---
title: "Obesity-associated inflammation and cancer: mechanisms linking adipose immune changes to tumor risk"
id: "frontiers-in-immunology-6-obesity-associated-inflammation-and-cancer-molecular-mechanisms-evidence-gaps"
canonical_url: "https://medichelpline.com/clinical-feed/frontiers-in-immunology-6-obesity-associated-inflammation-and-cancer-molecular-mechanisms-evidence-gaps"
content_type: "clinical_feed_article"
specialty: "Infectious Disease"
source_name: "Frontiers in Immunology"
source_url: "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1961059"
published_at: "2026-09-21T00:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Obesity-associated inflammation and cancer: mechanisms linking adipose immune changes to tumor risk
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/frontiers-in-immunology-6-obesity-associated-inflammation-and-cancer-molecular-mechanisms-evidence-gaps
- **Specialty:** [Infectious Disease](https://medichelpline.com/clinical-feed/infectious-disease.md)
- **Primary Source:** Frontiers in Immunology
- **Source URL:** [Original Journal Publication](https://www.frontiersin.org/articles/10.3389/fimmu.2026.1961059)
- **Published At:** 2026-09-21T00:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- Obesity establishes a chronic, low-grade systemic inflammatory state driven by changes in **adipose tissue** architecture (hypertrophy, hyperplasia), hypoxia, ER stress, and cell death, which together amplify inflammatory signaling. - Adipose tissue acts as an endocrine organ producing **pro-inflammatory cytokines** (notably **TNF-α**, **IL-6**, IL-1β), adipokines (e.g., **leptin**, adiponectin), free fatty acids, and reactive oxygen species that promote local and systemic inflammation. - Key intracellular inflammatory pathways activated in obesity include **NF-κB**, JNK, JAK-STAT, PI3K/AKT/mTOR and TLR signaling; these foster chemokine expression, immune cell recruitment, and sustained cytokine production. - Hypoxia in expanding fat depots elevates **HIF-α** activity and angiogenic/inflammatory mediators (VEGF, MIF, MMP-9), creating parallels with the tumor microenvironment and facilitating pro-tumor mechanisms (angiogenesis, glycolytic metabolism). - Immune-cell remodeling in obese adipose tissue — macrophage accumulation and polarization toward pro-inflammatory phenotypes, increased IFN-γ, T cell and NK cell recruitment — reinforces cytokine-driven inflammation and metabolic dysfunction. - Adipocyte pyroptosis and unresolved ER stress (maladaptive UPR) link organelle dysfunction to inflammatory pathway activation, ROS generation, and cell death, which can promote genomic instability and carcinogenic signaling. - Inflammatory mediators and signaling networks described in the source (e.g., TNF-α, IL-6, NF-κB, JAK-STAT, PI3K/AKT) are implicated mechanistically in DNA damage, oncogenic pathway activation (NF-κB, PI3K/AKT, MAPK), and processes supporting tumor proliferation, migration, and angiogenesis. - Adipose inflammation is heterogeneous: metabolically healthy obesity (MHO) shows lower inflammatory burden than metabolically unhealthy obesity (MUO); visceral, subcutaneous, and brown adipose depots have distinct inflammatory roles, with VAT disproportionately contributing to systemic risk. - The authors performed a structured literature search across major databases to July 2026; where clinical evidence is limited, animal and in vitro studies were included with limitations noted. - The review mentions inflammation-targeted therapeutic approaches (cytokine/receptor blockade, immune-cell reprogramming, natural anti-inflammatory agents, nanoparticle delivery) but the provided source text does not report detailed clinical trial results or specific therapeutic outcomes.
