Exercise-modulated IL-6 in cancer cachexia: molecular mechanisms and therapeutic potential.

Introduction

Cancer cachexia is a complex, multifactorial syndrome characterized by the involuntary and progressive loss of skeletal muscle mass, frequently accompanied by adipose tissue wasting, which cannot be fully reversed by conventional nutritional support. This condition is a major contributor to physical decline, diminished quality of life, and reduced survival in patients with advanced malignancies [ 1 – 3 ]. The pathogenesis of cachexia involves both a reduction in energy and protein intake and a profound alteration in metabolism, leading to a sustained negative energy balance [ 4 ]. Diagnostic criteria typically include an involuntary weight loss of > 5% over the past six months, or > 2% in individuals with a body mass index (BMI) < 20 kg/m² or underlying sarcopenia [ 4 ]. Clinically, weight loss, fatigue, and elevated systemic inflammatory markers are strongly correlated with functional impairment and mortality [ 5 ]. Despite its high prevalence and prognostic significance, cancer cachexia remains under-recognized in national cancer statistics and is rarely recorded as a direct cause of death, even though it most frequently manifests in late-stage, incurable disease [ 2 , 6 ].

Recent perspectives propose broadening the concept of cancer cachexia to include early or pre-cachectic phases, where measurable physiological disturbances precede overt weight loss. These early metabolic and inflammatory shifts, such as altered liver function and immune activity, may represent a critical window for therapeutic intervention that is lost once full-blown cachexia develops [ 7 ]. Among the array of inflammatory mediators implicated, IL-6 has emerged as a central orchestrator in the pathophysiology of cachexia. Elevated circulating IL-6 is consistently observed in both cancer patients with weight loss and in animal models of cachexia, where it drives muscle atrophy, adipose tissue depletion, and systemic metabolic derangement [ 8 – 10 ]. Chronically elevated IL-6 exacerbates lipolysis, promotes the browning of white adipose tissue, and suppresses appetite via interactions with leptin, thereby amplifying the overall energy deficit [ 9 – 12 ]. Experimental evidence supports this, demonstrating that sustained IL-6 elevation in mice induces significant body weight loss, primarily through the reduction of fat mass [ 11 ]. From a clinical perspective, increased IL-6 levels have been identified as a prognostic biomarker for cancer-associated weight loss and poor survival outcomes in advanced-stage patients [ 13 , 14 ]. IL-6 exerts its biological effects through context-dependent mechanisms, exhibiting both pro- and anti-inflammatory actions. Its classical signaling, via membrane-bound IL-6 receptors, activates STAT3 to promote epithelial regeneration and hepatic acute-phase protein synthesis, responses generally considered anti-inflammatory. In contrast, IL-6 trans-signaling, mediated by soluble IL-6 receptors, drives pro-inflammatory effects such as immune cell recruitment, inhibition of inflammatory cell apoptosis, and suppression of regulatory T cell differentiation [ 15 ]. This functional duality underscores the critical importance of distinguishing the source, duration, and context of IL-6 signaling in disease states versus healthy physiology.

Interestingly, exercise offers a paradigm in which IL-6 acts predominantly as a beneficial mediator. During physical activity, skeletal muscle releases IL-6 as a myokine, triggering anti-inflammatory cascades that include the downregulation of tumor necrosis factor-alpha (TNF-α) and other pro-inflammatory cytokines [ 16 ]. In chronic conditions such as type 2 diabetes, regular exercise, particularly combined resistance and aerobic training, lowers circulating levels of IL-6 and other inflammation-related markers in muscle [ 17 ]. In cancer populations, both resistance and endurance training have been shown to mitigate systemic inflammation and delay the progression of cachexia [ 18 ]. This clear functional contrast between chronic, tumor-derived IL-6 and acute, exercise-induced IL-6 raises a critical question: can exercise-induced IL-6 serve not only as a counter-regulatory signal but also as a potential biomarker or therapeutic modality in cancer cachexia ? Accordingly, this review aims to examine the regulatory dynamics of IL-6 in response to exercise, elucidate its mechanistic divergence from pathological IL-6 signaling, and discuss the implications for exercise-based interventions in the management of cancer cachexia.

Overview of IL-6

IL-6 belongs to the IL-6 cytokine family, a group defined by a characteristic four-α-helix bundle structure and the shared use of the glycoprotein 130 (gp130) subunit for downstream signal transduction [ 19 ]. Human IL-6 is a 26 kDa glycoprotein of 184 amino acids, first identified in 1986 as a regulator of B-cell differentiation. It functions by forming a hexameric signaling complex consisting of two IL-6 molecules, two IL-6 receptors (IL-6R), and two gp130 molecules [ 20 ]. The assembly of this complex activates distinct downstream pathways, primarily categorized as classical signaling (through membrane-bound IL-6R) and trans-signaling (through soluble IL-6R). This binary signaling paradigm forms the molecular basis for the context-dependent duality of IL-6 manifesting either as a pathological driver of cachexia or as a beneficial, exercise-induced myokine (Fig. 1 ).

Fig. 1 Classical vs. trans-signaling pathways of IL-6 and their systemic effects. IL-6 binds to either mIL-6R or sIL-6R to activate GP130 and downstream JAK/STAT signaling. Classical signaling through mIL-6R induces acute activation of STAT3, SHP2/MAPK, and PI3K/AKT pathways, promoting anti-inflammatory responses, tissue repair, and metabolic homeostasis. In contrast, IL-6 trans-signaling via sIL-6R drives chronic STAT3 activation, leading to enhanced inflammation, oxidative stress, reduced protein synthesis, and impaired metabolic function, contributing to tissue wasting and inflammation

Molecular signaling pathways: classical vs. trans-signaling

In the classical signaling pathway, IL-6 binds to the membrane-bound IL-6 receptor (mIL-6R), leading to the recruitment and homodimerization of gp130. This complex then activates key downstream cascades, including the Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3), mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathways [ 21 , 22 ]. Classical signaling is primarily associated with anti-inflammatory and regenerative functions, which are markedly evident under physiological conditions such as exercise. In contrast, trans-signaling is initiated when IL-6 binds to a soluble form of its receptor (sIL-6R). The resulting IL-6/sIL-6R complex can activate gp130 on nearly all cell types, including those that do not express mIL-6R, thereby dramatically broadening the cellular targets of IL-6. This pathway is strongly linked to pro-inflammatory effects and is critically involved in the pathogenesis of chronic diseases, including cancer, rheumatoid arthritis, inflammatory bowel disease, and neurodegenerative disorders [ 23 ]. The restricted expression of mIL-6R to only a few cell types, compared to the ubiquitous presence of gp130, underlies this functional dichotomy. Classical signaling, being more limited in scope, primarily supports tissue repair and metabolic homeostasis. Trans-signaling, by vastly expanding IL-6’s reach, acts as a key driver of chronic inflammation and disease progression [ 24 ]. This fundamental distinction is central to understanding the dual role of IL-6 in health and disease.

Context-dependent roles: pathological driver in cachexia vs. physiological myokine in exercise

The biological outcome of IL-6 signaling is profoundly context-dependent, a paradigm best exemplified by its opposing roles in cancer cachexia and exercise. This functional duality originates from critical differences in its cellular source, temporal release pattern, and the preferential engagement of either classical or trans-signaling pathways. Physiologically, IL-6 is a pleiotropic cytokine that regulates a wide array of homeostatic processes, including immune surveillance, hematopoiesis, metabolism, and tissue regeneration. For instance, it promotes B-cell maturation, orchestrates the hepatic acute-phase response, and modulates systemic metabolism [ 25 ]. In skeletal muscle, IL-6 enhances insulin-stimulated glucose uptake, glycogen synthesis, and lipid oxidation, while also supporting muscle differentiation and repair [ 26 – 28 ]. Within the liver, IL-6 induces the production of acute-phase proteins such as C-reactive protein (CRP) and serum amyloid A (SAA) [ 29 ], and stimulates hepcidin synthesis, which in turn inhibits ferroportin-mediated iron export, a key mechanism underlying the hypoferremia observed in inflammatory states [ 30 ]. In the hematopoietic system, IL-6 drives stem cell and megakaryocyte differentiation, thereby supporting platelet production [ 31 ]. Furthermore, IL-6 acts on adipose tissue to stimulate lipolysis, as evidenced by studies showing that its administration increases glycerol release and promotes free fatty acid turnover [ 32 ]. Consistent with this, acute IL-6 treatment has been shown to elevate whole-body lipid oxidation and fatty acid metabolism [ 26 , 33 ].

