pyroline-5-carboxylate, riboflavin, amino acids, peroxisomal and mitochondrial metabolism ^[31][91]. All are directly regulated by redox or the availability of NADPH, highlighting the importance of the mitochondria, cellular organelles that produce energy ^[31][91]. Sphingolipids and phospholipids accounted for almost 70% of the variation in metabolic phenotype in a study of 84 patients with chronic fatigue syndrome, and differences among males and females were observed. Area under the receiver operator characteristic curve analysis showed accuracies in predicting fatigue of 94% (95% CI = 84–100%) for males and 96% (95% CI = 86–100%) for females. Three other metabolomics studies of fatigue-associated diseases support the key role of sphingolipids and phospholipids in addition to irregularities in energy, amino acid, and nucleotide metabolism ^[32][33][34][92,93,94]. The alterations in sphingolipids may be related to impaired lipid metabolism and mitochondria energetics, with evidence suggesting that PPAR suppression in the muscle of cancer patients could mediate this ^[21][35][36][81,95,96]. Furthermore, in vitro studies have demonstrated that ceramides induce oxidant production in the mitochondria, have specific effects in certain tissues (e.g., adipocyte ceramides and inflammation) and increase oxidant activity ^[37][97], depressing muscle fiber force and exacerbating muscle fatigue ^[38][98]. While a number of pathological pathways have been identified as playing a role in cancer-related fatigue, it is possible that different mechanisms are responsible for different dimensions of fatigue (e.g., mental fatigue vs. physical fatigue). Further delineation of unique dimensions of fatigue associated with each pathway will assist in the identification of new intervention targets for the specific type of fatigue experienced.

Perpetuating factors are conceptualized as characteristics and behaviors that may worsen or prolong fatigue including poor dietary pattern, irregular meal timing ^[39][40][99,100], physical inactivity ^[41][101], and poor sleep ^{[42][43][44][45][46][47]}[102,103,104,105,106,107]. Previous research suggests that anti-inflammatory dietary patterns, such as prudent and Mediterranean diets, offer a plausible mechanism to mitigate cancer-related fatigue through reducing inflammation and improving body composition ^[48][49][50][108,109,110]. The key components of the Mediterranean dietary pattern include high intake of vegetables, fruits, whole grains, legumes, and nuts; moderate intake of seafood and red wine; and olive oil as the main fat source ^[51][52][111,112]. Anti-inflammatory dietary patterns are associated with improvements in the gastrointestinal (GI) microbiota and lessening of metabolic endotoxemia, defined as a 2- to 3-fold increase in circulating levels of bacterial endotoxin ^[53][113]. In comparison, pro-inflammatory dietary patterns, such as the Western dietary pattern, widely consumed in the United States, is characterized by high consumption of red and processed meats; high consumption of sugar-sweetened beverages and refined grains; and low consumption of fresh fruits, vegetables, and legumes ^[54][55][56][114,115,116]. Western diets contribute to metabolic endotoxemia through changes in the GI microbiome and bacterial fermentation end products, intestinal physiology and barrier function, and enterohepatic circulation of bile acids ^[53][113]. Additionally, the Western dietary pattern has been correlated with pro-inflammatory markers associated with cancer-related fatigue, including tumor necrosis factor (TNF)-α, C-reactive protein, interleukin (IL)-6, and IL-8 ^[57][117]. Dietary patterns promoting hyperinsulinemia and chronic inflammation, including the empirical dietary index for hyperinsulinemia (EDIH) and empirical dietary inflammatory pattern (EDIP), strongly influence risk of weight gain, type 2 diabetes, cardiovascular disease, and cancer ^[58][118]. The EDIH and EDIP have predicted concentrations of known insulinemic and inflammatory biomarkers, and the EDIH further predicted risk of future cancer ^[59][119].

In addition to evaluating dietary patterns based on self-reported questionnaires, the role of diet in cancer-related fatigue can be investigated through nutritional metabolomics, the study of food-related metabolites in a biofluid that can provide an objective measure of recent or habitual dietary intake ^[60][120]. Moreover, untargeted metabolomics offers a discovery tool to identify small molecules both influenced by dietary behavior and associated with disease, thus characterizing endogenous response to diet, and metabolic targets for dietary intervention for disease prevention. To our knowledge, nutritional metabolomics studies of cancer-related fatigue are yet to be implemented. The microbiota has been recognized to play a role in human disease ^[61][121], and the mechanisms by which these microorganisms contribute to host health have been extensively investigated over the past decade. The microbiome, specifically bacterial metabolites, has been linked with inflammation and oxidation. Two studies in mice have suggested that the gut microbiota produces metabolites from dietary tryptophan that regulate inflammation in the gut and central nervous system ^[62][122].