## Clinical Analysis & Structured Key Points
Frontiers | Obesity-associated inflammation and cancer: molecular mechanisms, evidence gaps, and therapeutic opportunities REVIEW article Front. Immunol. , 21 September 2026 Sec. Inflammation Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1961059 Published in Frontiers in Immunology Inflammation 7 impact factor 11.3 citescore Part of a Research Topic Innate immune signaling and inflammatory amplification in inflammation-driven diseases: mechanisms, biomarkers, and therapeutic targeting Submission open 4025 views 6 articles Editor & Reviewers Edited by Z Z Zhirui Zeng Reviewed by X W Xiumei Wang L D Li Ding Outline Figures and Tables Figure 1 View in article Figure 2 View in article Figure 3 View in article Table 1 Key inflammatory cytokines, signaling pathways, and mediators in the adipose tissue of obese patients. View in article Table 2 Summary of inflammation-targeted therapies for cancer treatment in obese patients. View in article REVIEW article Front. Immunol. , 21 September 2026 Sec. Inflammation Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1961059 Obesity-associated inflammation and cancer: molecular mechanisms, evidence gaps, and therapeutic opportunities J M Jiayi Meng 1 X B Xu Bao 2 * 1. The Second Affiliated Hospital of Dalian Medical University, Dalian, China 2. School of Public Health, Dalian Medical University, Dalian, China Article metrics View details Abstract Obesity, recognized as a significant global public health issue, has garnered widespread attention. The chronic systemic inflammatory state characteristic of obesity may act as a key pathophysiological factor in the development of obesity-related cancers. Based on a structured literature search of peer-reviewed databases, this review summarizes the features of the inflammatory microenvironment within adipose tissue in obesity, encompassing adipocyte hypertrophy and hyperplasia, hypoxia, and endoplasmic reticulum stress; activation of pro-inflammatory cytokines and signaling pathways; and the polarization of immune cells towards a pro-inflammatory phenotype. We emphasize the molecular mechanisms that link inflammation to carcinogenesis and explore targeted therapeutic strategies against inflammation, such as cytokine and receptor blockade, immune cell reprogramming, natural anti-inflammatory agents, and nanoparticle drug delivery systems. This review highlights the mechanistic link between obesity, inflammation, and cancer, providing insights for the development of precise preventive and therapeutic approaches for obesity-associated inflammation and tumorigenesis. 1 Introduction Epidemiological data from the Global Burden of Disease (GBD) 2021 study show that the prevalence of overweight and obesity has increased globally, regionally, and nationally between 1990 and 2021. In 2021, an estimated 1.00 billion adult males and 1.11 billion adult females were living with overweight and obesity (BMI ≥ 25 kg/m²). Without prompt and effective public health interventions, the global burden of overweight and obesity is projected to continue rising, particularly in Asia and Africa, driven by demographic growth, with substantial increases in the number of individuals affected ( 1 ). Obesity imposes significant metabolic strain, with research linking it to 21 distinct cardiometabolic, gastrointestinal, respiratory, neurological, musculoskeletal, and infectious diseases ( 2 ). Obesity-related insulin resistance is a key pathogenic factor in the development of type 2 diabetes mellitus ( 2 ). Concurrently, the risk of multisystem cardiometabolic disorders escalates with increasing BMI ( 3 ). Notably, obesity is closely associated with carcinogenesis. A prospective cohort study involving 3.5 million adults in Spain demonstrated a positive correlation between elevated body mass index (BMI) and nine types of cancers (endometrial carcinoma, renal cell carcinoma, gallbladder carcinoma, thyroid carcinoma, colorectal carcinoma, postmenopausal breast cancer, multiple myeloma, leukemia, and non-Hodgkin lymphoma). Additionally, an association was observed with three other cancers (head and neck cancers, brain and central nervous system tumors, and Hodgkin lymphoma) among never-smokers ( 4 ). Another population-based cancer research indicated that 48.47% of 651,342 cancer cases were linked to obesity, with age-standardized incidence rates (ASRs) for 12 obesity-related cancers increasing annually by 3.6% (p < 0.001), while ASRs for non-obesity-related cancers remained stable ( 5 ). These findings underscore the importance of addressing obesity as a significant public health concern and emphasize its impact on the global cancer burden. Obesity is mainly associated with localized adipose tissue and systemic low-grade chronic inflammation, which collectively contribute to the inflammatory microenvironment of adipose tissue and elevated systemic inflammatory cytokines ( 6 ). Evidence supports that excess adipose tissue in various