In cancer cachexia, IL-6 is predominantly derived from the tumor and associated stromal cells (e.g., macrophages, fibroblasts), leading to chronic, systemic elevation [ 34 ]. This persistent state favors the trans-signaling pathway, as key target tissues such as skeletal muscle largely lack the mIL-6R while ubiquitously expressing gp130 [ 35 ]. The ensuing IL-6/sIL-6R complexes drive sustained JAK/STAT3 activation, initiating a cascade of catabolic events: they promote muscle proteolysis, induce lipolysis and the “browning” of white adipose tissue, suppress appetite, and contribute to insulin resistance [ 36 – 39 ]. In contrast, IL-6 released during physical exercise is primarily secreted by contracting skeletal muscle fibers as a myokine [ 40 ]. Its release is acute and transient, peaking during or immediately following activity [ 41 , 42 ]. Exercise-induced IL-6 appears to engage predominantly classical signaling pathways in an autocrine/paracrine manner, contributing to beneficial effects such as enhanced glucose uptake, stimulation of anti-inflammatory cytokines such as IL-10, IL-1 receptor antagonist (IL-1ra), and support of metabolic adaptation [ 43 , 44 ]. This fundamental dichotomy, chronic, tumor-derived IL-6 promoting cachexia via trans-signaling versus acute, muscle-derived IL-6 supporting adaptation via classical signaling, forms the core conceptual framework of this review.

Pathological role of IL-6 in cancer cachexia

While IL-6 is indispensable for physiological homeostasis, its persistent dysregulation is a key contributor to various pathological states. Of note, IL-6 is frequently overexpressed in diverse malignancies, and its elevated levels are consistently associated with poor prognosis. Beyond its direct oncogenic roles, IL-6 is a central mediator in the development and progression of cancer cachexia. Elevated IL-6 levels originate from both tumor cells and stromal components within the tumor microenvironment, amplifying inflammatory responses and metabolic dysfunction, as shown in Fig. 2 .

Fig. 2 Pathological role of IL-6 in cancer cachexia. IL-6, produced by tumor cells, macrophages, and fibroblasts, acts as a central mediator linking tumor-derived inflammation to systemic metabolic dysfunction and tissue wasting. In the CNS, IL-6 alters hypothalamic signaling by decreasing orexigenic (NPY/AgRP) and increasing anorexigenic (POMC) neuropeptides, leading to anorexia, reduced dopamine, fatigue, and elevated energy expenditure. In skeletal muscle, IL-6 activates the ubiquitin-proteasome pathway (MuRF1, Atrogin-1), induces autophagy (LC3, Beclin-1), suppresses satellite cell regeneration, and impairs mitochondrial biogenesis (↓PGC-1α), resulting in progressive muscle atrophy. In adipose tissue, IL-6 promotes lipolysis (HSL, ATGL), inhibits lipogenesis, drives browning (UCP1, PGC-1α), and induces insulin resistance through SOCS3-mediated inhibition of insulin signaling. In the liver, IL-6 stimulates acute-phase protein and hepcidin production, contributing to anemia, while systemically it elevates basal metabolic rate, disrupts insulin receptor signaling (SOCS3-IRS), and reduces antioxidant capacity (↓SOD). These coordinated effects underpin the metabolic and catabolic alterations characteristic of cancer cachexia

IL-6 and activation of downstream pathways

Elevated circulating IL-6 concentrations are consistently observed in cachectic cancer patients and correlate strongly with body weight loss, marked systemic inflammation, and reduced survival [ 45 , 46 ]. Mechanistically, IL-6 drives the catabolic and inflammatory processes of cachexia through its signaling pathways. Since key target tissues like skeletal muscle largely lack the mIL-6R, IL-6 in cachexia primarily acts via trans-signaling, forming a complex with the sIL-6R to activate the ubiquitously expressed gp130 co-receptor [ 15 , 47 ]. Following receptor activation, the JAK/STAT3 axis serves as the dominant signaling cascade. Activated STAT3 drives the transcription of genes related to muscle proteolysis (e.g., Atrogin-1 and MuRF1) as well as pro-inflammatory mediators [ 48 , 49 ]. While IL-6 can also activate other pathways such as MAPK and PI3K/Akt [ 50 – 52 ], their specific contributions to cachexia remain less clearly defined. Furthermore, IL-6 perpetuates a chronic inflammatory state by stimulating the hepatic production of acute-phase proteins, including CRP, which systemically exacerbates metabolic dysregulation [ 21 ].

IL-6 and muscle wasting

IL-6 is a key driver of the progressive muscle wasting that characterizes cancer cachexia, acting predominantly through sustained activation of the JAK/STAT3 pathway. This signaling cascade directly upregulates central mediators of protein catabolism, such as the ubiquitin ligases MuRF1 and atrogin-1, while simultaneously suppressing anabolic signals [ 33 , 48 , 49 , 53 , 54 ]. This catabolic output is further amplified by the cooperation of STAT3 with other pathways, including NF-κB, and by the induction of suppressor of cytokine signaling 3 (SOCS3). SOCS3, in turn, impairs insulin/Akt signaling and promotes both proteasomal and autophagic protein degradation [ 55 – 60 ]. Furthermore, chronic IL-6/STAT3 signaling disrupts mitochondrial integrity and function. It suppresses the expression of peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α), a master regulator of mitochondrial biogenesis, and alters mitochondrial dynamics by reducing fusion and enhancing fission [ 61 – 64 ]. These changes lead to oxidative stress and bioenergetic failure. Particularly, therapeutic blockade of IL-6 or its receptor can restore PGC-1α expression, rebalance mitochondrial dynamics, and improve redox homeostasis, thereby mitigating mitochondrial dysfunction and attenuating muscle wasting [ 48 , 63 , 64 ]. These findings establish IL-6 not merely as a biomarker but as a direct mechanistic driver of mitochondrial pathology in cachexia.

Finally, IL-6 signaling undermines the regenerative capacity of skeletal muscle. Under physiological conditions, transient, acute IL-6 release activates muscle satellite cells (MuSCs) via STAT3, promoting their differentiation and supporting repair after exercise or injury [ 65 , 66 ]. In cachexia, however, chronic IL-6 exposure sustains STAT3 and SOCS3 signaling within a persistent inflammatory milieu. This aberrant activation impairs MuSC function, blunting their self-renewal and differentiation capacity, which contributes to defective regeneration and cumulative muscle loss. Inhibition of STAT3 has been shown to restore autophagic flux and regenerative potential in MuSCs, particularly in aged or cachectic models [ 57 , 67 ]. Thus, the IL-6/STAT3 axis exerts a context-dependent dual role: it is beneficial for acute adaptation and repair but becomes profoundly deleterious when chronically activated, thereby accelerating cachexia progression.

IL-6 and adipose tissue loss

IL-6 plays a central role in reshaping adipose tissue metabolism during cancer cachexia, driving a profound shift toward a catabolic state that exacerbates systemic energy imbalance. A key mechanism is the induction of lipolysis, primarily through JAK/STAT signaling, which upregulates critical lipolytic enzymes such as hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL), thereby sustaining the breakdown of stored triglycerides [ 68 – 70 ]. Beyond promoting lipid mobilization, IL-6 contributes to adipose tissue insulin resistance by upregulating SOCS3. SOCS3 interferes with insulin receptor substrate (IRS) signaling, further locking adipocytes into a catabolic phenotype [ 70 , 71 ]. Together, these actions significantly amplify the systemic negative energy balance that fuels cachexia progression. Furthermore, IL-6 drives the distinctive “browning” of white adipose tissue observed in cachexia. It induces the expression of thermogenic regulators, including uncoupling protein 1 (UCP1) and PGC-1α. This process enhances mitochondrial uncoupling and energy dissipation, leading to increased whole-body energy expenditure [ 72 , 73 ]. Thus, IL-6 acts as both a trigger and an amplifier of adipose tissue dysfunction, directly linking inflammatory signaling to metabolic remodeling. In summary, IL-6-driven alterations in adipose tissue, integrating enhanced lipolysis, impaired insulin action, and ectopic thermogenesis, collectively illustrate how chronic inflammation hijacks metabolic control to promote relentless energy wasting in cancer cachexia.

