Effect of Obesity Associated with Metabolic Changes on SASPs

Adipose tissue secretes a diverse and expanding repertoire of bioactive mediators — collectively termed adipokines — that extend well beyond the classical molecules discussed here. Adipokines including visfatin (NAMPT), chemerin, FGF21, omentin-1, and apelin have all been implicated in tumor development, progression, and therapeutic resistance, and the full scope of adipose-tumor crosstalk has been comprehensively reviewed elsewhere [47, 48]. The present review focuses specifically on leptin, adiponectin, resistin, and insulin as the four adipokines/metabolic hormones with the most extensively characterized mechanistic links to SASP amplification and obesity-associated oncogenesis. These four were selected on the basis of: (1) the strength and reproducibility of the evidence connecting them to the four principal SASP cytokines reviewed in Sect. Effect of SASPs on Cancer Progression (IL-6, IL-8, MCP-1, and IL-1β); (2) the availability of mechanistic data from both in vitro and in vivo models; and (3) their direct clinical relevance as measurable circulating biomarkers in individuals with obesity. While insulin is not a classical adipokine, its chronic elevation in obesity-associated insulin resistance makes it an obligate component of the metabolic hormonal milieu that drives SASP production, justifying its inclusion within this section.

Effect of Leptin on SASPs

A hallmark of obesity is hyperleptinemia, which occurs due to a breakdown in the hormone’s feedback loop [132]. While leptin normally signals energy sufficiency to the hypothalamus, central resistance in obesity blunts this signal [133]. Consequently, the brain fails to respond to elevated leptin, disrupting energy homeostasis and promoting continued weight gain [134]. Thus, the primary aberration is impaired leptin signal transduction in the brain, rather than a lack of hormone. This inherent resistance fundamentally limits the therapeutic potential of exogenous leptin administration, necessitating alternative strategies to overcome the signaling blockade. Leptin signaling in physiological and obese states is illustrated in Fig. 2A.

An important caveat to the mechanistic framework presented in this section is that most studies linking hyperleptinemia to SASP amplification have been conducted in cell lines or rodent models of diet-induced obesity. Whether leptin resistance, the dominant state in clinical human obesity, preserves or attenuates leptin’s pro-SASP signaling effects in peripheral tissues (as distinct from the brain) remains incompletely resolved. If peripheral leptin resistance parallels central resistance, the functional contribution of hyperleptinemia to SASP-driven oncogenesis in humans may be more complex and attenuated than preclinical models suggest. Effects of leptin on SASPs are illustrated in Fig. 2B.

Effect of Leptin on IL-6

The adipokine leptin contributes to chronic, low-grade inflammation, an effect strongly associated with its positive correlation with the pro-inflammatory cytokine IL-6. This relationship between elevated circulating leptin and IL-6 levels is consistently observed in both human studies and animal models of obesity and metabolic syndrome [135]. The mechanistic link involves leptin signaling through its long-form receptor (Ob-R), which directly stimulates IL-6 synthesis and release from a range of cell types, including monocytes, macrophages, T cells, adipocytes, and vascular smooth muscle cells (VSMCs) [136–138]. This process is primarily mediated by the activation of intracellular JAK/STAT and MAPK signaling cascades [139]. Notably, leptin-driven JAK2/STAT3 activation in VSMCs promotes vascular smooth muscle cell proliferation and a pro-inflammatory vascular phenotype, providing a direct cellular mechanism by which hyperleptinemia drives vascular pathology [140].

Consequently, hyperleptinemia functions as an endogenous driver of a pro-inflammatory state, amplifying systemic inflammation through IL-6 upregulation and thereby promoting the development of conditions such as insulin resistance and atherosclerosis [141]. The leptin-IL-6 relationship is among the better-supported adipokine-cytokine associations in obesity, with consistent positive correlations documented in multiple human cross-sectional studies. However, causality remains difficult to establish in human cohorts because both leptin and IL-6 rise in parallel with adiposity and systemic inflammation, precluding a clear determination of whether hyperleptinemia drives IL-6 elevation or vice versa. Interventional studies measuring IL-6 before and after pharmacological leptin receptor modulation in humans are needed to confirm the directionality implied by preclinical mechanistic data. Effects of Leptin on IL-6 are illustrated in Fig. 2B.

Effect of Leptin on IL-8

Within pro-inflammatory and pro-malignant contexts, leptin directly upregulates the potent chemokine IL-8 (CXCL8). This effect, characterized by concentration- and time-dependent increases in IL-8 transcript and protein, has been validated in multiple cancer and stromal cell types [142]. The mechanism involves Ob-R receptor signaling through PI3K/Akt and MAPK, culminating in NF-κB activation and IL-8 transcription [143]. This cascade functionally contributes to oncogenesis by enhancing EMT and invasive capacity, providing a molecular bridge from hyperleptinemia to cancer progression [143]. The mechanistic evidence linking leptin to IL-8 induction currently rests primarily on in vitro experiments in cancer cell lines and synovial fibroblast models; in vivo confirmation of this pathway in obesity-associated tumor models, and human data demonstrating that hyperleptinemia elevates tumor-associated IL-8 levels, are lacking. This pathway should therefore be regarded as a biologically plausible mechanistic hypothesis supported by cell-based evidence, rather than an established link in human obesity-associated oncogenesis. Effects of Leptin on IL-8 are illustrated in Fig. 2B.

Effect of Leptin on MCP-1

The activation of leptin-driven signaling cascades (JAK-STAT3, MAPK/ERK, PI3K-Akt) results in a pro-inflammatory TME [144]. This chemokine milieu drives the infiltration of immune cells that contribute to tumorigenesis by promoting angiogenesis and sustaining proliferation [145, 146].

