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Review
. 2025 May;292(9):2189-2207.
doi: 10.1111/febs.17312. Epub 2024 Nov 4.

Obesity, white adipose tissue and cancer

Estel Solsona-Vilarrasa  1 , Karen H Vousden  1
Affiliations
Review

Obesity, white adipose tissue and cancer

Estel Solsona-Vilarrasa et al. FEBS J. 2025 May.

Abstract

White adipose tissue (WAT) is crucial for whole-body energy homeostasis and plays an important role in metabolic and hormonal regulation. While healthy WAT undergoes controlled expansion and contraction to meet the body's requirements, dysfunctional WAT in conditions like obesity is characterized by excessive tissue expansion, alterations in lipid homeostasis, inflammation, hypoxia, and fibrosis. Obesity is strongly associated with an increased risk of numerous cancers, with obesity-induced WAT dysfunction influencing cancer development through various mechanisms involving both systemic and local interactions between adipose tissue and tumors. Unhealthy obese WAT affects circulating levels of free fatty acids and factors like leptin, adiponectin, and insulin, altering systemic lipid metabolism and inducing inflammation that supports tumor growth. Similar mechanisms are observed locally in an adipose-rich tumor microenvironment (TME), where WAT cells can also trigger extracellular matrix remodeling, thereby enhancing the TME's ability to promote tumor growth. Moreover, tumors reciprocally interact with WAT, creating a bidirectional communication that further enhances tumorigenesis. This review focuses on the complex interplay between obesity, WAT dysfunction, and primary tumor growth, highlighting potential targets for therapeutic intervention.

Keywords: cancer; obesity; white adipose tissue.

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Conflict of interest statement

KHV is on the board of directors and shareholder of Bristol Myers Squibb and on the science advisory board (with stock options) of PMV Pharma, RAZE Therapeutics, Volastra Pharmaceuticals and Kovina Therapeutics. She is on the SAB of Ludwig Cancer and a co‐founder and consultant of Faeth Therapeutics. She has been in receipt of research funding from Astex Pharmaceuticals and AstraZeneca and contributed to CRUK Cancer Research Technology filing of patent application WO/2017/144877. The other authors declare no conflicts of interest.

Figures

Fig. 1
Fig. 1
White adipose tissue (WAT) heterogeneity. WAT is a highly heterogeneous organ in terms of anatomical location, cellular composition and functionality. Anatomical location: Adipose tissue is organized into discrete depots throughout the body. Subcutaneous WAT is found beneath the skin, while visceral fat is located around internal organs. Major visceral depots in humans comprise epicardial/pericardial, retroperitoneal, omental, mesenteric and gonadal WAT. Other smaller WAT depots include the bone marrow and mammary fat. Cellular composition: Besides adipocytes, WAT is also composed of pre‐adipocytes, ASCs and a wide range of immune cells among others. Functionality: Apart from storing and releasing energy in the form of fat, WAT has an additional role as an endocrine organ, and it is also involved in insulin and glucose homeostasis as well as appetite and energy balance regulation. Created with BioRender.com.
Fig. 2
Fig. 2
Hallmarks of healthy and dysfunctional obese WAT. Healthy WAT is identified by its flexible expandability through controlled hyperplasia and/or hypertrophy, adequate lipid storage and responsiveness to insulin. It exhibits minimal inflammation, high vascularization, and lacks fibrosis and hypoxia. By contrast, in the context of obesity, compromised WAT displays abnormal expandability and lipid storage, insulin resistance, and increased release of lipids that accumulate in other organs. Additionally, it releases numerous pro‐inflammatory molecules leading to the recruitment of pro‐inflammatory immune cells and the formation of adipose crown‐like structures. Besides inflammation, dysfunctional obese WAT is further characterized by reduced angiogenesis, increased hypoxia, and fibrosis attributed to the excessive production of extracellular matrix components. Created with BioRender.com.
Fig. 3
Fig. 3
Impact of obesity on WAT‐cancer interactions. Some cancers are locally affected by WAT depots as they are embedded or in close contact with them. WAT also mediates endocrine effects through the bloodstream, impacting not only those cancers directly connected to fat depots but also others that lack such proximity. Certain tumors can also interact with cells from adipose tissue that infiltrate the tumor environment. Furthermore, specific cancer types can spread to the omental fat and adipose‐containing sites such as the bone marrow. Obesity can fuel cancer progression not only through various independent mechanisms such as diet and the microbiome but also by directly altering WAT function, thus creating a more favorable environment for tumor growth. Created with BioRender.com.
Fig. 4
Fig. 4
Main systemic effects of dysfunctional WAT on tumor progression. Dysfunctional WAT systemically impacts cancer progression mainly by inducing changes in the circulating levels of WAT‐derived factors and insulin resistance, altering the systemic lipid metabolism, and triggering an inflammatory state. Created with BioRender.com.
Fig. 5
Fig. 5
Major local effects of dysfunctional WAT on tumor progression. The local effects of unhealthy WAT involve abnormal release of adipokines and nutrients and local inflammation. In addition, aberrant WAT triggers extracellular matrix remodeling, generating a favorable microenvironment for tumor progression. In the adipose‐rich TME, there is also extensive crosstalk between cancer cells and different adipose‐derived cell types such as adipocytes and adipose‐derived stromal/stem cells (ASCs). Apart from mature adipocytes feeding the tumor, cancer cells can also induce the transformation of adipose cells into cancer‐associated adipocytes and later into myofibroblast‐, mesenchymal stem cell‐ and macrophage‐like cells to further satisfy their oncogenic needs. Cytokines and adipokines made by the adipocytes also act on immune cells present in the TME. Mature adipocytes can enhance T‐regs function and inhibit CD8+ T and NK cells activity, overall leading to decreased anti‐tumoral activity. Created with BioRender.com.
See this image and copyright information in PMC

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