IL-6 and CNS regulation

IL-6 exerts profound effects on the central nervous system (CNS), driving key behavioral and metabolic features of cancer cachexia, including anorexia, apathy, and disrupted energy balance. Circulating IL-6 primarily accesses the brain via circumventricular organs, such as the area postrema (AP), where it activates neuronal circuits involving the nucleus tractus solitarius (NTS) and hypothalamic nuclei (e.g., the paraventricular nucleus, PVN) [ 74 – 76 ]. As most CNS cells lack the mIL-6R, IL-6 acts predominantly through trans-signaling via the sIL-6R and gp130. The critical role of this pathway is underscored by studies showing that brain-restricted blockade of trans-signaling with soluble gp130 (sgp130) reduces neuroinflammation and ameliorates sickness behavior [ 77 – 79 ]. Activation of the area postrema to paraventricular nucleus (AP-PVN) pathway promotes anorexia and increases energy expenditure, largely through stimulation of the hypothalamic-pituitary-adrenal (HPA) axis and the melanocortin system. This hypothalamic dysfunction, a key downstream manifestation of IL-6-driven inflammation, has been further corroborated by neuroimaging and animal studies.

At the cellular level, IL-6 suppresses appetite by inhibiting orexigenic NPY/AgRP neurons and stimulating anorexigenic POMC neurons in the hypothalamus, processes mediated by JAK/STAT3 and NF-κB signaling [ 80 – 82 ]. IL-6 also synergizes with leptin to exacerbate anorexia, in part by inducing SOCS3, which promotes leptin resistance [ 83 , 84 ]. Beyond appetite regulation, IL-6 contributes to motivational deficits (apathy) by dampening mesolimbic dopamine signaling, an effect reversible upon IL-6 blockade [ 74 – 76 ]. Furthermore, IL-6 can delay gastric emptying and reduce ghrelin secretion, thereby weakening peripheral hunger signals. In short, these multi-level actions establish central IL-6 trans-signaling as a pivotal regulator of cachexia-associated CNS dysfunction, making it a compelling therapeutic target for restoring appetite, motivation, and energy homeostasis in affected patients.

IL-6 and oxidative stress

Oxidative stress is a defining feature of cancer cachexia, significantly contributing to the progressive loss of skeletal muscle mass and function through mitochondrial dysfunction and disrupted redox homeostasis [ 85 ]. In cachectic patients, elevated levels of reactive oxygen species (ROS) alongside altered glutathione (GSH) profiles indicate heightened oxidative activity and a concomitant antioxidant response [ 86 ]. A central mediator of this imbalance is IL-6, which inhibits the expression of PGC-1α, promotes mitochondrial ROS production, and induces proteolysis in myotubes [ 61 , 64 , 87 ]. The resulting oxidative stress further activates major protein degradation pathways, including the ubiquitin-proteasome system and autophagy, thereby accelerating muscle breakdown [ 64 , 85 ]. IL-6 also contributes to mitochondrial damage, potentially triggering the release of mitochondrial DNA (mtDNA) into the cytosol, which can initiate pro-apoptotic signaling and exacerbate muscle wasting [ 88 ]. Compounding these effects, IL-6 suppresses the expression of key endogenous antioxidant enzymes, such as superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPx), undermining the cell’s ability to restore redox equilibrium [ 89 ]. Given its pivotal role in driving oxidative stress and muscle catabolism, targeting IL-6 signaling represents a promising therapeutic strategy to counteract inflammation-mediated muscle deterioration in cancer cachexia.

IL-6 and insulin resistance

Insulin resistance (IR) is an early and pervasive metabolic derangement in cancer cachexia, impairing nutrient partitioning to skeletal muscle and accelerating functional decline [ 90 ]. IL-6 is a pivotal mediator of this process, disrupting glucose homeostasis across key metabolic tissues. The primary mechanism involves IL-6 activation of the JAK/STAT3 pathway, which induces SOCS3. SOCS3 then directly interferes with insulin signaling by inhibiting the phosphorylation of the insulin receptor (IR) and insulin receptor substrates (IRS-1/IRS-2), thereby blunting downstream PI3K/Akt activation and glycogen synthesis [ 91 – 96 ]. These mechanistic insights are supported by experimental evidence showing that both acute and chronic IL-6 exposure recapitulates these signaling defects in hepatocytes and adipocytes, with SOCS3 playing a central role [ 97 ]. Furthermore, IL-6-driven IR is reinforced through crosstalk with mammalian target of rapamycin (mTOR) signaling, particularly in the liver, amplifying metabolic dysfunction [ 96 ]. Especially, IL-6 trans-signaling via the sIL-6R propagates this metabolic disruption systemically. It facilitates inter-tissue communication between the tumor, adipose tissue, and muscle, promoting ectopic lipid deposition (e.g., muscle steatosis), elevating circulating sIL-6R levels, and sustaining inflammatory feedback loops that perpetuate insulin resistance [ 98 ]. Trans-signaling also enhances autophagic flux in muscle, directly linking impaired insulin action to catabolic wasting [ 99 ]. Altogether, chronic IL-6 elevation, particularly through trans-signaling, acts as a central node that couples systemic inflammation to insulin resistance and tissue catabolism, thereby accelerating the metabolic decline characteristic of cancer cachexia.

Mechanisms of exercise-induced IL-6

IL-6 as a myokine

Skeletal muscle is increasingly recognized as an endocrine organ capable of producing and releasing a range of cytokines and peptides, termed as myokines. Among these, IL-6 is considered a prototypical member. During repeated muscle contractions, IL-6 is secreted from muscle fibers, exerting autocrine and paracrine effects that regulate local and systemic energy metabolism, including the stimulation of hepatic glucose production [ 40 ]. Importantly, type II (fast-twitch) fibers are the predominant source of exercise-induced IL-6, contributing to more than 90% of its acute circulating increase [ 100 ]. Current evidence indicates that three principal, often interlinked, pathways mediate its secretion. The first involves calcium-dependent signaling. Muscle depolarization during exercise opens ryanodine receptors (RyR) on the sarcoplasmic reticulum, releasing Ca²⁺. The calcium-calmodulin complex then activates calcineurin, which dephosphorylates nuclear factor of activated T cells (NFAT), enabling its nuclear translocation and subsequent binding to the IL-6 promoter to initiate transcription [ 101 , 102 ]. In parallel, ROS activate mitogen-activated protein kinase (MAPK) signaling. Exercise increases mitochondrial electron leakage or NADPH oxidase activity, generating superoxide anions that are converted to ROS such as H₂O₂. These ROS inhibit MAPK phosphatases (e.g., MKP-1), sustaining p38 MAPK phosphorylation, which in turn stabilizes IL-6 mRNA [ 103 , 104 ]. A third mechanism involves sympathetic activation. Exercise stimulates the release of epinephrine, which binds to β₂-adrenergic receptors (β₂-AR) on muscle fibers. This signaling promotes IL-6 transcription and synergizes with the Ca²⁺/calcineurin pathway via the formation of an NFAT-cAMP response element-binding protein (CREB) complex, further amplifying IL-6 expression [ 105 ]. In concert, these pathways underscore the sophisticated, multi-layered regulation of IL-6 as a key myokine released in response to muscle activity.

Triggers of IL-6 production during exercise

Beyond acute signaling, IL-6 expression during exercise is modulated by a network of physiological factors. Glycogen availability plays a central role. Low pre-exercise muscle glycogen correlates with a greater IL-6 release, whereas higher post-exercise glycogen levels are inversely related to circulating IL-6. This relationship suggests IL-6 acts as an energy sensor, coordinating glucose mobilization during prolonged activity [ 106 ]. For example, Nieman et al. demonstrated in exhaustive running trials that post-exercise glycogen was inversely correlated with plasma IL-6, but not with muscle IL-6 mRNA, indicating a complex regulation at the post-transcriptional level [ 107 ]. This discrepancy suggests that factors within the muscle secretome may influence cytokine processing and systemic release. Functionally, while glycogen depletion stimulates IL-6 production, IL-6 in turn appears to facilitate muscle glucose uptake, partly through AMP-activated protein kinase (AMPK)- and hypoxia-inducible factor alpha (HIF-1α)-dependent signaling [ 108 ].

Hypoxia is another potent regulator. Both acute and chronic hypoxic conditions elevate basal IL-6 and amplify its exercise-induced release, an effect attenuated by adrenergic blockade [ 109 ]. Mechanistically, hypoxia stabilizes HIF-1α, which binds to hypoxia response elements in the IL-6 promoter to directly enhance transcription, a process further amplified by ROS. These insights suggest that training under conditions of combined hypoxia and carbohydrate restriction may synergistically augment the anti-inflammatory actions of IL-6 via HIF-1α and AMPK co-activation [ 110 ]. Moreover, Lactate accumulation further modulates IL-6. During exercise, lactate enters muscle cells via monocarboxylate transporters (MCT1/4), lowering intracellular pH and activating G protein-coupled receptors. This stimulates the cAMP-PKA pathway to promote IL-6 secretion [ 111 ]. Concurrently, lactate inhibits histone deacetylases (HDACs), facilitating chromatin relaxation and enhancing IL-6 transcription [ 112 ]. The potential involvement of specific receptors such as GPR132 warrants further investigation.

