There are about 600 myokines that are regulated in response to muscle contraction (Di Felice et al., 2020). IL-6 was the first described myokine with anti-inflammatory properties in mammals (Pedersen et al., 2003). Some of other myokines are: brain-derived neurotrophic factor (BDNF), angiopoietin-like 4 (ANGPTL4), BAIBA (β-aminoisobutyric acid, a non-protein amino acid), fibroblast growth factor 21 (FGF-21), chemokine (C–C motif) ligand-2 (CCL-2) (also called monocyte chemoattractant protein-1 (MCP-1), chemokine (C–X3–C motif) ligand 1 (CX3CL1) (also called fractalkine (FKN)), irisin, leukemia inhibitory factor (LIF), interleukin-6 (IL-6), IL-7, IL-8, IL-15, myostatin, meteorin-like protein (Metrnl), and secreted protein acidic and rich in cysteine (SPARC) (Hoffmann and Weigert, 2017; Severinsen and Pedersen, 2020).

The beneficial effects of myokines include the regulation of energy expenditure, insulin sensitivity, lipolysis, free fatty acid oxidation, adipocyte browning, glycogenolysis, glycogenesis and general metabolism (Severinsen and Pedersen, 2020).

More recently, novel metabolites as mediators of communication between skeletal muscle and other organs have emerged (Severinsen and Pedersen, 2020): the already mentioned “exerkines” (Safdar et al., 2016; Safdar and Tarnopolsky, 2018). Many studies identified different circulating factors released with the exercise and derived from other organs such as heart (cardiokines), liver (hepatokines), white adipose tissue (WAT; adipokines), brown adipose tissue (BAT; baptokines) and the nervous system (neurokines) (Chow et al., 2022). Exerkines thus consist of a broad range of signalling molecules, including cytokines, nucleic acids (microRNA, mRNA and mitochondrial DNA), lipids and metabolites, which are driven by exosomes and play a key role in the cross-talk between organs during exercise (Vechetti et al., 2021).

Exosomes are one type of Extracellular Vesicles (EVs) that differ among them for size, tissue of origin, biochemical composition and density. Through ultracentrifugation, it is possible to classify EVs into large, medium and small size (Trovato et al., 2019). Moreover, EVs are divided in “ectosomes” or “exosomes” based on the biogenesis pathway, i.e., release after the fusion of multivesicular bodies with the plasma membrane or production of micro-vesicles by outward budding of the plasma membrane (Yáñez-Mó et al., 2015; Trovato et al., 2019; Di Felice et al., 2020). Exosomes and their biogenesis represent a protein quality control mechanism, since their release produces a remodelling of the extracellular matrix and the communication among cells (Pegtel and Gould, 2019; Rong et al., 2020). Recent research on exosomes focuses on their ability to deliver complex signals through the engagement and clustering of specific receptors on the cell surface (Dai et al., 2020; Benjamin-Davalos et al., 2021). Guescini and colleagues were the first to demonstrate that skeletal muscle cells produce EVs, including exosomes (Guescini et al., 2010). In addition to proteins, myokines and cytokines, there are other molecules whose production is induced by exercise: miRNAs (see Figure 1). In fact, it has been observed that after exercise the expression of different miRNAs was increased in exosomes (Estébanez et al., 2021) as miR-1 in response to acute cycling exercise (D’Souza et al., 2018) or miR-1, miR-133a and b, miR-206, miR-208a, miR-499 after chronic exercise (Yin et al., 2019). Similarly, other studies evidenced the increase of exosomes circulating-miRNAs as a consequence of different type of exercise (Muroya et al., 2015; Hou et al., 2019).

In recent years, growing interest on the role of physical exercise in preventing cancer emerged. Approximately 30%–40% of cancer can be prevented by lifestyle modification, including physical exercise, diet and environmental factors (Huang et al., 2022). However, the effect of exercise in reducing cancer risk depends from intensity and frequency (Wang and Zhou, 2021). Most evidences on the effect of exercise on breast cancer has been provided: the incidence was reduced in fertile women who performed high-intensity exercise for at least 3–5 h/week, even in postmenopausal women (Magnè et al., 2011; Desnoyers et al., 2016; Orlandella et al., 2021).