Leptin signaling promotes key hallmarks of cancer progression often in conjunction with elevated MCP-1 expression, suggesting a functional interplay between these pathways [147]. The reprogramming of TAMs toward an M1-like phenotype by leptin leads to elevated MCP-1 levels and a more immunosuppressive TME. On the other hand, it was found that MCP-1 expression is positively associated with CD68 or CD163 expression, marker of M2 macrophage, in DLBCL [112]. Transcript levels of both M1-like (CD11c, iNOS) and M2-like (CD206) macrophage markers were increased in the mammary glands of mice fed a high-fat diet [148]. These changes collectively promote tumor aggressiveness and can compromise the efficacy of immunotherapeutic interventions [149]. An unresolved controversy regarding leptin’s effect on MCP-1 concerns the net polarization outcome of the macrophages recruited by this axis. Some preclinical studies describe leptin-driven MCP-1 upregulation as promoting M1-like macrophage recruitment with pro-inflammatory cytokine secretion, while others describe the recruited TAMs as adopting an M2-like, immunosuppressive phenotype, consistent with the broader TAM literature [150–152]. This apparent contradiction likely reflects cancer-type and microenvironment-specific differences in macrophage programming, and direct single-cell resolution data from human obese tumor tissue are needed to characterize the dominant macrophage phenotype recruited by the leptin-MCP-1 axis in vivo. Effects of Leptin on MCP-1 are illustrated in Fig. 2B.

Effect of Leptin on IL-1β

In breast and ovarian cancer cells, leptin directly stimulates the expression of IL-1β and related IL-1 system components (e.g., IL-1α, IL-1Ra, IL-1RI) at the transcriptional and translational levels. This induction is mediated through multiple signaling pathways, such as JAK2/STAT3, MAPK/ERK, and PI3K/AKT. Consequently, leptin-driven IL-1β production constitutes a critical element of a pro-inflammatory and pro-angiogenic program that fuels tumor progression [153, 154].

Leptin-driven upregulation of IL-1β subsequently enhances the expression of VEGF and its receptor VEGFR2, thereby promoting angiogenesis, which is critical for tumor growth and expansion [154]. The functional importance of this axis is demonstrated by the fact that inhibition of IL-1 signaling significantly attenuates leptin-induced VEGF/VEGFR2 upregulation [155, 156]. In breast and hepatic cancer cells, leptin stimulates IL-1β maturation and inflammasome activation, processes that are mechanistically linked to enhanced tumor growth [157, 158]. The pro-tumorigenic effects of this pathway can be attenuated by the adipokine adiponectin or through the induction of the cytoprotective HO-1 pathway [159]. Effects of Leptin on IL-1β are illustrated in Fig. 2B.

Fig. 2: (A) Leptin signaling in physiological and obese states. In the healthy state, adipose tissue secretes leptin, which travels through circulation to the hypothalamus, where it binds to leptin receptors on target neurons and activates downstream signal transduction pathways. This intact signaling cascade promotes satiety, suppresses appetite, increases energy expenditure, and maintains stable body weight. In contrast, during obesity, enlarged adipose tissue produces elevated levels of circulating leptin; however, central leptin resistance impairs hypothalamic signaling. Despite receptor engagement, intracellular signal transduction is attenuated or blocked, resulting in a failure to elicit satiety responses. Consequently, appetite remains elevated, energy expenditure is reduced, and continued weight gain occurs. The diagram also highlights therapeutic limitations associated with this signaling blockade (The blue for healthy state and the red half for the obese state). (B) Schematic representation illustrating leptin-mediated signaling pathways in obesity and their downstream effects on inflammation, metabolism, and tumor-related processes. In obese individuals, elevated leptin levels activate the Ob‑Rb receptor, triggering multiple signaling cascades including JAK/STAT, MAPK, and PI3K/AKT pathways. These pathways promote the production of IL‑6, IL‑8, IL‑1β, and MCP‑1. IL‑6 contributes to insulin resistance and atherosclerosis, while IL‑8 enhances epithelial–mesenchymal transition (EMT) and tumor cell invasiveness. IL‑1β promotes angiogenesis via VEGF‑B, and MCP‑1 is associated with immune modulation and responses to immunotherapy. Collectively, these signaling events highlight the role of leptin in linking obesity to inflammation, metabolic dysfunction, and cancer progression. Akt: Protein Kinase B, EMT: Epithelial-Mesenchymal Transition, ERK: Extracellular signal-Regulated Kinase, IL-1β: Interleukin-1 beta, IL-6: Interleukin 6, IL-8: Interleukin 8, JAK: Janus kinase, MAPK: Mitogen-Activated Protein Kinase, MCP-1: Monocyte Chemoattractant Protein-1, PI3K: Phosphoinositide 3-kinase, STAT: Signal Transducer and Activator of Transcription, VEGF-B: Vascular Endothelial Growth Factor B

Effect of Adiponectin on SASPs

Adiponectin counteracts cellular senescence by mitigating oxidative stress, primarily through the suppression of ROS production [160, 161]. The coordinated activation of AMPK, SIRT1, and AdipoR1/APPL1 pathways by adiponectin enhances fundamental survival mechanisms, such as autophagic flux, metabolic equilibrium, and stress resistance [162, 163]. Furthermore, adiponectin counteracts senescence through a multi-faceted approach: it suppresses the expression of key markers (p16, p21) and the SASP while promoting telomere maintenance and enhancing mitochondrial function [163–165]. Mechanism of adiponectin signaling counteracts cellular senescence is illustrated in Fig. 3A. The anti-senescent and anti-SASP properties of adiponectin described in this section are well documented at the mechanistic level, and the inverse association between circulating adiponectin and cancer risk has been consistently observed across epidemiological studies of breast [166, 167], colorectal [168, 169], and endometrial cancers [170] in human cohorts. However, a critical translational challenge is that adiponectin’s multimeric complexity, with distinct biological activities associated with trimeric, hexameric, and high-molecular-weight forms, means that total circulating adiponectin measurements may not accurately reflect the biologically active fraction relevant to cancer risk. This complicates both the interpretation of epidemiological associations and the development of therapeutic adiponectin-based strategies.

Collectively, these findings suggest adiponectin as a multifunctional brake on the senescence program: by simultaneously dampening oxidative stress, sustaining autophagic flux, suppressing SASP marker expression, and preserving telomere integrity, adiponectin counteracts each of the principal mechanisms through which obesity drives adipose tissue senescence. Its deficiency in obesity therefore creates a permissive environment in which SASP amplification proceeds unchecked, directly linking hypoadiponectinemia to the pro-tumorigenic remodeling of the tissue microenvironment. Effects of adiponectin on SASPs are illustrated in Fig. 3B.