In summary, exercise-induced IL-6 production is orchestrated by the convergence of multiple acute signaling pathways, including calcium/ calcineurin-NFAT, adrenergic/cAMP-PKA-CREB, and ROS/p38 MAPK, which are dynamically integrated with real-time metabolic and environmental cues such as glycogen depletion, hypoxia, and lactate accumulation. These inputs converge on central regulators like AMPK and HIF-1α, forming a tightly regulated metabolic- inflammatory feedback loop. This system not only coordinates energy homeostasis with immune adaptation but also underscores IL-6 as a pivotal mediator linking skeletal muscle contraction to systemic physiological benefits (Fig. 3 ).

Fig. 3 Signaling pathways regulating IL-6 expression during exercise. IL-6 production in skeletal muscle is controlled by multiple convergent pathways. Calcium signaling activates the calcineurin-NFAT axis, promoting IL-6 transcription. Sympathetic nerve regulation stimulates β-adrenergic receptors, triggering the cAMP/PKA/CREB pathway to enhance IL-6 promoter activity. In parallel, ROS-MAPK signaling activates p38 MAPK and MNK1, stabilizing IL-6 mRNA via HuR

Dynamics of IL-6 response to different exercise modalities

Exercise comprises various modalities, each eliciting distinct acute effects and long-term adaptations in IL-6 regulation. The magnitude, duration, and physiological consequences of the IL-6 response depend not only on the intensity and type of exercise but also on the individual’s training status and physiological adaptation (Fig. 4 , and Table 1 ).

Fig. 4 IL-6 responses to different exercise modalities. Different types of exercise induce distinct IL-6 dynamics. Endurance exercise triggers a rapid, transient increase in circulating IL-6 (5-100 fold), accompanied by reduced baseline IL-6, lower inflammation, and decreased visceral fat with long-term training. HIIT acutely increases IL-6 sixfold via ROS signaling and enhances mitochondrial antioxidant capacity. Resistance exercise induces a modest IL-6 elevation (1.5-3.0 pg/mL) acutely through NF-κB, with no significant long-term IL-6 change but increased muscle mass. Low-intensity activity (e.g., daily walking) slightly lowers IL-6 (~ 0.3 pg/mL) and reduces visceral fat

Table 1 Exercise modalities, their effects on IL-6 regulation, and clinical significance in cancer cachexia Modality Protocol IL-6 Response Dynamics Mechanisms of Induction Systemic Effects Relevance to Cancer Cachexia References Endurance Exercise Moderate intensity (60–75% VO₂max); prolonged duration Rapid exponential rise (up to 100-fold), peaks during exercise, declines quickly post-exercise; chronic training lowers basal IL-6 Calcium signaling, glycogen depletion, ROS generation IL-1ra↑, IL-10↑, TNF-α↓; Improved insulin sensitivity ( HOMA-IR 20%↓) Potent transient anti-inflammatory and metabolic regulator; counters chronic catabolic IL-6 signaling [ 103 – 106 ] Resistance Training High load (e.g., 80% 1RM), eccentric contractions Modest acute rise; peaks immediately, returns to baseline within 6 h; muscle IL-6 mRNA increases without serum changes in some groups Muscle micro-damage, NF-κB activation, local repair Glucose uptake↑, satellite cell proliferation↑, antioxidant defenses↑ Reduces CRP, TNF-α, IFN-γ; exercise-derived IL-6 associates with protein synthesis and anabolic signaling↑ [ 107 – 111 ] High-Intensity Interval Training (HIIT) Near-maximal repeated efforts (e.g., 30s sprints; Ironman triathlon) Acute 5-6-fold plasma IL-6 elevation within 1 h; rises during recovery; trained individuals show blunted peaks and faster recovery HIF-1α/ROS- MAPK synergy, mitochondrial biogenesis, lactate accumulation PGC-1α signaling↑, Mitochondrial biogenesis↑ (COX IV ↑40%), Antioxidant capacity (SOD↑30%)↑ Reduces CRP, improves insulin sensitivity; potential to maximize transient IL-6 anti-inflammatory/metabolic benefits without chronic catabolism [ 112 – 119 ] Chronic Low-Intensity Exercise (LICE) 40–50% VO₂max, ~ 60 min per session, long-term (12 week-12 month) Mild IL-6 elevation during exercise; chronic IL-6 (-0.3 pg/mL)↓, CRP (-1.2 mg/L)↓ Gradual metabolic adaptation (AMPK-GLUT4 pathway) Visceral adiposity↓, insulin sensitivity↑, cardiovascular function↑ Limited IL-6 elevation may not trigger sufficient IL-1ra/IL-10 to offset cachexia inflammation; inconsistent outcomes in cancer patients [ 120 – 122 ]

Endurance exercise

Endurance exercise is the most well-characterized modality for inducing IL-6 release from contracting skeletal muscle, leading to a rapid rise in circulating levels during activity that swiftly declines upon cessation. Moderate-intensity exercise (60–75% VO₂max) triggers IL-6 secretion through mechanisms including calcium signaling, glycogen depletion, and ROS generation. The resulting increase can be substantial, reaching up to 100-fold during prolonged aerobic activity—with the magnitude of the response proportional to exercise duration, intensity, and the total muscle mass recruited [ 113 – 115 ]. Critically, the IL-6 profile induced by exercise differs fundamentally from that driven by tumors or chronic inflammation. While pathological IL-6 sustains catabolic signaling, exercise-induced IL-6 acts as a transient metabolic and anti-inflammatory myokine. This acute surge stimulates the release of anti-inflammatory mediators such as IL-1ra and IL-10 while suppressing TNF-α signaling, thereby potentially counteracting the catabolic pathways active in cancer cachexia. Supporting this, aerobic interval training in animal models has been shown to enhance the IL-10/TNF-α ratio and upregulate IL-15 in muscle, contributing to muscle preservation [ 116 ]. Clinically, endurance exercise exhibits a dual temporal role. Acutely, even a single 30-minute session of moderate-intensity activity in sedentary individuals elevates plasma IL-6, which typically returns to baseline within hours [ 114 ]. Chronically, however, long-term training reduces basal systemic IL-6 levels and confers sustained metabolic benefits. For example, a six-month endurance training program in patients with metabolic syndrome significantly decreased circulating IL-6 and was associated with a 20% reduction in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), indicating improved insulin sensitivity [ 117 ]. Overall, these findings position endurance exercise as a potent physiological modulator of IL-6, capable of eliciting both immediate anti-inflammatory effects and long-term metabolic improvements. Harnessing this dual regulatory capacity may offer a valuable strategy to mitigate the progression of cancer cachexia.

Resistance training

In contrast to the robust systemic IL-6 elevation elicited by endurance exercise, resistance training induces a more modest yet biologically significant IL-6 response. Acute high-load protocols, particularly those involving eccentric contractions (e.g., at 80% of one-repetition maximum), provoke localized muscle microdamage that activates NF-κB signaling and stimulates IL-6 release, with post-exercise creatine kinase levels often correlating positively with the magnitude of IL-6 increase [ 118 ]. The temporal pattern of this response varies; in healthy young men (22 ± 2 years), IL-6 rises immediately post-exercise and normalizes within six hours [ 119 ], whereas in postmenopausal women, resistance exercise may not alter serum cytokine levels but can markedly increase IL-6 mRNA expression within skeletal muscle [ 118 ]. With chronic resistance training, basal circulating IL-6 levels typically remain stable. This stability may be attributed to enhanced endogenous antioxidant defenses (e.g., a ~ 30% increase in superoxide dismutase activity) that counteract the acute pro-inflammatory stimulus of each session. Mechanistically, IL-6 released during eccentric contractions has been linked to localized benefits, including enhanced glucose uptake and the activation/proliferation of muscle satellite cells [ 120 , 121 ]. Most importantly, in the context of cachexia, repeated resistance training has been shown to reduce markers of systemic inflammation (e.g., CRP, TNF-α, IFN-γ) while paradoxically associating elevated, exercise-derived IL-6 with increased rates of muscle protein synthesis and anabolic signaling [ 122 ]. This observation highlights the critical functional duality of IL-6: while chronic, tumor-derived IL-6 promotes catabolism via STAT3, acute, exercise-induced IL-6 acts as a localized myokine that facilitates adaptive remodeling and hypertrophy. Therefore, resistance training represents a strategically valuable modality for counteracting cancer-associated muscle wasting. It not only helps rebalance systemic inflammatory tone but also harnesses the inherent adaptive capacity of skeletal muscle by leveraging IL-6’s beneficial role in promoting metabolic homeostasis and structural preservation.