Regular exercise, together with a healthy lifestyle, has a positive impact on the incidence of colorectal cancer: many studies indicated that the risk of this cancer was reduced of 19% in subjects with higher levels of fitness (Liu et al., 2016), and similarly, on gastric cancer incidence, where it was reduced of 19% in trained subjects (Psaltopoulou et al., 2016). In smokers, the risk of lung cancer was lower in exercised subjects, even if this benefit disappeared in non-smokers (Schmid et al., 2016). Exercise also affects the IGF-1 signaling pathway involved in cancer proliferation/survival, expecially in different epithelial tumors thus explaining, at least in part, the molecular mechanisms underlying cancer prevention (Cevenini et al., 2018). Conversely, limited evidences in other types of cancers (such as blood, pancreatic, ovarian) regarding the effects of exercise on prevention and progression of cancer were reported (Wang and Zhou, 2021).

Present in up to 80% of cancer patients, cachexia is a complex metabolic syndrome characterized by significant loss of muscle mass (up to 75% of skeletal muscle mass) with poor quality of life and decreased survival (Tisdale, 2010). Cachexia is considered the immediate cause of death in 20%–50% of all cancer patients (Marinho et al., 2018). Despite its clinical relevance, this syndrome is underdiagnosed and not yet fully elucidated.

High levels of circulating pro-inflammatory cytokines associated with tumor cachexia represent a potential target of exercise. Exercise, in fact, represents a non-pharmacological therapeutic strategy, in synergy with anticancer therapy, to counteract systemic inflammation through the production and secretion of anti-inflammatory myokines, thus promoting the reduction of muscle wasting and the improvement of response rates and survival (Leal et al., 2021).

Furthermore, recent studies demonstrated that one of the mechanisms that may be involved in the transduction of inflammatory signals and the activation of the catabolic state in muscle is linked to exosomes containing miRNAs and myomiRs. He and colleagues evidenced that lung and pancreatic cancer cells secrete exosomes containing miR-21 that, once transported in the bloodstream, is able to induce apoptosis of muscle cells (He et al., 2014). More recently, Zhang and colleagues (Zhang et al., 2017) demonstrated that HSP70 and HSP90 proteins, present in the membrane of exosomes, are released by cancer cells thus inducing muscle wasting in cancer cachexia models. Conversely, Hudson and colleagues showed that miR-182, present in exosomes, counteracts the role of Foxo3 in inducing atrophy in the skeletal muscle (Hudson et al., 2014).

Interestingly, recent evidences demonstrated that exercise could increase cytoprotective proteins expression, counteracting muscle atrophy. In particular, exercise improves the expression of Hsp60 protein, associated to mitochondrial biogenesis and oxidative capacity of muscle cells (Di Felice et al., 2022). Similarly, Morton and colleagues found significantly increased (25%) Hsp60 expression levels in the vastus lateralis muscle of trained compared to sedentary individuals (Morton et al., 2008); moreover, a significant release of Hsp60-bearing exosomes was found in the blood of BALB/c mice subjected to a 6-week training program compared to sedentary animals (Campanella et al., 2008). Recently, a potential anti-cachexia drug based on Hsp60-containing nanovesicles has been proposed, which could mimic the beneficial effects of exercise by improving patient survival and quality of life (Di Felice et al., 2022).

Although several mechanisms have been hypothesized as crucially related to the anti-cancer benefits of exercise, the exact mechanism by which exercise may produce this effect remains unclear (Magnè et al., 2011; Goncalves et al., 2014; Desnoyers et al., 2016; Reis et al., 2017; Wang and Zhou, 2021). It has been demonstrated that exercise, through the circulating muscle derived-exosomes, secretes more than 300 molecules such as proteins, myokines, miRNAs and glycolytic enzymes (Whitham et al., 2018). It can act as a tumour suppressor, both by influencing several distinctive features of cancer cells (Hojman et al., 2011; Ruiz-Casado et al., 2017) and by inducing changes in the metabolic activity of tumour cells (Pedersen and Saltin, 2015). In fact, exercise can affect cancer metabolism and anaerobic glycolysis, strongly enhanced in cancer cells: these effects on tumor metabolism represent an useful tool to better understand cancer biology and to develop therapies targeting cancer energy metabolism (Vulczak and Alberici, 2022).