Fig. 3: (A) Adiponectin signaling counteracts cellular senescence through coordinated AMPK–SIRT1 activation and metabolic protection. Schematic representation of the molecular mechanisms by which adiponectin mitigates cellular senescence. Binding of adiponectin to its receptor AdipoR1 recruits the adaptor protein APPL1, leading to coordinated activation of the AMPK–SIRT1 signaling axis. This pathway promotes mitochondrial function and reduces oxidative stress, resulting in suppressed ROS production and maintenance of metabolic homeostasis. Concurrently, adiponectin enhances fundamental survival mechanisms, including increased autophagic flux and improved cellular stress resistance. At the genomic level, adiponectin preserves telomere integrity and regulates cell cycle progression through suppression of senescence-associated cyclin-dependent kinase inhibitors, including p16 and p21. Additionally, activation of this pathway attenuates inflammatory signaling by limiting the senescence-associated secretory phenotype (SASP), including pro-inflammatory cytokines and matrix remodeling factors. (B) Schematic representation of adiponectin signaling and its dysregulation in obesity, highlighting downstream effects on inflammation, tumor progression, and cellular responses. In obese individuals, reduced adiponectin levels limit activation of AdipoR1 and AdipoR2 receptors, leading to stimulation of STAT3 and TNF‑α pathways, resulting in increased IL‑6 and IL‑8 production, which promote tumor cell proliferation, angiogenesis, and immunosuppression. Additional signaling via STAT3/AMPK/LKB1 and p53/p21/p27 pathways regulates IL‑1β expression, influencing proliferation and apoptosis. Concurrent activation of NF‑κB signaling increases MCP‑1 production, further supporting tumor cell growth. Collectively, these pathways illustrate how impaired adiponectin signaling in obesity contributes to a pro-tumorigenic microenvironment. AMPK: adenosine monophosphate-activated protein kinase, APPL1: Adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1, ERK: Extracellular signal-Regulated Kinase, IL-1β: Interleukin-1 beta, IL-6: Interleukin 6, IL-8: Interleukin 8, LKB1: Liver kinase B1, MCP-1: Monocyte Chemoattractant Protein-1, NF-κB: Nuclear Factor kappa B, SASP: Senescence-Associated Secretory Phenotype, SIRT1: Sirtuin 1, STAT: Signal Transducer and Activator of Transcription, TNF-α: Tumor Necrosis Factor-alpha

Effect of Adiponectin on IL-6

Adiponectin functions as an anti-inflammatory and anti-cancer agent, primarily by suppressing the production and signaling of IL-6 and other pro-inflammatory cytokines in immune cells like macrophages. This action attenuates the tumor-promoting inflammatory milieu, thereby impeding cancer progression [171]. Adiponectin and IL-6 exert counteracting influences on tumor behavior; high adiponectin levels correlate with suppressed proliferation, metastasis, and better survival, in contrast to the pro-tumorigenic effects of IL-6 in colorectal cancer [172]. This improved prognosis associated with adiponectin is likely mediated by its inhibition of IL-6 signaling in nasopharyngeal carcinoma [173]. By reducing STAT-3 phosphorylation and activation, adiponectin administration on MC-38 cells inhibited IL-6-induced cell proliferation [172]. Taken together, these findings establish adiponectin as a suggested antagonist of IL-6-driven oncogenesis: it suppresses IL-6 production by macrophages [171], disrupts IL-6/STAT3 signaling in tumor cells [174], and thereby reverses the proliferative and survival advantages that IL-6 confers on malignant cells. In the context of obesity where adiponectin is chronically depressed and IL-6 chronically elevated, this antagonism is lost, effectively removing a key endogenous brake on tumor-promoting inflammation and positioning hypoadiponectinemia as a direct mechanistic contributor to obesity-associated cancer progression. Effects of adiponectin on IL-6 are illustrated in Fig. 3B.

Effect of Adiponectin on IL-8

Adiponectin exerts an anti-inflammatory effect on vascular endothelium by suppressing TNF-α-induced IL-8 production [175]. The mechanism involves dual action: inhibition of the NF-κB pathway and cAMP/PKA-dependent activation of Akt, leading to reduced IL-8 expression and secretion [176]. In the context of obesity-associated cancer, this adiponectin-mediated restraint on IL-8 is mechanistically critical: as established in Sect. Effect of IL-8 on cancer progression, IL-8 drives tumor angiogenesis [177, 178], recruits immunosuppressive myeloid populations [179, 180], and promotes metastatic dissemination [177, 178]. The obesity-driven decline in adiponectin therefore removes a dual vascular and immunological restraint, permitting IL-8 to fuel tumor neovascularization and therapeutic resistance within an inflammatory microenvironment that is already permissive to cancer progression. Effects of adiponectin on IL-8 are illustrated in Fig. 3B.

Effect of Adiponectin on MCP-1

A key anti-cancer mechanism of adiponectin involves the suppression of pro-inflammatory mediators like MCP-1, leading to the inhibition of cancer cell growth. This is exemplified in lung epithelial cells, where adiponectin attenuates MCP-1 production, an effect potentially mediated through the inhibition of the master inflammatory regulator NF-κB [181, 182]. This suppression of MCP-1 is of direct relevance within the framework of this review: MCP-1 is the primary recruiter of circulating monocytes into the tumor-adjacent adipose stroma, where they differentiate into pro-tumorigenic TAMs as described in Sect. Introduction. By restraining MCP-1 through NF-κB inhibition [183, 184], adiponectin normally limits this macrophage recruitment axis. Hypoadiponectinemia in obesity therefore disinhibits NF-κB [185], permitting unchecked MCP-1-driven monocyte infiltration and perpetuating the immunosuppressive CLSs environment characteristic of patients with obesity adipose tissue — a microenvironment that directly feeds the SASP-driven pro-tumorigenic niche. Effects of adiponectin on MCP-1 are illustrated in Fig. 3B.