anatomical regions promotes inflammation, which can progress to tumor development. In breast tissue, features such as cancer-associated adipocytes, crown-like structures (CLS) surrounding adipocytes, and immune cell infiltration are instrumental in inflammation-driven progression to breast carcinoma ( 7 ). In the gastrointestinal tract, increased levels of adipose-derived pro-inflammatory markers such as leptin are linked to abnormal signaling and genetic mutations associated with colorectal cancer ( 8 ). Moreover, obesity also contributes to the progression of metabolic dysfunction-associated steatohepatitis (MASH), the inflammatory hepatic subtype of metabolic dysfunction-associated steatotic liver disease (MASLD, formerly non-alcoholic fatty liver disease [NAFLD]), and hepatocellular carcinoma (HCC) through multiple mechanisms ( 9 ). In the pancreas, elevated cytokine levels in obese individuals activate ferroptosis and oncogenic signaling pathways, leading to pancreatic ductal adenocarcinoma ( 10 ). Furthermore, obesity correlates with heightened inflammatory markers and increased expression of pro-tumorigenic genes, elevating the risk of endometrial carcinoma ( 11 ). Overall, chronic inflammation is widely recognized as a contributing factor to carcinogenesis and tumor progression, with mechanisms including dysfunctional repair of inflammation-induced tissue damage, activation of carcinogenic signaling pathways, oxidative stress-induced genomic instability, and immune cell dysfunction ( 12 – 15 ). This review synthesizes recent research on how obesity induces adipose tissue inflammation, elucidating the mechanisms through pro-inflammatory cytokines, inflammatory signaling pathways, immune cell inflammatory states, and unique inflammatory microenvironments, and their links to tumor development. Additionally, we synthesize emerging anti-inflammatory targeted therapies—including novel drugs and mechanisms—which may provide therapeutic benefits for managing cancer in obese patients. We conducted a structured literature search of PubMed, Web of Science, Embase, and Scopus from database inception to July 2026 to identify peer-reviewed original research articles, systematic reviews, and meta-analyses relevant to obesity-associated inflammation and cancer. The search strategy combined Medical Subject Headings (MeSH) and free-text keywords, including “obesity”, “overweight”, “adipose tissue”, “inflammation”, “pro-inflammatory cytokines”, “adipokines”, “inflammasome”, “tumor microenvironment”, “carcinogenesis”, “cancer risk”, and “anti-inflammatory therapy”, using Boolean operators. The reference lists of the retrieved articles were manually screened to identify additional relevant studies. Articles were included if they were published in English and reported original data or comprehensive syntheses on the molecular mechanisms linking obesity-related inflammation to tumor development, or evaluated inflammation-targeted therapeutic strategies in cancer; conference abstracts, editorials, and non-peer-reviewed sources were excluded. Where clinical evidence was limited, findings from animal models and in vitro experiments were included, with explicit acknowledgement of their limitations for extrapolation to humans. 2 Characteristics of obesity-associated adipose tissue Adipose tissue functions as an energy reservoir, and white adipose tissue (WAT) is the most prevalent type of fat storage, with lipids primarily stored as triglycerides (TAG) within lipid droplets ( 16 ). Evidence indicates that overnutrition induces a chronic inflammatory response, which may underpin cardiometabolic complications. Mechanistically, the accumulation of adipocytes triggers the activation of metabolic signaling pathways—including c-Jun N-terminal kinase (JNK), nuclear factor kappa-B (NF-κB), Wnt, and Toll-like receptor (TLR)—which further amplify inflammatory processes ( 17 ). Additionally, adipose tissue is regarded as an endocrine organ, secreting various hormones and factors collectively known as adipokines. These adipokines play key roles in systemic metabolic regulation, including pro-inflammatory cytokines (e.g., TNF-α, IL-6, IL-1β, IL-8), pro-tumor adipokines (e.g., leptin) and anti-inflammatory cytokines (e.g., adiponectin) ( 18 – 21 ). Obesity can also trigger adipocyte hypertrophy and hyperplasia, apoptosis, and tissue remodeling, thereby fostering a state of chronic, subclinical inflammation within adipose tissue ( 22 ). Enlarged adipose tissue secretes excessive free fatty acids (FFA), reactive oxygen species (ROS), and pro-inflammatory cytokines. The surplus systemic FFAs and dietary lipids infiltrate non-adipose organs such as the liver, muscle, and pancreas, leading to ectopic fat deposition and lipotoxicity. Lipotoxicity can disrupt cellular organelles, such as mitochondria, the endoplasmic reticulum, and lysosomes, leading to the release of excess ROS and pro-inflammatory mediators and, ultimately, to systemic inflammation ( 23 ). Moreover, dead