The authors performed a structured literature search of PubMed, Web of Science, Embase, and Scopus from database inception to July 2026. Search terms combined MeSH and free-text keywords such as “obesity”, “adipose tissue”, “inflammation”, “pro-inflammatory cytokines”, “inflammasome”, “tumor microenvironment”, and “anti-inflammatory therapy”. The review included peer-reviewed original studies, systematic reviews, and meta-analyses published in English. Conference abstracts, editorials, and non–peer-reviewed sources were excluded. When clinical data were sparse, animal models and in vitro experiments were considered, with explicit acknowledgement of translational limitations.
Global epidemiology indicates substantial increases in overweight and obesity prevalence between 1990 and 2021, with over a billion adults affected in 2021. Excess adiposity is linked to multiple chronic diseases and is epidemiologically associated with elevated risks for several cancers. Large cohort and population-based studies cited in the source find positive associations between body mass index (BMI) and cancers including endometrial, renal, gallbladder, thyroid, colorectal, postmenopausal breast cancer, multiple myeloma, leukemia, and non-Hodgkin lymphoma, among others. The review frames obesity-associated low-grade chronic inflammation as a central pathophysiological factor that can promote carcinogenesis and tumor progression via multiple molecular mechanisms.
In obesity, white adipose tissue (WAT) undergoes structural and functional remodeling. Adipocyte hypertrophy and hyperplasia, increased apoptosis and pyroptosis, and tissue remodeling create a chronically inflamed microenvironment. Enlarged adipocytes and infiltrating immune cells release excess free fatty acids (FFAs), reactive oxygen species (ROS), and pro-inflammatory cytokines, contributing to both local and systemic inflammation.
Endoplasmic reticulum (ER) stress and maladaptive/unresolved unfolded protein response (UPR) are described as molecular links between obesity and inflammatory activation. Persistent ER stress hyperactivates UPR signaling cascades that intersect with inflammatory pathways (JNK, IKK, NF-κB) and ROS generation, leading to cell death and further inflammation.
Expanding adipose depots also experience hypoxia. Hypoxia-induced stabilization and nuclear activity of HIF-α trigger transcription of genes involved in angiogenesis, metabolism, and inflammation (e.g., VEGF, MIF, MMP-9, leptin, IL-6). The hypoxic signature in obese adipose tissue parallels hallmark features of the tumor microenvironment (TME), including promotion of angiogenesis and glycolytic reprogramming.
The review emphasizes that adipose inflammation is heterogeneous. Metabolically healthy obesity (MHO) preserves a relatively favorable immune landscape with limited pro-inflammatory macrophage infiltration, while metabolically unhealthy obesity (MUO) shows progressive immune-cell remodeling, adipokine dysregulation (rising leptin, declining adiponectin), and escalating systemic inflammation. Depot-specific differences are highlighted: visceral adipose tissue (VAT) is a dominant source of inflammatory mediators and metabolic risk, subcutaneous adipose tissue (SAT) is comparatively protective until overwhelmed, and brown adipose tissue (BAT) loses thermogenic function in obesity and contributes to inflammation.
Adipose tissue contains adipocytes, endothelial cells, fibroblasts, and multiple leukocyte subsets. Adipose tissue macrophages are a major source of TNF-α in obesity, and infiltrating immune cells contribute substantially to circulating IL-6 (the text estimates adipose tissue accounts for roughly 15–35% of systemic IL-6, approaching one-third in obese individuals). These cytokines engage canonical inflammatory signaling networks:
Collectively, these pathways link adipose-derived cytokine exposure to sustained inflammatory gene expression and downstream effects on tissue function and systemic metabolism.
Members of the interferon family, particularly IFN-γ, are elevated in adipose tissue in diet-induced obesity models and modulate expression of inflammatory chemokines and cytokines (e.g., MCP-1). IFN-γ promotes recruitment and activation of immune cell subsets—T cells, macrophages, NK cells—thus amplifying local inflammation and contributing to systemic metabolic dysfunction.
Leptin, produced by white adipocytes, is elevated in obesity and acts beyond energy balance as a pro-inflammatory, proliferative, and anti-apoptotic adipokine. Leptin signaling engages JAK-STAT, MAPK, and PI3K pathways to increase production of TNF-α, IL-6, IL-12 and to promote M1-like macrophage activation, neutrophil recruitment, and Th1/Th17–biased responses. The review describes a positive feedback loop in which inflammatory stimuli (TNF-α, IL-1) raise leptin expression, which in turn amplifies inflammatory signaling.
The source connects obesity-associated inflammatory features to pro-tumorigenic mechanisms. Chronic inflammation contributes to carcinogenesis through dysregulated tissue repair, activation of oncogenic signaling pathways (including NF-κB, PI3K/AKT, and MAPK), oxidative stress–driven genomic instability, and immune dysfunction. Adipocyte death and crown-like structures formed by macrophage encirclement further maintain pro-inflammatory microenvironments. Hypoxia-driven HIF-α activity promotes angiogenic and metabolic programs that resemble tumor biology (e.g., VEGF induction, glycolytic enzyme upregulation), potentially creating permissive niches for tumor initiation and progression in adjacent tissues.
Specific organ examples cited include breast tissue (cancer-associated adipocytes and crown-like structures), colorectal cancer (leptin-linked signaling abnormalities), metabolic dysfunction–associated steatohepatitis progressing to hepatocellular carcinoma, pancreatic ductal adenocarcinoma (cytokine-driven ferroptosis and oncogenic signaling), and endometrial carcinoma (inflammatory marker elevation and pro-tumor gene expression).
The review underscores that inflammatory burden varies by metabolic phenotype and fat distribution. VAT, due to higher immune-cell density, lipolytic flux, and portal drainage, disproportionately drives systemic inflammation and metabolic risk. SAT is relatively protective until its buffering capacity is overwhelmed. BAT undergoes functional decline in obesity, contributing to low-grade inflammation. These distinctions argue against using BMI alone to infer inflammatory state or cancer risk; metabolic phenotype and depot distribution should inform interpretations.
The abstract and article mention inflammation-directed therapeutic avenues, including cytokine and receptor blockade, immune-cell reprogramming, natural anti-inflammatory agents, and nanoparticle drug-delivery systems. However, the provided source text does not detail specific clinical trial results, single-agent efficacy measures, dosing, or outcome data for these strategies. Where clinical evidence is limited, the authors included preclinical findings but explicitly note translational limitations. Specifics summarizing Table 2 or trial-level evidence were not reported in the provided excerpt.
Overall, the source synthesizes mechanistic links between obesity, inflammation, and cancer and highlights opportunities for anti-inflammatory interventions while acknowledging heterogeneity across adipose depots and the need for translational research to move preclinical insights into precise preventive and therapeutic approaches.