In terms of general lifestyle, prior research in fatigue-associated diseases highlights the role of lipid mediators including sphingolipids, phospholipids, and oxygenated polyunsaturated fatty acids (PUFAs) (oxylipins). Sphingolipid metabolites play key roles in the regulation of both trafficking and function of immune cells, and there are indications that sphingolipid metabolism might be altered by inflammation ^[63][123]. Ceramides, key sphingolipids, promote numerous inflammatory processes, including induction of macrophages and B cells ^[64][124]. Prior studies indicate alteration of ceramide metabolism among patients with chronic fatigue syndrome ^[32][92]. Intervention trials show that diet can lower ceramide levels ^[65][125]. In the PREDIMED study, a Mediterranean dietary intervention mitigated potential deleterious effects of elevated plasma ceramide concentrations on cardiovascular disease ^[66][126]. Similarly, omega-3 polyunsaturated fatty acid (n3-PUFA) is a common phospholipid, which plays an important role in immunomodulatory activities. Ceramides and its metabolites have been proposed as an intermediate link between over-nutrition and certain underlying abnormalities driving disease risk, insulin resistance and low-grade inflammation ^[67][68][69][127,128,129]. Data suggest beneficial effects of n3-PUFA in reducing fatigue in cancer patients ^{[70][71][72][73][74]}[33,130,131,132,133]. N-3 PUFA therapy upregulates the muscle transcriptome, including several pathways that control mitochondrial function in both human ^[75][134], and animal studies ^[76][77][78][135,136,137], emphasizing the role of energy metabolism. Other metabolic pathways related to diet that might also contribute to fatigue include dysregulated tryptophan catabolism. Tryptophan is an amino acid metabolized into several molecules involved in energy production ^[27][28][29][87,88,89]. Potential interventions might target modulation of tryptophan-related molecules via administration of branched chain amino acids. In addition to endogenous metabolites, untargeted approaches may identify unexpected or novel exposures that might play an important role in cancer-related fatigue by implicating exogenously derived chemicals. Adherence to specific dietary patterns (e.g., time-restricted eating) may offer a novel, cost-effective strategy to reduce cancer-related fatigue while quantification of targeted metabolites may allow for a robust evaluation of metabolite changes in people with cancer-related fatigue over time ^[79][138].

There is an interaction of diet, physical activity, and sleep on many levels (e.g., behavioral, circadian, obesity, metabolic). Particularly, intermittent fasting regimens have been hypothesized to influence metabolic regulation via effects on (a) circadian biology, (b) the gut microbiome, and (c) modifiable lifestyle behaviors, such as sleep ^[40][100]. Evidence suggests that irregular meal timing may impact metabolic health. Specifically, eating more frequently, reducing evening energy intake, and fasting for longer nightly intervals may lower systemic inflammation and subsequently reduce breast cancer risk ^[39][99]. In another study examining associations between fasting duration, timing of first and last meals, and cardiometabolic endpoints using data from the National Health and Nutrition Examination Survey (NHANES), evidence suggested that there were beneficial effects on cardiometabolic health of starting energy consumption earlier in the day ^[80][139].

In addition to diet, physical inactivity and sleep disturbance represent key modifiable perpetuating factors associated with cancer-related fatigue ^[41][101]. In a systematic review and meta-analysis of randomized controlled trials, physical activity has been identified as effective for mitigating cancer-related fatigue in colorectal cancer ^[81][140]. Moderate-intensity aerobic exercise training and a combination of moderate-intensity aerobic and resistance training have reduced fatigue in patients with breast and prostate cancer, both during and following cancer therapy ^[82][83][141,142]. Reductions in fatigue from exercise training appear to result from both independent and supervised interventions ^[84][143], highlighting its potential applicability to a wide range of cancer patients and survivors. Similarly, sleep disturbance confers risk of cancer-related fatigue across various cancer diagnoses. A recent meta-analysis studying risk factors for cancer-related fatigue in 84 studies with 144,813 participants found that patients with insomnia had significantly higher odds of cancer-related fatigue ^[9][69]. Notably, the odds ratio for insomnia was higher than the odds ratio for treatment of chemoradiotherapy, although the magnitude of these effects was not formally compared. In patients with chronic myeloid leukemia receiving cognitive behavioral therapy for targeted-therapy-related fatigue, improvements in sleep and physical activity were associated with declines in fatigue ^[41][101]. Sleep disturbance and physical inactivity both contribute to known pathways for cancer-related fatigue (e.g., inflammation, circadian disruption) ^[85][86][144,145]. Emerging evidence suggests that sleep disturbance and physical inactivity may also implicate additional pathways, such as accelerated aging and gene expression through DNA methylation. For example, one study of 2078 women found that those with insomnia showed advanced biological age relative to chronological age ^[87][146]. In another study, individuals with insufficient sleep showed hypomethylation of DNA in regions associated with neuroplasticity and neurodegeneration ^[88][147].