Effect of Adiponectin on IL-1β

Adiponectin counteracts IL-1β-mediated oncogenesis by inhibiting cancer cell proliferation and inflammation [172, 173, 182]. In colon cancer, this protective effect—synergized by metformin—operates through STAT3 and AMPK/LKB1 pathways to restore cell cycle control by upregulating p53/p21/p27 and suppressing cyclins [186]. Raut and Park [159] showed that Globular adiponectin inhibits tumor growth by suppressing inflammasome activation (IL-1β/caspase-1) in breast and liver cancer cells, leading to reduced proliferation and increased apoptosis via HO-1 and estrogen receptor-α pathways. Nigro, Scudiero [182] Showed that via the AdipoR1 receptor, adiponectin counteracts IL-1β-induced damage in lung epithelial cells by promoting viability, suppressing apoptosis and NF-κB signaling, and selectively upregulating anti-inflammatory IL-10.

Collectively, these data demonstrate that adiponectin suppresses IL-1β-mediated oncogenesis through potential complementary upstream and downstream mechanisms: blockade of inflammasome activation, inhibition of NF-κB-driven inflammatory transcription, and restoration of tumor-suppressive cell cycle checkpoints via p53/p21/p27 upregulation. In obesity, where adiponectin is deficient and the NLRP3 inflammasome may be constitutively primed by metabolic danger signals, this protective circuit is disrupted — allowing IL-1β contribution to propagate the SASP, drive EMT, stimulate angiogenesis, and suppress anti-tumor immunity without restraint. Adiponectin thus functions as a potential physiological senomorphics agent, and its loss in obesity may represent a key vulnerability through which the SASP-driven pro-tumorigenic program is licensed to proceed.

Adiponectin’s modulation of all four SASP cytokines in obesity suggests a compelling mechanistic case for hypoadiponectinemia as a critical permissive factor in obesity-associated oncogenesis. The evidence is strongest for the adiponectin-IL-6 and adiponectin-IL-1β axes, where both mechanistic pathway data and human epidemiological correlations converge. The adiponectin-IL-8 and adiponectin-MCP-1 evidence bases are more limited and predominantly mechanistic. A broader unresolved controversy is whether the cancer-preventive effects attributed to adiponectin in epidemiological studies are causally driven by adiponectin itself or confounded by correlated variables such as insulin sensitivity, physical activity, and overall metabolic health — all of which track with adiponectin levels and independently affect cancer risk. Effects of adiponectin on IL-1β are illustrated in Fig. 3B.

Effect of Insulin on SASPs

The case for insulin and hyperglycemia as drivers of SASP amplification is mechanistically strong, with the NLRP3/IL-1β axis providing a potential well-characterized molecular link supported by both cell-based and in vivo evidence. However, a key unresolved question is how much of the cancer risk attributable to insulin resistance is mediated by SASP amplification specifically, versus direct mitogenic IGF-1R/AKT/mTOR signaling on tumor cells, which may operate independently of SASP and has a substantial literature of its own. Disentangling these two routes of insulin-associated cancer promotion is clinically important because they imply different therapeutic strategies: SASP suppression versus IGF-1R blockade versus metabolic normalization.

Baboota, Spinelli [187] showed that chronic hyperinsulinemia drives hepatocyte senescence through p53/p21 activation and increased susceptibility to stress, mediated in part by sustained Cyclin D1 expression. This pro-senescent effect is reversible by senolytic treatment with dasatinib and quercetin. The translational potential of senolytic strategies has begun to be evaluated in early-phase human studies. A first-in-human pilot trial of the dasatinib plus quercetin (D + Q) combination in patients with idiopathic pulmonary fibrosis, a senescence-driven fibrotic disease, demonstrated selective reduction of senescent cell burden in adipose tissue and skin biopsies, alongside improvements in physical function, providing proof-of-concept for the clinical feasibility of pharmacological senescent cell clearance in humans [188]. In the oncology context, D + Q and the senolytic navitoclax (ABT-263) are currently under investigation in early-phase clinical trials for their capacity to improve responses to chemotherapy and immunotherapy in solid tumors. Studies such as NCT01557777 investigates the effect of navitoclax on subjects with chronic lymphocytic leukemia (CLL) while NCT03366103 study effect of navitoclax and vistusertib in treating patients with relapsed small cell lung cancer and other solid tumors, however, critical translational challenges remain: (i) the absence of validated, tumor-specific SASP biomarkers for patient selection and pharmacodynamic monitoring; (ii) the risk of on-target toxicity from broad senescent cell clearance, which could impair wound healing and tissue homeostasis; and (iii) the difficulty of distinguishing obesity-driven senescence burden from age-related senescence in clinical populations, which complicates trial design. These challenges highlight that while senolytics represent a scientifically compelling strategy for interrupting the obesity-SASP-cancer axis, their clinical application in oncology remains at an early stage and requires both biomarker development and carefully designed combination trial strategies. Insulin/IGF‑1 signaling in aging and the role of chronic hyperinsulinemia in driving cellular senescence is illustrated in Fig. 4A.

Fig. 4: (A) Insulin/IGF‑1 signaling in aging and the role of chronic hyperinsulinemia in driving cellular senescence, with reversal by senolytic therapy. (1) Overview of the insulin/IGF‑1 pathway in aging regulation. Balanced or reduced insulin/IGF‑1 signaling promotes longevity, partly through stress resistance pathways including STAT3 and p53. In contrast, excessive signaling accelerates aging, shortens lifespan, and promotes tissue dysfunction. (2) Mechanism of chronic hyperinsulinemia‑induced senescence. Sustained insulin exposure enhances insulin receptor (IR) signaling, leading to increased activation of STAT3 and p53/p21 pathways. This signaling cascade induces DNA damage responses, cell cycle arrest, and increased susceptibility to cellular stress. These events culminate in the development of a senescence characterized by altered morphology, metabolic dysfunction, and acquisition of a senescence‑associated secretory phenotype (SASP). (3) Reversal of senescence by senolytic therapy. Treatment with senolytic agents (Dasatinib and Quercetin, D + Q) selectively induces apoptosis in senescent cells, thereby reducing senescent cell burden. Clearance of senescent cells restores tissue function and reverses the pro‑senescent environment induced by chronic hyperinsulinemia. (B) Schematic overview of insulin signaling in obesity and its downstream effects on inflammation, tumor progression, and immune modulation. In obese individuals, elevated insulin levels activate the insulin receptor, triggering multiple signaling pathways including STAT3/PTX3, IL‑8, and NLRP3 axes. STAT3/PTX3 signaling induces IL‑6 production, promoting tumor invasion, while IL‑8 enhances angiogenesis and immunosuppression. Activation of the NLRP3 inflammasome increases IL‑1β levels, contributing to tumor progression and reduced responsiveness to immunotherapy. Additionally, insulin-associated adipokines such as leptin and resistin upregulate MCP‑1, facilitating the recruitment of tumor-promoting macrophages. Collectively, these pathways highlight the role of hyperinsulinemia in shaping a pro-tumorigenic microenvironment. IGF-1: Insulin-like Growth Factor 1, IL-1β: Interleukin-1 beta, IL-6: Interleukin 6, IL-8: Interleukin 8, MCP-1: Monocyte Chemoattractant Protein-1, NLRP3: NOD-, LRR- and pyrin domain-containing protein 3, PTX3: Pentraxin 3, STAT: Signal Transducer and Activator of Transcription