High-intensity interval training (HIIT)

HIIT represents a potent physiological stimulus for IL-6 secretion, primarily due to the extreme metabolic stress elicited by repeated near-maximal efforts. Short, maximal exertion bouts, such as 30-second all-out sprints, can elevate plasma IL-6 up to sixfold above baseline within one hour, with levels often continuing to rise during recovery. Similarly, athletes completing extreme endurance events (e.g., an Ironman triathlon) exhibit a substantial (e.g., fivefold) increase in IL-6 [ 123 – 125 ]. Mechanistically, HIIT-induced IL-6 transcription is mediated through the synergistic activation of HIF-1α and ROS-MAPK pathways. The magnitude of this response is modulated by training status, with well-trained athletes typically exhibiting attenuated IL-6 peaks and faster recovery, reflecting enhanced metabolic resilience [ 126 ]. Beyond acute cytokine surges, repeated HIIT sessions (e.g., twice daily for 20 days) promote mitochondrial biogenesis via PGC-1α signaling (increasing markers such as COX IV by ~ 40%) and boost antioxidant capacity (e.g., elevating SOD activity by ~ 30%). These adaptations help mitigate chronic low-grade inflammation while preserving IL-6’s acute metabolic functions [ 127 ]. Although direct evidence in cancer cachexia is limited, studies in other inflammatory and metabolic conditions indicate that HIIT can reduce systemic markers like CRP and improve insulin sensitivity more effectively than moderate continuous training [ 128 , 129 ]. Complementary research in tumor-bearing rodent models shows that endurance exercise can improve the IL-10/TNF-α balance and modulate monocyte infiltration [ 18 , 130 ], suggesting shared anti-inflammatory mechanisms that may be accentuated by HIIT. In aggregate, these findings position that HIIT may optimally harness the transient, beneficial profile of IL-6, promoting lipid mobilization and glucose utilization without perpetuating its catabolic actions.

Chronic low-intensity exercise

Chronic low-intensity exercise (CLIE), typically defined as activity performed at 40–50% of VO₂max for sustained durations (e.g., 60 min), exerts a nuanced influence on systemic inflammation and IL-6 dynamics. In healthy and metabolically compromised populations (e.g., individuals with obesity), prolonged CLIE can gradually attenuate basal inflammation through sustained metabolic adaptation. This is evidenced by studies showing reductions in serum IL-6 (e.g., -0.3 pg/mL) and C-reactive protein (e.g., -1.2 mg/L) following 12-week interventions, alongside decreased visceral adiposity and improved glucose metabolism mediated via AMPK-GLUT4 signaling [ 131 ]. Similarly, elderly participants engaging in long-term, multimodal low-intensity training (combining aerobic, resistance, balance, and flexibility exercises) exhibited significant decreases in circulating IL-6, accompanied by enhanced insulin sensitivity and cardiovascular function [ 44 ]. However, when applied to cancer cachexia, the anti-inflammatory benefits of CLIE appear more constrained. The modest IL-6 elevation induced by such exercise may not reach the threshold required to robustly stimulate downstream anti-inflammatory mediators like IL-1ra or IL-10, thereby limiting its capacity to counter the pronounced systemic inflammation of cachexia. Clinical trials in cancer patients report inconsistent outcomes, with some noting persistent fatigue or even elevated CRP despite adherence to low-intensity programs [ 132 ]. Therefore, while CLIE retains value for its safety, role in maintaining mobility, and support of cardiometabolic health, it is likely less potent than endurance, resistance, or high-intensity interval training for directly attenuating the inflammatory drive and muscle wasting central to cancer cachexia.

Exercise induced IL-6 as a biomarker in cancer cachexia

IL-6 plays a dual and paradoxical role in cancer cachexia, driven by its context of release. Chronic elevation of IL-6, produced by both tumor and host tissues, promotes skeletal muscle wasting and adipose tissue catabolism primarily through sustained JAK/STAT3 activation and the induction of autophagy. This pathological process is often mediated by IL-6 trans-signaling via the sIL-6R. Notably, transcription factors NF-κB and STAT3 can cooperate to directly enhance IL6 gene expression in stressed cancer cells, creating a self-reinforcing inflammatory loop [ 133 ]. Pharmacological inhibition of NF-κB has been shown to suppress IL-6 production and attenuate cachexia in preclinical models, underscoring its upstream role in amplifying this signaling axis within the tumor microenvironment [ 134 ]. Elevated circulating IL-6 levels are consistently associated with weight loss, systemic inflammation, and poor prognosis across multiple cancer types, though their diagnostic specificity varies [ 8 , 10 , 98 , 99 , 135 – 137 ]. By contrast, contracting skeletal muscle releases IL-6 acutely during exercise as a myokine. This results in transient spikes that enhance metabolic flexibility and stimulate anti-inflammatory mediators such as IL-1ra and IL-10 [ 138 – 141 ]. The sharp distinction between chronic, disease-driven IL-6 and transient, exercise-induced IL-6 provides a compelling rationale for examining IL-6 dynamics , rather than static levels, as a biomarker in cancer cachexia (Fig. 5 ).

Fig. 5 Contrasting roles of chronic and exercise-induced IL-6 and their biomarker potential. Chronic IL-6 signaling in cancer cachexia, often derived from the tumor microenvironment, drives NF-κB-mediated IL-6 amplification, muscle atrophy via Atrogin-1/MuRF1, and adipose tissue lipolysis and browning, contributing to tissue wasting. In contrast, acute exercise-induced IL-6, released from contracting skeletal muscle, exerts anti-inflammatory effects by inhibiting TNF-α/IL-1β, activating AMPK to enhance glucose uptake and fat oxidation, and promoting hepatic CRP/fibrinogen synthesis. Potential biomarkers include baseline IL-6, exercise-induced IL-6 dynamics, and soluble IL-6R/sgp130 levels

Current evidence indicates that a single, baseline IL-6 measurement has limited diagnostic utility. While elevated levels correlate with adverse outcomes, they do not consistently distinguish cachectic from non-cachectic patients across all cancer types [ 10 , 136 ]. An emerging concept is the “exerkine challenge”-evaluating IL-6 reactivity to a standardized exercise bout. In healthy and clinical populations, acute exercise reliably provokes IL-6 surges alongside anti-inflammatory mediators, reflecting skeletal muscle’s secretory capacity [ 138 – 141 ]. In cachexia, a blunted or absent response could indicate impaired myokine reserve, whereas a preserved acute surge alongside reduced resting IL-6 may signal favorable metabolic remodeling. Integrating measurements of sIL-6R and its natural antagonist, sgp130, could further improve specificity by distinguishing pathological trans-signaling from adaptive, muscle-derived IL-6 [ 98 , 138 ].

Clinically, such a biomarker strategy could serve three purposes: (i) risk stratification, where IL-6 combined with CRP and body composition indices aids early detection of pre-cachexia [ 142 ]; (ii) predicting exercise responsiveness, where IL-6 dynamics could identify patients most likely to benefit from training interventions [ 143 , 144 ]; and (iii) therapeutic monitoring, where serial profiling of IL-6 and its soluble receptors could track responses to anti-IL-6/IL-6R therapies while ensuring preservation of beneficial myokine signaling [ 8 , 98 ]. However, methodological challenges remain, including accounting for genetic variants (e.g., IL6R Asp358Ala), standardizing the timing of assessments, and employing high-sensitivity assays. Future cachexia trials should embed harmonized exerkine-challenge protocols with longitudinal follow-up to validate IL-6 dynamics as a clinically actionable biomarker, thereby bridging mechanistic biology with translational application [ 137 ].

Therapeutic potientials of exercise-regulated IL-6 in cancer cachexia

The therapeutic rationale for exercise in cancer cachexia is fundamentally grounded in the context-dependent duality of IL-6 signaling. The core therapeutic strategy aims to harness the acute, beneficial cascade triggered by exercise-induced IL-6, primarily mediated through classical (cis-) signaling, to counteract, reprogram, or mitigate the chronic, detrimental effects driven by tumor-derived IL-6, which largely operates via trans-signaling. The following sections delineate how this physiological IL-6 response to exercise opposes the key pathological mechanisms of cachexia across systemic, tissue, and molecular levels.