adipocytes often become encircled by macrophages, forming crown-like structures that further promote pro-inflammatory phenotypes—a process elaborated upon later. Under severe metabolic stress, hypertrophic adipocytes are prone to undergo pyroptosis, a form of programmed cell death associated with inflammation ( 24 ). Adipocyte pyroptosis not only leads to local and systemic inflammation but is also associated with a poor prognosis for cancer treatment ( 25 , 26 ). Additionally, endoplasmic reticulum (ER) stress is observed in hepatic steatosis in patients with obesity, serving as a molecular bridge connecting obesity and hepatitis progression ( 27 ). ER stress is both a cause and a consequence of inflammatory responses. Despite moderate ER stress helping restore ER homeostasis, persistent or unresolved ER stress in obesity hyperactivates the unfolded protein response (UPR), which ultimately triggers cell death and inflammatory pathways, termed “maladaptive/terminal UPR” ( 28 – 30 ). UPR signaling can directly interfere with downstream inflammatory pathways, including JNK, IKK, and NF-κB signaling cascades, as well as ROS generation ( 31 ). This phenomenon manifests as elevated systemic cytokine levels in obese patients, such as TNF-α, IL-6, and IL-1β ( 32 ). Interestingly, these inflammatory responses may also function as key mediators of carcinogenesis, causing DNA damage, mutations, and activating pathways such as NF-κB, PI3K/AKT, and MAPK, ultimately enhancing tumor proliferation, migration, and angiogenesis ( 13 , 33 ). Another characteristic of adipose tissue in obesity is the rapid expansion-induced hypoxia, where hypoxia-sensitive genes—including GLUT1, MIF, matrix metalloproteinase 9 (MMP-9), PAI-1, and TNF-α—exhibit increased mRNA expression under hypoxic conditions ( 34 ). Hypoxia stimulates the expression and secretion of several inflammation-related adipokines, including vascular endothelial growth factor (VEGF), IL-6, leptin, macrophage migration inhibitory factor (MIF), and angiopoietin-like proteins ( 35 ). Hypoxia-inducible factor-α (HIF-α) mediates upregulation of these inflammatory adipokines, playing a critical role in hypoxic responses. HIF-α translocates into the nucleus, binds hypoxia response elements within target gene promoters, and activates their transcription—genes involved in angiogenesis, proliferation, survival, apoptosis, vascular tone regulation, and glucose and energy metabolism ( 36 , 37 ). Interestingly, hypoxia is also a hallmark of the tumor microenvironment (TME), with HIF-α involved in regulating various oncogenic mechanisms. HIF-α promotes the transcription of angiogenic factors such as VEGF, aiding tumor vascularization ( 14 ). HIF-α also induces the expression of glucose transporters and glycolytic enzymes, enhancing glycolytic metabolism consistent with the “Warburg effect” observed in cancer cells ( 38 ). These observations suggest that the hypoxic microenvironment of adipose tissue may facilitate tumor progression by creating conditions conducive to cancer cell growth in low-oxygen environments. Importantly, obesity-associated adipose tissue inflammation is not a uniform or monolithic state; its burden varies substantially with metabolic phenotype and fat-depot distribution. In metabolically healthy obesity (MHO), adipose tissue retains a comparatively favorable immune landscape, marked by limited pro-inflammatory macrophage infiltration, a more balanced T-cell repertoire, and reduced levels of inflammatory mediators. In contrast, progression to metabolically unhealthy obesity (MUO) entails progressive immune-cell remodeling, adipokine dysregulation (rising leptin with declining adiponectin), and escalating systemic low-grade inflammation ( 39 , 40 ). Building on this phenotypic heterogeneity, individual adipose depots display distinct inflammatory biology: visceral adipose tissue (VAT), characterized by high immune-cell density, high lipolytic flux, and direct portal drainage, serves as a dominant source of systemic inflammation and metabolic risk; subcutaneous adipose tissue (SAT) is comparatively metabolically protective, although its buffering capacity erodes under prolonged nutrient excess; and brown adipose tissue (BAT), while thermogenically and metabolically beneficial, undergoes whitening and functional decline in obesity, further amplifying low-grade inflammation ( 41 – 44 ). These observations argue against treating adipose inflammation as a binary process and underscore that metabolic phenotype and fat distribution, rather than body mass index alone, should be integrated when interpreting inflammatory signatures and their consequences. 