Effect of Insulin on IL-6

A pathogenic cycle links insulin resistance, IL-6, and cancer, particularly in obesity. AT-derived IL-6 impairs insulin signaling, fostering hyperinsulinemia, which in turn can promote tumor growth [189, 190]. Concurrently, IL-6 directly shapes a pro-tumorigenic microenvironment. This vicious cycle is evidenced by the strong association between elevated IL-6 levels and an increased risk of cancer [191]. Xie, Ruan [192] Showed that the enhanced invasiveness was attributable to elevated IL-6, which was secreted by mature adipocytes in culture and present at higher concentrations in the serum of obese mice. The functional role of IL-6 was confirmed by treating cells with the recombinant cytokine, which directly stimulated triple-negative breast cancer (TNBC) cell migration and invasion and activated the STAT3/PTX3 signaling axis [193]. These findings reveal a self-reinforcing pathological circuit uniquely amplified in obesity: adipose-derived IL-6, driven in part by the hyperinsulinemia state, may worsen insulin resistance while simultaneously activating oncogenic STAT3 signaling in neighboring cancer cells. This bidirectional crosstalk means that metabolic and oncogenic dysfunction are not merely parallel consequences of obesity but mutually reinforcing processes, and that IL-6 functions as a potential molecular bridge between systemic metabolic disorder and the local pro-tumorigenic microenvironment — a mechanistic insight that directly implicates the hyperinsulinaemia-IL-6-SASP axis as a therapeutic target in obesity-associated cancers. Effects of Insulin on IL-6 are illustrated in Fig. 4B.

Effect of Insulin on IL-8

Insulin acts synergistically with fatty acids (e.g., palmitate) to upregulate the pro-tumorigenic chemokine IL-8 in macrophages, thereby promoting processes critical for cancer progression, like angiogenesis and metastasis [194, 195]. In vitro, insulin synergizes with palmitate to markedly enhance IL-8 secretion, beyond its modest effect on mRNA alone, mimicking the amplified inflammatory response seen in metabolic dysfunction [196]. This synergy between hyperinsulinemia and dyslipidemia in driving macrophage IL-8 production is particularly consequential in obesity, where both conditions chronically co-exist. The resulting IL-8 surge promotes tumor angiogenesis [197, 198], recruits immunosuppressive myeloid populations to the TME [179, 180], and generates a chemotactic environment favoring metastatic dissemination — effects that neither metabolic perturbation would produce in isolation. This observation highlights that the suggested pro-tumorigenic impact of obesity on the SASP is not simply additive across individual metabolic derangements, but is qualitatively amplified by their convergence, reinforcing the importance of simultaneously addressing multiple metabolic risk factors in obesity-associated cancer prevention and management. Effects of Insulin on IL-8 is illustrated in Fig. 4B.

Effect of Insulin on MCP-1

Sartipy and Loskutoff [199] results suggest that the effect of insulin on MCP-1 is determined by metabolic status: it increases MCP-1 in AT of insulin-resistant individuals, potentially worsening inflammation, but decreases serum MCP-1 in insulin-sensitive individuals. Elevated MCP-1 itself may promote adipocyte dysfunction and contribute to diabetic pathogenesis [200, 201]. Through elevated levels of leptin and resistin, MCP-1 in type 2 diabetes exacerbates insulin resistance and decreased glucose tolerance [202]. Critically, these findings reveal that MCP-1 is not merely a downstream effector of insulin resistance but an active perpetuator of it: once elevated by obesity, hyperinsulinemia state, MCP-1 may drive monocyte infiltration into adipose tissue, further worsening local inflammation and insulin signaling. This feed-forward loop in which metabolic dysfunction elevates MCP-1 and MCP-1 deepens metabolic dysfunction, may simultaneously amplifies the SASP, sustains CLSs formation, and continuously recruits tumor-promoting macrophages into the adipose and peritumoral microenvironment, cementing MCP-1 as a potential important mechanistic link between insulin resistance and obesity-driven oncogenesis [199, 202]. Effects of Insulin on MCP-1 is illustrated in Fig. 4B.

Effect of Insulin on IL-1β

The metabolic dysfunction of high insulin and glucose promotes cancer by upregulating IL-1β. In cholangiocarcinoma (bile duct cancer), Khawkhiaw, Chomphoo [203] showed that in tumor cells, hyperglycemia promotes IL-1β expression, which in turn drives proliferation and aggression. The reversibility of this effect by IL-1β blockade confirms a causative role for this cytokine in metabolically driven cancer progression [204].

IL-1β orchestrates key pro-tumorigenic processes including chronic inflammation, angiogenesis, cancer cell proliferation and dissemination, and immunosuppression [205–207]. In preclinical studies, IL-1β blockade with receptor antagonists not only suppresses tumor progression but also synergizes with immunotherapies, highlighting its potential as a combination strategy [208]. Metabolic disturbances characterized by high insulin and glucose promote cancer by upregulating IL-1β. This mechanistic link positions IL-1β signaling as a compelling therapeutic target for metabolically associated cancers [209].