Anti-inflammatory effects

Resistance exercise can improve systemic inflammation in conditions such as sarcopenia, partly through the modulation of IL-6 and related inflammatory networks. Although post-exercise changes in IL-6 levels may not always reach statistical significance in clinical studies, consistent trends and interactions with other cytokines suggest its role in inflammatory regulation, ultimately contributing to enhanced physical function and quality of life [ 145 ]. In cancer cachexia, exercise-induced IL-6 appears to counterbalance the chronic inflammatory milieu by suppressing pro-inflammatory cytokines such as TNF-α while promoting anti-inflammatory mediators including IL-10 and IL-1ra [ 43 , 121 , 146 ]. Preclinical evidence supports this mechanism. For example, sedentary tumor-bearing mice (C26 colon carcinoma model) exhibit elevated plasma IL-6, splenomegaly, and systemic inflammation. Moderate-intensity aerobic, resistance, or combined exercise interventions in these models normalize plasma IL-6 levels and reduce splenic hypertrophy, indicating an attenuation of systemic inflammation [ 147 ]. Similarly, combined high-intensity training has been shown to lower multiple inflammatory markers (IL-1β, IL-6, TNF-α, IFN-γ, leptin, resistin) while increasing anti-inflammatory cytokines such as IL-4 and IL-10 [ 44 ].

At the cellular level, IL-6 is implicated in modulating immune cell phenotypes. Exercise-induced IL-6 may promote a shift in macrophage polarization from the pro-inflammatory M1 state toward the anti-inflammatory and tissue-reparative M2 phenotype [ 146 , 148 , 149 ]. This phenotypic transition likely contributes to reduced inflammation within skeletal muscle, creating a microenvironment more conducive to preservation of muscle mass. As a whole, these findings illustrate that exercise-induced IL-6 exerts a multifaceted, regulatory influence on the inflammatory network, positioning it as a key physiological mediator through which exercise may counteract the systemic and tissue-level inflammation that drives cachexia progression.

Muscle preservation

Exercise modulates IL-6 expression and its downstream effects through a complex network of molecular pathways. In vitro, electrical stimulation of C2C12 myotubes activates the JNK/AP-1 signaling axis, promoting a transient, adaptive IL-6 response [ 43 ]. In vivo, exercise training increases the expression of SOCS3, a key negative regulator of IL-6 signaling, and modulates NF-κB activity, thereby limiting sustained inflammatory cascades [ 43 ]. Beyond regulating IL-6 expression, exercise directly counteracts the proteolytic pathways activated in cachexia. It downregulates key autophagy markers (e.g., Atg5, Beclin-1, LC3β) and components of the ubiquitin-proteasome system (e.g., Atrogin-1, MuRF1), thereby attenuating excessive protein degradation. Exercise also helps maintain the inhibitory phosphorylation of forkhead box O (FoxO) transcription factors, preventing their nuclear translocation and the subsequent transcription of proteolytic genes [ 61 ].

Resistance training, particularly when periodized, appears especially effective. In preclinical models, periodized resistance training has been shown to mitigate chemotherapy-induced IL-6 elevation and associated inflammation more effectively than non-periodized protocols, offering superior protection against muscle wasting, even if it does not completely prevent oxidative stress or atrophy [ 150 ]. In tumor-bearing mice, resistance training lowers plasma IL-6 and reduces the phosphorylation of STAT3 in skeletal muscle, leading to the downregulation of catabolic markers such as Atrogin-1 and LC3B-II [ 151 ]. Given the central role of STAT3 in driving cachexia, this exercise-induced attenuation is of clear therapeutic relevance. In parallel, exercise helps restore anabolic pathways that are suppressed by chronic IL-6 exposure. IL-6 disrupts mTORC1 signaling, a critical regulator of muscle protein synthesis. In cachectic Apc Min/+ mice, treadmill training restores muscle insulin-like growth factor 1 (IGF-1) mRNA expression and normalizes the phosphorylation of key mTORC1 downstream effectors, including p70S6K and 4E-BP1. Exercise also reduces aberrantly elevated AMPK activity, further supporting a pro-anabolic environment [ 152 ].

The physiological context of IL-6 release is critical. Exercise-induced IL-6 is primarily secreted by contracting muscle fibers as a myokine, distinct from the pathological release by immune or tumor cells. Evidence suggests muscle contraction itself, rather than tissue damage, is the dominant stimulus for this acute secretion [ 153 ]. This transient IL-6 surge activates beneficial feedback loops, such as the STAT3-SOCS3 axis and AMPK, which support myogenic differentiation and metabolic regulation [ 154 , 155 ]. While acute exercise elevates circulating IL-6, long-term training consistently reduces basal IL-6 levels [ 155 ]. This adaptation is particularly relevant in cancer cachexia, where chronic IL-6 overexpression drives muscle wasting [ 152 , 156 ]. The therapeutic potential of targeting this axis is underscored by clinical trials of tocilizumab, an IL-6 receptor antagonist, which reduces circulating IL-6, alleviates muscle loss, and does not promote tumor growth [ 157 , 158 ]. The convergence of evidence from exercise studies and pharmacological blockade strongly suggests that harnessing the physiological modulation of IL-6 through exercise presents a viable, multi-target strategy for managing cancer cachexia.

Mitochondrial biogenesis and function

Exercise-induced IL-6 plays a pivotal role in regulating mitochondrial biogenesis and function in skeletal muscle. It activates AMPK, a cellular energy sensor that, in turn, enhances mitochondrial biogenesis by upregulating PGC-1α [ 121 , 159 , 160 ]. Through this AMPK-PGC-1α axis, exercise-induced IL-6 contributes to increased mitochondrial content and oxidative capacity in muscle cells [ 161 ]. Beyond biogenesis, IL-6 helps regulate mitochondrial dynamics, the balance of fission and fusion that is critical for maintaining functional, healthy mitochondrial networks. In the Apc Min/+ mouse model of cachexia, exercise counteracts the deleterious effects of chronic IL-6 by increasing the expression of mitochondrial fusion proteins (Mfn1 and Mfn2) and suppressing the IL-6-driven elevation of the fission protein FIS1 [ 61 ]. This restoration of balanced dynamics supports efficient energy production and cellular homeostasis.

By concurrently promoting mitochondrial biogenesis and optimizing network dynamics, exercise-induced IL-6 enhances the muscle’s oxidative capacity and metabolic efficiency, ultimately improving endurance and energy metabolism [ 161 ].

Exercise-induced IL-6 in lipid metabolism

IL-6 is a prototypical exerkine, secreted by contracting skeletal muscle in a manner dependent on exercise duration and intensity [ 162 ]. Its transient, pulsatile elevation during and immediately after exercise acts on adipose tissue, liver, and skeletal muscle to stimulate lipid mobilization and oxidation, thereby counteracting the dysregulated lipid metabolism characteristic of cancer cachexia [ 33 , 146 ]. Human clamp-infusion studies corroborate this role, demonstrating that exercise-like concentrations of IL-6 enhance whole-body fat oxidation and free-fatty-acid (FFA) turnover [ 33 ]. Conversely, pharmacological blockade of IL-6 signaling with tocilizumab reduces FFA appearance both at rest and during exercise, underscoring the necessity of basal IL-6 tone for normal lipid metabolism [ 163 ]. Notably, recombinant IL-6 administration during low-intensity exercise does not further augment lipolysis, highlighting the context- and intensity-dependency of IL-6 action [ 164 , 165 ]. At the mechanistic level, exercise-induced IL-6 engages gp130/JAK/STAT signaling and activates AMPK in skeletal muscle and adipose tissue [ 166 ]. AMPK, in turn, promotes fatty-acid transport, oxidation, and intramyocellular triacylglycerol turnover, functions that are remarkably blunted in IL-6-deficient mice [ 167 ]. Together, these findings establish IL-6 as a key physiological link between acute muscle contraction and the regulation of lipid metabolism and energy balance.

The impact of IL-6 on adipose tissue, however, critically depends on its temporal and contextual profile. Acute, exercise-induced IL-6 promotes lipolysis through HSL and ATGL pathways and can contribute to adaptive beige adipocyte programming; in rodents, IL-6 is required for exercise- and cold-induced UCP1 expression [ 10 , 72 , 146 ]. In this setting, IL-6-driven browning enhances lipid flux and metabolic flexibility. In stark contrast, chronically elevated IL-6 derived from tumors or host tissues drives maladaptive lipolysis and white adipose tissue browning, accelerating energy wasting and cachexia progression [ 8 , 10 ]. Training studies further suggest that intact IL-6 signaling supports reductions in visceral fat and habitual lipid turnover, whereas IL-6R blockade in sedentary or obese individuals impairs FFA mobilization and may paradoxically favor fat retention [ 163 , 164 ]. Thus, appreciating the fundamental dichotomy between acute, beneficial and chronic, deleteriou s IL-6 actions is essential. Repeated bouts of moderate to-vigorous exercise that elicit transient IL-6 surges can enhance lipid-oxidative capacity without sustaining the persistent IL-6 elevation that exacerbates adipose wasting in cancer cachexia [ 43 , 168 ].