Muscle-derived exosomes appear to directly interact with tumour cells by altering their structure, as well as by modifying the function of tumour-infiltrating immune cells, thereby influencing the growth rate of cancer cells (Sadovska et al., 2021). Recent data provide novel evidence on the effects of muscle-derived exosomes on delay prostate cancer progression and metastasis, acting on several physiological processes including protein folding, energy metabolism and regulation of immune responses triggered by exercise (Sadovska et al., 2021). Furthermore, a pattern of several miRNAs in the urinary exosomes including miR-21, miR-451 and miR-636 has been recently identified as non-invasive prognostic biomarker for prostate cancer (Shin et al., 2021; Zhang et al., 2021). Finally, Bryant and colleagues demonstrated that several miRNAs, such as miR-107, miR-130b, miR-141, were increased in circulating exosomes from prostate cancer patients compared to healthy individuals, reinforcing the relevance of molecules carried by exosomes as prognostic markers for prostate cancer (Bryant et al., 2012).

Exercise-induced miRNAs are closely linked to the Hippo Tumor Suppressor Pathway, whose activation, through the inhibition of two homologous transcription factors, the Yes-Associated Protein (YAP) and Transcriptional Co-activator with PDZ-binding Motif (TAZ), block target genes, involved in cancer cell proliferation and survival (Badouel and McNeill, 2011; Yu et al., 2013). Du and colleagues recently demonstrated that miR-223-3p transcription levels were increased in breast cancer cells. The inhibition of miR-223-3p transcription reduces proliferation, migration and invasion of breast cancer cells, through the Hippo/Yap signaling pathway (Du et al., 2021). Furthermore, Dethlefsen and colleagues demonstrated that catecholamines induced by exercise could activate the Hippo Tumor Suppressor Pathway, thus reducing the risk of breast cancer development (Dethlefsen et al., 2017).

Furthermore, circulating muscle-derived factors produced during exercise can counteract tumorigenesis and cancer progression by influencing the tumor microenvironment constituted by different cell types, mechanical and chemical stressors and humoral factors (Koelwyn et al., 2017). The interaction of all these components greatly affects cancer cells and, subsequently, the growth rate of tumor. To data, few studies focused on the exercise and tumor microenvironment adaptations. Koelwyn and colleagues pointed out that exercise affects tumor microenvironment through several mechanisms such as tumor perfusion, vascularization, hypoxia and immune response, playing a key role in cancer suppression (Koelwyn et al., 2017).

Regular exercise stimulates cross-talk between organs through the secretion of hormones, cytokines and growth factors from various tissues, including skeletal muscle, which promotes many adaptations, including: enhancing energy metabolism through the availability of nutrients, and the modulation of growth factors such as insulin and IGF-1 which promote cell proliferation; reducing inflammation by decreasing the circulating levels of cytokines such as IL-6 and C-reactive protein (CRP) with evident pro-tumorigenic action (see Figure 2). These exercise-induced adaptations also modify key regulatory mechanisms of tumor microenvironment, such as angiogenesis, immune regulation and metabolism, thus having a cumulative antitumorigenic effect. Furthermore, during exercise, blood flow is redirected to active skeletal muscle with surprisingly increased tumor blood perfusion and reduced tumor hypoxia: this represents an alternative mechanism of exercise regulation on the tumor microenvironment (Koelwyn et al., 2017).

Finally, regular exercise, through exercise-induced circulating molecules, also modifies the immune-system response as demonstrated by many studies that highlighted the role of miR-486-5p in regulating the breast cancer microenvironment, through increased recognition of tumor cells by cytotoxic T lymphocytes and natural killer cells in patients with breast cancer (ElKhouly et al., 2020; Siqueira et al., 2021, 2023).