The most clinically significant human evidence for IL-1β blockade in the cancer-metabolism interface comes from the CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) trial, a landmark randomized controlled trial of the anti-IL-1β monoclonal antibody canakinumab in 10,061 patients with prior myocardial infarction and elevated C-reactive protein, a population enriched for metabolic inflammation [210]. Strikingly, canakinumab significantly reduced incident lung cancer and cancer-related mortality [211]. This finding provided the first large-scale human evidence that systemic IL-1β suppression can reduce cancer incidence in a metabolically dysregulated population, directly validating the mechanistic framework presented in this review. Ongoing trials including Canakinumab (NCT03626545) and combination studies pairing IL-1β blockade with Docetaxel in NSCLC and other solid tumors will help define the therapeutic window and optimal combinatorial context for IL-1β-targeted strategies in obesity-associated cancers.

Beyond pharmacological SASP targeting, metabolic interventions that directly address the underlying drivers of hyperinsulinemia and adipose tissue inflammation represent a clinically actionable and evidence-backed strategy for disrupting the obesity-SASP-cancer axis. Metformin, the most widely prescribed insulin-sensitizing agent, has shown consistent associations with reduced cancer incidence and improved oncological outcomes in retrospective and observational studies of patients with type 2 diabetes, with particular evidence in colorectal, breast, and endometrial cancers [212, 213]. The proposed mechanisms include AMPK activation leading to mTOR suppression and reduced SASP secretion, direct anti-proliferative effects via cell cycle arrest, and reduction of hyperinsulinemia and IGF-1 signaling.

Integrating these observations, hyperinsulinemia and hyperglycemia act as metabolic primers of the NLRP3 inflammasome, establishing a potential state of constitutive IL-1β activation in patients with obesity adipose and hepatic tissue. This chronically activated IL-1β axis propagates the SASP by sustaining NF-κB-driven cytokine transcription, fuels cancer progression through EMT, angiogenesis, and immune evasion, and simultaneously deepens insulin resistance through a feedback loop that further elevates glucose and insulin levels. In the context of obesity-associated cancer, metabolic dysfunction and SASP amplification are therefore not sequentially ordered events but simultaneous, mutually reinforcing processes — an integrated pathological circuit in which IL-1β occupies a central node with both mechanistic and therapeutic significance. Effects of Insulin on IL-1β is illustrated in Fig. 4B.

Effect of Resistin on SASPs

The inhibition of SIRT1 by resistin in hepatocytes identifies a potential mechanistic link between this adipokine and the onset of cellular senescence in liver disease [214] .Yu, Zheng [214] show that Treatment with recombinant resistin impairs SIRT-1 function in hepatocytes by reducing its expression, disrupting its interaction with key partners like PPARα and PGC-1α, and increasing PGC-1α acetylation. This suppression of SIRT-1 activity alters the transcription of its target genes and, critically, induces cellular senescence, as evidenced by increased SA-β-gal activity. The senescent phenotype is rescued by SIRT-1 agonists, confirming the central role of SIRT1 inhibition in resistin-mediated senescence. An important species-specific caveat must be acknowledged when interpreting the resistin literature: unlike leptin and adiponectin, resistin is produced predominantly by adipocytes in rodents, but in humans it is secreted primarily by monocytes and macrophages [215, 216]. This fundamental biological difference means that mechanistic data generated in murine models may not directly translate to human obesity-associated physiology, where resistin’s cellular sources and regulation are fundamentally different. Resistin induction of hepatocyte senescence is illustrated in Fig. 5A.

In the context of obesity-associated cancer, this resistin–SIRT1–senescence axis carries a critical implication: SIRT1 normally deacetylates and inactivates both NF-κB [217] and p53 [218], thereby restraining SASP factor transcription and maintaining cellular homeostasis. Resistin-mediated SIRT1 suppression therefore may simultaneously unleashes NF-κB-driven SASP amplification and dysregulates p53-dependent tumor suppression — providing a plausible molecular explanation for the epidemiological link between elevated resistin, hepatic steatosis, and HCC risk observed in individuals with obesity. All effects of resistin on SASPs are illustrated in Fig. 5.

Fig. 5: (A) Resistin promotes hepatocyte senescence through SIRT1 inhibition and disrupted metabolic signaling. Schematic illustration of the mechanism by which hyperresistinemia in liver disease induces hepatocyte senescence. Recombinant resistin treatment reduces SIRT1 expression and disrupts its interaction with key metabolic regulators, including PPARα and PGC‑1α. Impaired SIRT1 activity leads to increased acetylation of PGC‑1α, resulting in altered transcription of target genes that regulate lipid metabolism and mitochondrial function. These metabolic alterations promote cellular senescence, as evidenced by increased senescence-associated β‑galactosidase (SA‑β‑gal) activity in resistin-treated hepatocytes compared to healthy controls. Pharmacologic activation of SIRT1 restores its function, re-establishes interactions with metabolic partners, and reverses the senescent phenotype. Collectively, these findings identify SIRT1 inhibition as a central mechanism linking resistin signaling to hepatocyte senescence in liver disease and suggest that SIRT1 activation may represent a therapeutic strategy to rescue resistin-induced dysfunction. (B) Schematic illustration of resistin-mediated signaling pathways in obesity and their effects on tumor progression. In obese individuals, resistin binding to its receptor activates multiple downstream pathways, including STAT3, AP‑1, cAMP/PKA, NF‑κB, and PI3K/AKT. These signaling cascades induce the production of pro-inflammatory cytokines such as IL‑6, IL‑8, IL‑1β, and MCP‑1. IL‑6 promotes tumor cell proliferation and invasiveness, while IL‑8 enhances invasion. IL‑1β further supports tumor cell proliferation, and MCP‑1 contributes to metastatic dissemination via NF‑κB and PI3K/AKT signaling. Collectively, these pathways highlight the role of resistin in promoting inflammation-driven tumor growth and metastasis in obesity. AKT: Protein Kinase B, AP-1: Activator Protein-1, cAMP: cyclic adenosine monophosphate, IL-1β: Interleukin-1 beta, IL-6: Interleukin 6, IL-8: Interleukin 8, MCP-1: Monocyte Chemoattractant Protein-1, NF-κB: Nuclear Factor kappa B, PGC-1α: Peroxisome proliferator-activated receptor gamma coactivator 1-alpha, PI3K: Phosphoinositide 3-kinase, PKA: Protein Kinase A, PPAR-α: Peroxisome Proliferator-Activated Receptor Alpha, SIRT1: Sirtuin 1, STAT: Signal Transducer and Activator of Transcription

