Obesity is established as one of the most important risk factors for endometrial cancer. Current evidence indicates that excess adiposity contributes not only to increased incidence but also to disease progression. The tumor-promoting effects of obesity are multifactorial and involve endocrine, metabolic, and immune mechanisms that operate both systemically and within the tumor microenvironment.
Recent work synthesizes three central, interrelated mechanisms by which obesity drives endometrial carcinogenesis: elevated estrogen levels, insulin resistance, and chronic inflammation. These mechanisms interact to form a malignant positive feedback loop. Elevated estrogen produced or modified by adipose tissue stimulates endometrial proliferation. Insulin resistance and hyperinsulinemia alter growth and metabolic signaling. Chronic inflammation originating in adipose depots sustains pro-tumorigenic signaling and immune changes. Together, these processes reinforce one another and promote initiation and progression of endometrial tumors.
Visceral and subcutaneous fat depots do not act identically. The review highlights that visceral and subcutaneous obesity differentially regulate secretion of adipose-derived factors and shape distinct metabolic microenvironments. These depot-specific differences can influence the molecular subtypes of endometrial cancer, pathological characteristics, and how tumors respond to treatments. Recognizing heterogeneity across obesity phenotypes is therefore important when considering mechanisms and therapeutic strategies.
Adipose tissue secretes a variety of signaling molecules—collectively termed adipokines—that link systemic metabolic state to tumor biology. Changes in adipokine profiles driven by obesity alter local and systemic signaling pathways, contributing to a microenvironment that favors tumor development. Differential adipokine secretion from distinct fat depots may underlie variations in tumor phenotype and clinical behavior across patients with obesity.
Chronic, low-grade inflammation associated with obesity is a key contributor to endometrial cancer risk. Inflammatory signaling originating in adipose tissue shapes the tumor microenvironment, modifies immune cell composition and function, and promotes pro-tumorigenic processes. The interaction between adipose-derived inflammatory mediators and tumor cells supports a permissive milieu for tumor initiation and progression.
Obesity influences estrogen production and metabolism, which are central to endometrial epithelial proliferation and oncogenesis. Elevated estrogen levels in the context of excess adiposity are identified as a primary mechanism linking obesity to endometrial cancer. Altered local and systemic estrogen metabolism contributes to the hormonal milieu that encourages endometrial tumorigenesis.
Insulin resistance is another core pathway connecting obesity to endometrial cancer. Metabolic dysregulation and accompanying hyperinsulinemia can activate growth-promoting signaling cascades within endometrial tissue and the tumor microenvironment. These metabolic signals interact with hormonal and inflammatory pathways to amplify tumor-promoting effects.
Epigenetic changes are implicated as an important mechanism by which obesity affects endometrial cancer biology. Obesity-associated epigenetic regulation may influence gene expression patterns relevant to tumor initiation, progression, and therapeutic response. The review underscores epigenetic processes as potential biomarkers and targets for intervention in obesity-related endometrial cancer.
The authors frame a unifying concept: the adipose-immune-metabolic axis, encompassing cross-talk among adipose tissue, immune components, and metabolic signaling, plays a central role in the initiation and progression of endometrial cancer in the context of obesity. This axis integrates adipokine secretion, inflammatory signaling, hormonal changes, metabolic dysfunction, and epigenetic regulation to shape tumor behavior.
Future research priorities recommended in the review include integrating multi-omics approaches with detailed tumor microenvironment analyses. Such integration aims to delineate mechanisms across molecular, cellular, and tissue levels and to identify obesity subtype–specific features. The authors propose developing precision therapeutic strategies informed by obesity phenotypes (for example, visceral versus subcutaneous predominance) and by epigenetic biomarkers. These approaches are intended to provide new insights for clinical management and targeted interventions in obesity-related endometrial cancer.
In summary, obesity promotes endometrial cancer via a constellation of interlinked mechanisms—elevated estrogen, insulin resistance, and chronic inflammation—that together form a malignant feedback loop. Depot-specific adipose biology, adipokine signaling, inflammatory pathways, metabolic dysfunction, and epigenetic regulation all contribute to tumor heterogeneity and influence clinical course. The review calls for multi-omics and microenvironment-focused research to enable precision strategies tailored to obesity subtypes and epigenetic markers, with the goal of improving prevention and treatment of obesity-associated endometrial cancer.