Anti-oxidative properties

One of IL-6’s primary protective mechanisms centers on its activation of nuclear factor erythroid 2-related factor 2 (Nrf2). This key transcription factor upregulates a suite of antioxidant enzymes, including SOD, GPx, and catalase, thereby directly mitigating oxidative damage in skeletal muscle [ 169 , 170 ]. In parallel, IL-6 stimulates AMPK and its downstream target, PGC-1α. This axis promotes mitochondrial biogenesis and improves oxidative metabolism, which synergistically enhance mitochondrial efficiency and reduce ROS production [ 61 , 171 , 172 ]. Furthermore, exercise-induced IL-6 drives a systemic shift toward an anti-inflammatory state. It stimulates the release of anti-inflammatory cytokines such as IL-10 while inhibiting pro-inflammatory mediators like TNF-α and IL-1β [ 121 , 173 ]. By dampening chronic inflammation, a major source of oxidative stress, this action provides an indirect yet powerful defense against redox imbalance. Taken together, these coordinated actions of exercise-mediated IL-6 play a crucial role in preserving redox homeostasis and counteracting the oxidative stress associated with cachexia.

Insulin sensitivity and glucose metabolism

Exercise-mediated IL-6 release plays a key role in enhancing glucose metabolism. By promoting the translocation of glucose transporter 4 (GLUT-4) vesicles to the muscle cell membrane, IL-6 facilitates glucose transport into the cell and supports glycogen synthesis [ 174 ]. This myokine also enhances whole-body insulin sensitivity, as demonstrated in human clamp studies where recombinant IL-6 (rhIL-6) infusion improved peripheral insulin-stimulated glucose uptake [ 26 ]. Furthermore, IL-6 activates AMPK signaling, which not only improves cellular glucose uptake but also contributes to its broader anti-inflammatory effects, thereby helping to counteract insulin resistance [ 26 , 155 ]. An additional metabolic benefit arises from the ability of IL-6 to stimulate the release of glucagon-like peptide-1 (GLP-1), which promotes insulin secretion [ 175 ]. These effects are particularly beneficial for cancer cachexia patients, who often suffer from insulin resistance and impaired glucose tolerance. Therefore, exercise plays a crucial role in preventing and treating cancer cachexia by harnessing the beneficial effects of IL-6.

Appetite regulation

Chronic inflammation is a key driver of malnutrition in cancer cachexia, contributing directly to anorexia and reduced food intake [ 176 ]. Exercise-induced IL-6 can counteract this process through its anti-inflammatory actions, such as promoting the release of IL-10 and reducing levels of the anorexigenic cytokine TNF-α [ 177 ]. By attenuating this chronic inflammatory state, muscle-derived IL-6 may help alleviate inflammation-driven anorexia. Furthermore, physical activity enhances sensitivity to appetite-regulating hormones like leptin and insulin, a process potentiated by IL-6 [ 178 ]. This improved sensitivity may help counteract the leptin resistance frequently observed in cachexia, thereby supporting the restoration of normal hunger signaling. Conversely, some evidence suggests that muscle-derived IL-6 released during exercise might itself have a transient appetite-suppressing effect [ 179 , 180 ]. This potential duality underscores the complex, context-dependent role of IL-6 in energy balance, warranting further mechanistic investigation.

Therapeutic implications

Regular, structured exercise is widely regarded as first-line supportive care in cancer cachexia. Current guidelines recommend combining moderate-intensity aerobic training with resistance exercise (typically 2–3 sessions of each per week), even during active anti-cancer treatment [ 181 , 182 ]. These programs are safe for most patients and effectively improve key outcomes such as functional capacity, muscle strength, fatigue, and quality of life. Critically, contracting muscle acutely releases IL-6 as a myokine, triggering an anti-inflammatory cascade (e.g., ↑IL-10/IL-1ra, ↓TNF-α) that fundamentally differs from the chronic, pathogenic IL-6 derived from tumors and host stroma [ 43 , 121 , 183 ]. Therefore, exercise serves as a foundational non-pharmacologic strategy to mitigate systemic inflammation and preserve lean mass.

Persistent activation of the IL-6/JAK/STAT3 pathway drives both muscle and adipose tissue wasting, making the combination of exercise with IL-6 pathway inhibition a rational and testable therapeutic strategy. Preclinical and early clinical studies have demonstrated the potential benefits of IL-6 or IL-6 receptor inhibitors, such as tocilizumab and ALD518 in non-small cell lung cancer [ 184 , 185 ], tocilizumab in case reports and retrospective cohorts [ 157 , 158 , 186 ], anti-IL-6 monoclonal antibodies in AIDS-related lymphoma [ 187 ] and metastatic renal-cell carcinoma [ 188 ], and siltuximab in prostate cancer [ 189 ] and multiple myeloma [ 190 ]. More recently, a randomized phase II trial in advanced pancreatic cancer showed that adding tocilizumab to gemcitabine/nab-paclitaxel attenuated muscle loss over 2–4 months and improved 18-month survival, although it did not meet the primary 6-month overall survival endpoint and was associated with increased grade ≥ 3 toxicities [ 191 ] (see Fig. 6 and Table 2 for details). Conceptually, exercise may “reprogram” systemic inflammatory tone and enhance anabolic sensitivity, while pharmacological IL-6 blockade directly suppresses pathological signaling. This combination holds promise for synergistic effects on muscle mass, function, and symptom control. Future trials should focus on optimizing treatment sequencing (e.g., initiating IL-6 blockade during acute catabolic phases, followed by supervised exercise as tolerance improves), biomarker-guided patient selection (e.g., based on baseline CRP, IL-6, or STAT3 activity), and vigilant safety monitoring for infections and cytopenias.

Fig. 6 Therapeutic strategies targeting IL-6 signaling in cancer cachexia. Blocking pathological IL-6 signaling can be achieved through monoclonal antibodies such as Siltuximab, Tocilizumab, or sgp130Fc constructs (selectively inhibiting IL-6 trans-signaling), thereby reducing STAT3 activation, lipolysis, and muscle atrophy. Harnessing beneficial IL-6 signaling through exercise leverages IL-6 as a myokine to promote mitochondrial biogenesis, lipid metabolism, anti-oxidative stress, improved insulin sensitivity, and anti-inflammatory effects, contributing to muscle preservation. A combined therapeutic approach targeting both pathological blockade and physiological enhancement may preserve lean body mass, attenuate muscle wasting, and improve quality of life and survival

Table 2 Potential benefits of IL-6/IL-6 receptor Inhibition in preclinical and early clinical studies Phase Patient Population Core Intervention (Anti-IL-6) Effect on IL-6/Inflammation Key Efficacy on Cachexia Primary Safety Conclusion Clinical Implications References Case Report lung cancer (stage IIIA) with cancer cachexia Tocilizumab CRP ↓ Body weight/OS ↑ Well-tolerated IL-6 neutralization improves cachexia-related symptoms [ 148 , 149 ] Phase I and Phase II Advanced NSCLC patients ALD518 CRP ↓ Body weight/OS ↑, Hand grip strength↑ Hemorrhoidal and rectal hemorrhage Improve anemia, reduce cancer-related cachexia and ameliorate fatigue [ 176 ] Phase II RCT/Observational Pancreatic Cancer/NSCLC with Inflammation Tocilizumab CRP ↓ Muscle Mass↑ Increased hematologic toxicity, but well-tolerated IL-6R blockade preserves muscle and improves prognosis [ 175 , 182 ] IL-6R mAb Body weight/OS ↑ Open-Label AIDS-Related Lymphoma BE-8 CRP ↓ (inferred) Weight ↑, fever resolution Manageable thrombocytopenia and neutropenia Early validation: IL-6 neutralization improves cachexia [ 178 ] Anti-IL-6 mAb Phase II Obs/Interventional Renal Cell Carcinoma BE-8 Acute phase proteins ↓ Confirmed correlation between IL-6 levels and weight loss Well-tolerated Establishes causal link between IL-6 and cachexia [ 179 ] Anti-IL-6 mAb Phase I Prostate Cancer Siltuximab CRP ↓, p-STAT3 ↓, p-ERK ↓ IL-6 pathway ↓, Androgen synthesis enzymes ↓ No drug-related SAEs Siltuximab safely inhibits IL-6 signaling, potential anti-tumor effect [ 180 ] Anti-IL-6 mAb Phase I (Open-Label) Multiple Myeloma Siltuximab CRP reduction (indirect measure) Stable symptoms (MDASI), no worsening Manageable pneumonia and thrombocytopenia Siltuximab with chemo without increasing symptom burden [ 181 ] Anti-IL-6 mAb