Effect of Resistin on IL-6

Clinically, Kallio, Hämäläinen [219] showed that elevated resistin and IL-6 levels correlate with advanced disease and poor survival in cancers such as renal cell and breast carcinoma. Mechanistically, resistin directly upregulates IL-6 expression in cancer cells, with a particularly potent effect in models derived from African American patients, mirroring higher serum levels observed in this population. This resistin-IL-6 axis drives tumor aggressiveness by activating STAT3, as confirmed by the abolition of STAT3 phosphorylation upon IL-6 blockade, establishing a clear signaling hierarchy [220]. These findings are significant within the broader framework of this review because it position resistin as a potential upstream adipokine regulator of the IL-6/STAT3 axis — already established as a principal mediator of tumor proliferation, invasion, and immune evasion in Sect. Effect of IL-6 on cancer progression. In obesity, where circulating resistin is chronically elevated, this resistin–IL-6–STAT3 hierarchy provides a suggested additional and independent hormonal input that sustains pro-tumorigenic SASP signaling, operating in parallel with hyperleptinemia and hyperinsulinemia. This convergence of multiple obesity-associated adipokines on a shared oncogenic pathway underscores the difficulty of interrupting SASP-driven cancer promotion at the level of individual cytokines and suggests that upstream adipokine normalization may offer greater therapeutic leverage. Effects of Resistin on IL-6 is illustrated in Fig. 5B.

Effect of Resistin on IL-8

A key mechanism of resistin action is the direct activation of AP-1, which drives the transcription of pro-inflammatory, pro-adhesive, and vascular remodeling genes [221]. Resistin promotes a robust pro-inflammatory response by activating the AP-1 transcription factor, leading to the upregulation of key cytokines such as TNF-α, IL-1β, IL-6, IL-8, and IL-12 [222]. In the context of this review, resistin’s activation of AP-1 is particularly noteworthy because it positions resistin as a potential broad-spectrum transcriptional inducer of SASP components rather than a cytokine-specific regulator: a single adipokine elevated in obesity simultaneously upregulates IL-6, IL-8, IL-1β, and TNF-α through one shared transcription factor [222]. This mechanistic convergence on AP-1 means that in the patients with obesity adipose microenvironment, resistin may function as a master switch amplifying multiple arms of the SASP in parallel, with the combined cytokine output driving immune evasion, tumor angiogenesis, and cancer cell invasion more effectively than any individual SASP component would in isolation. Effects of Resistin on IL-8 is illustrated in Fig. 5B.

Effect of Resistin on MCP-1

The inflammatory adipokine resistin contributes to tumor progression by enhancing the pro-tumorigenic microenvironment, in part through the upregulation of chemokines such as MCP-1 [223]. Clinically, elevated resistin levels are correlated with advanced disease characteristics, including larger tumor size, higher grade, and increased metastasis in breast cancer [224, 225]. Although direct evidence for resistin-induced MCP-1 in cancer is still emerging, resistin’s established role as a pro-inflammatory mediator and its capacity to activate key signaling pathways such as NF-κB and PI3K/AKT, both known regulators of MCP-1, provide a strong mechanistic rationale for this connection [121]. While direct causal evidence for resistin-driven MCP-1 induction in obesity-associated tumors is still emerging, the convergence of NF-κB and PI3K/AKT signaling as potential shared downstream effectors of both resistin and MCP-1 regulation suggests that hyperresistinemia in obesity contributes to MCP-1-mediated macrophage recruitment into the tumor microenvironment. If confirmed, this would identify resistin as an adipokine that amplifies the SASP not only through direct cytokine induction but also by reinforcing the macrophage infiltration axis that sustains chronic adipose tissue inflammation and TAM polarization creating a self-perpetuating cycle that links adipokine dysregulation in obesity to immunological tumor promotion. Effects of Resistin on MCP-1 is illustrated in Fig. 5B.

Effect of Resistin on IL-1β

The pro-inflammatory actions of resistin, such as the induction of IL-1β, IL-6, and TNF-α, are mediated through the CAP1 receptor [226]. Ligand binding triggers a cAMP/PKA signaling cascade that activates NF-κB and enhances the transcription of target cytokines [227]. Resistin promotes a pro-tumorigenic feedback loop by activating NF-κB in macrophages to induce IL-1β production. This, in turn, drives the recruitment of inflammatory cells and further cytokine secretion, creating a self-reinforcing cycle of chronic inflammation that fuels cancer progression [228, 229]. This resistin–CAP1–NF-κB–IL-1β circuit is particularly meaningful in the context of obesity-associated cancer because it may link the adipokine excess of obesity directly to the most potent SASP inflammasome axis reviewed in this article. Elevated resistin activates NF-κB [229] to induce IL-1β [230], which in turn activates NF-κB [231] further and primes NLRP3 inflammasome assembly [232, 233], creating a self-amplifying inflammatory loop that is independent of direct tumor cell input and can therefore be established and maintained by the patients with obesity adipose microenvironment alone. This provides a suggested mechanistic basis for the contribution of obesity to cancer initiation not merely progression and positions the resistin–IL-1β axis as a pre-tumorigenic therapeutic target in individuals with obesity who have not yet developed malignancy.

In summary, the mechanistic evidence for resistin as a SASP amplifier is consistent across its four cytokine targets but rests predominantly on in vitro cell-based studies and animal model data. Human clinical evidence linking circulating resistin levels to SASP marker concentrations or cancer outcomes is limited and, in the case of cancer risk, has produced inconsistent findings across studies, with some cohort analyses reporting a positive association between resistin and cancer risk while others have found no significant relationship after metabolic covariate adjustment. This inconsistency likely reflects both the species-specific biology of resistin and the difficulty of measuring meaningful resistin levels in human populations where monocyte-derived, rather than adipocyte-derived, resistin predominates. Future research should prioritize human adipose tissue and immune cell studies that directly measure resistin’s effects on SASP factor secretion in the context of clinical obesity, alongside prospective cohort data linking circulating resistin to cancer incidence and SASP biomarker profiles. Effects of Resistin on IL-1β is illustrated in Fig. 5B.