3 Pro-inflammatory components in obesity 3.1 Pro-inflammatory cytokines and inflammatory signaling pathways In WAT, apart from adipocytes, which are the most abundant cell type, the tissue also comprises endothelial cells, fibroblasts, leukocytes, and notably, macrophages. Adipose tissue macrophages are a major source of TNF-α in obesity, whereas the adipose tissue—mainly via its infiltrating immune cells rather than mature adipocytes—contributes an estimated 15–35% of circulating IL-6, reaching approximately one-third in obese individuals ( 45 , 46 ). Both cytokines can activate numerous pro-inflammatory signaling pathways, thereby contributing to the inflammatory state of the adipose tissue ( 47 ). TNF-α activates downstream signaling pathways such as mitogen-activated protein kinase (MAPK) and NF-κB, thereby directly promoting inflammatory processes. This activation leads to increased expression of a variety of chemokines and inflammatory mediators ( 48 ). Furthermore, TNF-α is involved in the activation of additional signaling cascades, including JNK, IKK, and JAK pathways, ultimately integrating into immune-metabolic programs ( 49 ). NF-κB is a crucial inflammatory signaling pathway, serving as the common downstream effector for multiple inflammatory mediators including TNF-α and IL-1 ( 50 ). In canonical signaling pathways, NF-κB/Rel dimers are maintained in an inactive state within the cytoplasm through association with IκB inhibitors or interactions with unprocessed NF-κB1 and NF-κB2 precursors. Obesity-induced pro-inflammatory cytokines can activate the IKK complex, comprising IKKβ, IKKα, and IKKγ (NEMO), leading to phosphorylation and subsequent proteasomal degradation of IκB proteins, and the release of NF-κB for nuclear translocation ( 51 , 52 ). Activated NF-κB undergoes further phosphorylation and translocation to the nucleus, where it induces the transcription of target genes involved in inflammatory responses, including pro-inflammatory cytokines, chemokines, and growth factors including TNF-α, IL-1, IL-6, and vascular endothelial growth factor, thereby sustaining chronic inflammation ( 53 ). Upon binding to cytokines (e.g., IL-6), JAKs undergo phosphorylation on specific tyrosine residues, thereby activating signal transduction and activators of transcription, known as STATs. The activation and dimerization of STAT proteins reveal their nuclear localization signals, allowing them to translocate to the nucleus. Once there, they bind to specific enhancer elements within the promoters and enhancers of target genes, initiating the transcription of inflammatory genes ( 54 , 55 ). Additionally, IL-6-induced activation of PI3K modulates the mTOR complex 1 (mTORC1) pathway, impacting various cellular processes such as metabolism and redox homeostasis ( 56 ). 3.2 Pro-inflammatory molecules Interferon (IFN) family members, particularly IFN-γ, play a crucial role in obesity, inflammation, and immune regulation. Elevated expression of IFN-γ has been observed in adipose tissue correlating with diet-induced obesity (DIO) murine models ( 57 ). Additionally, experimental data demonstrate that IFN-γ deficiency results in a significant reduction in the expression of inflammatory cytokines and chemokines, such as monocyte chemoattractant protein-1 (MCP-1) and IL-10, indicating that IFN signaling modulates the inflammatory gene expression within adipose tissue ( 58 ). The increased levels of IFN-γ activate immune cells, promoting their inflammatory phenotype and recruiting various immune cell subsets—including T lymphocytes, macrophages, and natural killer (NK) cells—to adipose tissue ( 58 – 60 ). This immune activation contributes to local and systemic inflammatory responses, which can facilitate the development of obesity-related comorbidities such as insulin resistance and MASLD ( 61 , 62 ). Leptin, a 16-kDa cytokine primarily secreted by white adipocytes, exerts anorexigenic effects and augments energy expenditure. It is also recognized as a potent pro-inflammatory, proliferative, and anti-apoptotic mediator, serving as a key regulator in nutrient sensing, metabolic processes, and immune homeostasis ( 63 ). Substantial evidence indicates that obese individuals exhibit elevated circulating leptin levels ( 64 ). The pro-inflammatory effects have been demonstrated to promote the production of cytokines, such as TNF-α, IL-6, and IL-12, through the JAK-STAT, MAPK, and PI3K pathways. Exposure to inflammatory stimuli like TNF-α and IL-1 increases leptin levels and expression in adipose tissue, establishing a positive feedback loop that further amplifies inflammation through mutual interactions with other cytokines ( 47 , 65 ). In addition, leptin can affect specific immune responses that further exacerbate inflammation. Leptin-mediated activation of M1-like macrophages significantly enhances CXCL2 production and neutrophil recruitment by modulating the JNK/STAT3/AKT signaling pathways, concurrently elevating levels of Th1/Th17-associated inflammatory cytokines and promoting pro-inflammatory M1 macrophage activation states ( 66 ). Despite its essential role in early T cell development and the maturation of CD4 + T cells, leptin significantly contributes to the promotion of immune cell-driven inflammatory responses, p
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