Personalized approaches are essential due to heterogeneity in tumor biology, treatment course, and symptom burden. While combined aerobic and resistance training forms the therapeutic backbone, programs must be tailored to the treatment phase (e.g., prehabilitation, dose-adapted training during active therapy, progressive loading in survivorship), comorbidities, and patient preference [ 181 , 182 , 192 , 193 ]. Practical safeguards include pre-exercise screening, withholding sessions during fever or severe cytopenias, and close coordination with the oncology team. Several barriers impede translation into routine care, including tumor-specific variability in IL-6 dependence, safety concerns when combining with cytotoxic/immunotherapy, and a lack of standardized endpoints (e.g., weight vs. CT-derived muscle indices vs. patient-reported outcomes). Research priorities include biomarker-enriched trials, adaptive exercise dosing, comparative studies of exercise modalities, and factorial designs evaluating exercise with or without IL-6 pathway inhibition under robust safety surveillance.

Challenges and future directions

A central challenge in cancer cachexia research is reconciling the so-called “IL-6 paradox.” Transient, exercise-induced surges of muscle-derived IL-6 support metabolic flexibility and exert anti-inflammatory effects via classical (cis-) signaling pathways, including upregulation of IL-10 and IL-1Ra [ 115 , 194 ]. Conversely, chronically elevated IL-6, often tumor- or host-derived, drives systemic catabolism and muscle wasting via persistent JAK/STAT3 activation, frequently through feed-forward trans-signaling loops among tumor, adipose tissue, and skeletal muscle [ 8 , 56 , 98 , 99 ]. Disambiguating when IL-6 acts as a beneficial myokine versus a pro-cachectic cytokine will require pathway-specific, tissue-targeted studies distinguishing classical from trans-signaling and mapping their kinetics across exercise and recovery in diverse cancer contexts.

A major methodological barrier is the difficulty of attributing circulating IL-6 to its cellular source. Standard assays rarely capture the complete signaling milieu, which includes IL-6, sIL-6R, sgp130, and tissue-specific downstream effectors like phosphorylated STAT3 [ 56 , 195 ]. The clinical utility of sIL-6R and sgp130 relative to IL-6 alone also remains unclear. To determine whether exercise shifts IL-6 signaling toward protective pathways in cachexia, standardized, time-resolved sampling protocols (pre-exercise, peak, recovery), complemented by optional tissue biopsies, are essential. Given the variation in IL-6 biology across tumor types, for example, robust trans-signaling in pancreatic cancer, clinical trials must incorporate careful stratification and consistent cachexia endpoints (e.g., lean mass, strength, patient-reported function) [ 8 , 98 , 99 , 122 , 196 ].

Equally critical is the lack of dose-response data for the “therapeutic” IL-6 pulses evoked by exercise. IL-6 kinetics depend on exercise intensity, duration, muscle mass recruited, and individual training status [ 194 , 197 ]. Oncology exercise programs must therefore optimize modality, intensity, and timing to elicit short-lived, beneficial IL-6 surges without exacerbating chronic inflammation. Adaptive trial designs, guided by physiological feedback (e.g., heart rate, %VO₂peak, %1RM), are promising. Integrating paired muscle biopsies with phospho-proteomic analyses could further reveal whether exercise blunts pathological STAT3 activation, informing combination strategies that selectively inhibit trans-signaling (e.g., with sgp130Fc) or target downstream JAK/STAT3. Early reports of IL-6/IL-6R blockade and JAK inhibition in cachexia, though limited, suggest potential benefit in IL-6-high states [ 48 , 195 , 198 ].

Looking ahead, integrating exercise with pharmacological and technological innovations holds substantial promise. Effective strategies must balance suppressing pro-cachectic IL-6 signaling while preserving beneficial myokine functions—for example, by pairing structured exercise with metabolic agents (e.g., metformin) or trans-signaling-selective inhibitors. Precision exercise prescriptions, informed by real-time IL-6 dynamics, wearable biosensors, and AI-driven analytics, could be tailored to an individual’s genetics, conditioning, adiposity, and treatment context. Systems-biology approaches integrating multi-omics data will enable better patient stratification and outcome prediction [ 199 , 200 ]. Simultaneously, implementation science is needed to translate these insights into scalable, equitable oncology care. Remote monitoring, behavioral support, and digital platforms may enhance adherence, while pragmatic endpoints (e.g., treatment tolerance, hospitalizations, cost-effectiveness) will strengthen clinical relevance. Ultimately, resolving the IL-6 paradox and developing effective cachexia therapies will require sustained interdisciplinary collaboration across oncology, immunology, exercise physiology, and bioengineering.

Conclusion

Cancer cachexia is a complex metabolic syndrome characterized by systemic inflammation, progressive muscle wasting, and energy imbalance, with IL-6 serving as a central pathogenic mediator. Chronic, tumor- and host-driven elevation of IL-6 promotes muscle catabolism, adipose tissue lipolysis, anorexia, and insulin resistance. Paradoxically, IL-6 also exhibits a context-dependent, beneficial role when released transiently from contracting skeletal muscle during exercise, acting as a myokine that confers anti-inflammatory and metabolic advantages. This exercise-induced IL-6 enhances glucose uptake, stimulates lipid oxidation, and promotes the secretion of anti-inflammatory cytokines such as IL-10, jointly contributing to improved energy homeostasis and muscle preservation. This review has elucidated the dual nature of IL-6 signaling and underscores the therapeutic potential of structured exercise to beneficially modulate this axis. A precise understanding of the temporal dynamics and cellular source of IL-6 is crucial for designing effective exercise interventions that can mitigate the detrimental effects of chronic inflammation while harnessing the protective, adaptive responses elicited by physical activity in patients with cancer cachexia.

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Shujuan Wei, Xinyi Lv and Yiming Xu contributed equally to this work.

Acknowledgements

We acknowledge BioRender ( https://BioRender.com ) for figure preparation and thank the anonymous reviewers for their constructive comments, which improved this manuscript.

Author contributions

WS, LX, XY, and DS conceived and designed the review and contributed to manuscript drafting. Figures were primarily prepared by WS and DS. DS provided critical revisions and approved the final manuscript. All authors have read and confirmed the published version of the manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (Grant No. 82103021 to S. Ding) and the China Postdoctoral Science Foundation (Grant No. 2022M721725 to S. Ding). Additional funding was provided by the “14th Five-Year Plan” Nantong Clinical Medical Center (Innovation Platform) and the Youth Medical Expert Training Program, both funded by the Nantong Municipal Health Commission. Further support was received from the 2024 School-Level Graduate Research and Practice Innovation Program of the Medical School, Nantong University (Grant No. YJS2004006 to X. Lv).

Data availability

Not applicable.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no conflicts of interest.

Abbreviations

Body mass index

Interleukin-6

Membrane-bound IL-6 receptor

Soluble IL-6R

IL-6 receptors

Recombinant IL-6

Tumor necrosis factor-alpha

glycoprotein 130

Janus kinase/signal transducer and activator of transcription 3

Mitogen-activated protein kinase

Phosphatidylinositol 3-kinase/protein kinase B

C-reactive protein

Serum amyloid A

IL-1 receptor antagonist

Suppressor of cytokine signaling 3

Peroxisome proliferator-activated receptor-gamma coactivator 1-alpha

Muscle satellite cells

Hormone-sensitive lipase

Adipose triglyceride lipase

Insulin receptor

Insulin receptor substrate

Uncoupling protein 1

Central nervous system

Area postrema

Nucleus tractus solitarius

Paraventricular nucleus

Hypothalamic-pituitary-adrenal

Reactive oxygen species

Glutathione

Mitochondrial DNA

Superoxide dismutase

Glutathione peroxidase

Mammalian target of rapamycin

Ryanodine receptors

Nuclear factor of activated T cells

β₂-adrenergic receptors

Element-binding protein

AMP activated protein kinase

Monocarboxylate transporters

Hypoxia-inducible factor alpha

Histone deacetylases

Homeostatic Model Assessment of Insulin Resistance

Chronic low-intensity exercise

Forkhead box O

Insulin-like growth factor 1

Free fatty acid

Nuclear factor erythroid 2-related factor 2

Glucose transporter 4

Glucagon-like peptide-1

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