A growing body of clinical evidence demonstrates that the SASP cytokines reviewed herein — IL-6, IL-1β, IL-8, and MCP-1 — are not merely mechanistic constructs derived from preclinical models, but measurable biomarkers in human clinical trials enrolling obesity-related cancer populations. Table 1 summarizes registered clinical trials in which one or more of these SASP factors were prospectively measured as primary or secondary outcomes in cancer patients or individuals at elevated cancer risk due to obesity. These trials span breast cancer, endometrial cancer, prostate cancer, and solid tumor survivors, and encompass a range of interventional designs including exercise, dietary weight loss, bariatric surgery, and pharmacological IL-1β blockade. Collectively, they validate the translational relevance of the obesity-SASP-cancer axis and highlight the emerging use of SASP cytokines as pharmacodynamic endpoints in obesity-cancer clinical research. Table 1 assesses SASP Cytokines in Clinical Trials in Obesity-Related Cancer Populations.

NCT number | Cytokine(s) measured | Population | Trial title | Trial description
NCT02466061 | IL-1βIL-6IL-8 | Endometrial Cancer Survivors (Obese/Overweight) | Transdisciplinary Research on Energetics and Cancer — Obesity and Weight Loss in Endometrial Cancer Survivors: A Randomized, Multi-site Trial (Lifestyle Beyond Cancer Study) | Multi-site RCT of weight loss intervention (diet + exercise) vs. attention control in obese endometrial cancer survivors. IL-6, IL-1β, and IL-8 measured as secondary biomarker outcomes to assess whether weight loss-driven SASP reduction correlates with improved cancer prognosis.
NCT02453139 | IL-6 | Obese and Non-obese Men with Advanced Prostate Cancer | Evasion of Immune Editing by Circulating Tumour Cells in an Exercise Modifiable Mechanism Underlying Aggressive Behaviour in Obese Men With Prostate Cancer | Observational study examining exercise effects on circulating tumour cell immune evasion in obese vs. non-obese men with advanced prostate cancer. Serum IL-6 measured as a primary obesity-cancer inflammatory mediator linking adiposity to aggressive tumour behaviour.
NCT02135562 | IL-6 | Obese Endometrial Cancer Survivors | A Pilot Study of a Protein-Sparing Modified Fast for Weight Loss in Obese Endometrial Cancer Survivors | Pilot study of protein-sparing modified fast (PSMF) diet in obese endometrial cancer survivors. Serum IL-6 measured as a biomarker of adipose tissue-driven systemic inflammation; reduction in IL-6 is assessed as a potential indicator of reduced cancer recurrence risk following weight loss.
NCT02152462 | IL-6 | Breast Cancer (Black Women — Obesity-Associated Biomarkers) | Exergaming Intervention and Breast Cancer Biomarkers in Black Women | RCT examining the effect of an exergaming (active video game) exercise intervention on breast cancer biomarkers in Black women. Serum IL-6 measured as an obesity-related inflammatory biomarker; trial addresses racial disparities in obesity-driven breast cancer inflammation.
NCT02431676 | IL-6IL-8 | Cancer Survivors Previously Diagnosed with a Malignant Solid Tumor | Trial of Behavioral Weight Loss and Metformin Treatment to Lower Insulin Growth Factor in Cancer Survivors | RCT of behavioral weight loss plus metformin vs. placebo in cancer survivors. IL-6 and IL-8 measured as secondary SASP biomarker outcomes to assess whether combined weight reduction and metformin treatment reduces obesity-driven pro-inflammatory cytokine levels in cancer survivors.
NCT06046755 | IL-6R | Obesity-Related Breast Cancer (During Active Oncological Treatment) | Evaluation of Changes in the Methylome and Prognosis of Obesity-related Breast Cancer After Nutritional Intervention-induced Weight Loss During the Oncological Treatment (NUTOBREST) | RCT of ketogenic vs. standard hypocaloric diet during oncological treatment of obesity-related breast cancer. IL-6 receptor (IL-6R) measured to assess the impact of weight loss on IL-6/STAT3 signaling; epigenetic (methylome) changes are the primary outcome, with IL-6R as a mechanistic SASP biomarker.
NCT03091842 | IL-6IL-8 | Obese Breast Cancer Survivors | Targeting Adiposity and Inflammation With Movement to Improve Prognosis in Breast Cancer Survivors (AIM Trial) | Phase II RCT of circuit aerobic + resistance exercise vs. traditional exercise vs. attention control in 276 obese breast cancer survivors (Dana-Farber Cancer Institute). Serum IL-6 and IL-8 are pre-specified secondary outcome measures alongside TNF-α, hs-CRP, leptin, and adiponectin. Primary outcome: adipose tissue macrophage phenotype by core biopsy. (Source: Kang et al., Front Oncol 2022; PMID: 35814430)
NCT04540263 | IL-1βIL-6IL-8MCP-1 | Obese Patients at Elevated Cancer Risk (Bariatric Surgery Cohort) | Evaluation of Blood Cytokine Levels of Patients Who Underwent Sleeve Gastrectomy and Gastric Bypass Operations Due to Obesity | Observational study measuring 13 cytokines — including IL-1β, IL-6, IL-8, and MCP-1 (CCL2) — by flow cytometry before and after sleeve gastrectomy or gastric bypass in obese patients. Directly assesses whether surgical weight loss reduces the obesity-driven SASP cytokine panel associated with elevated cancer risk. (Source: ClinicalTrials.gov diagnostic test description)
NCT01327846 (CANTOS) | IL-1β | Obese/Metabolic Syndrome Patients — Pre-specified Lung Cancer Subanalysis | Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease (CANTOS Trial) | Landmark Phase 3 RCT of canakinumab (anti-IL-1β mAb) vs. placebo in 10,061 patients with prior MI and elevated hs-CRP, an obesity/metabolic syndrome-enriched population. Pre-specified exploratory analysis: canakinumab 150 mg q3 months produced significant dose-dependent reduction in lung cancer incidence (HR 0.33, P = 0.0002) and cancer mortality. Strongest human clinical evidence that IL-1β blockade in an obese/inflamed cohort reduces cancer incidence. (Source: Ridker et al., Lancet 2017; PMID: 28869257)