Adipose tissue, long regarded as a passive energy reserve, is now recognized as a dynamic endocrine compartment that substantially influences cancer biology. Within the tumor microenvironment (TME), adipocytes exposed to cancerous cells become cancer-associated adipocytes (CAAs). These CAAs undergo marked reprogramming and participate actively in tumor progression by altering local inflammation, nutrient availability, extracellular matrix (ECM) structure, and angiogenesis.
CAAs exhibit clear morphological and functional transformation compared with healthy adipocytes. The phenotypic hallmarks described include loss of large lipid droplets, acquisition of fibroblast-like characteristics, and intensified lipolysis. This reprogramming shifts adipocytes from a lipid-storage role to a state in which they release metabolites and signaling molecules that favor tumor cell growth and survival.
The bidirectional communication between tumor cells and CAAs is mediated by a complex secretome. CAAs secrete proinflammatory mediators, cytokines and adipokines, and they release extracellular vesicles, including exosomal microRNAs. These factors orchestrate immune cell recruitment, promote ECM remodeling, stimulate angiogenesis, and directly enhance cancer cell proliferation and invasiveness. The extracellular vesicle component allows transfer of regulatory RNAs and proteins that reprogram recipient cells within the TME.
Mechanistic integration at the adipose–tumor interface involves several conserved signaling pathways. YAP/TAZ, STAT3, and PI3K/AKT are highlighted as central nodes that integrate mechanical stress, inflammatory tone, and nutrient cues. Activation of these pathways in either adipocytes or tumor cells contributes to the cellular and metabolic changes observed, linking extracellular signals to transcriptional programs that enable CAA transformation and support tumor progression.
A metabolic partnership forms between CAAs and cancer cells. CAAs intensify lipolysis and provide fatty acids that tumors can use as fuel. This supports enhanced fatty acid oxidation in cancer cells alongside glycolytic rewiring, creating a flexible metabolic network that supplies energy and maintains redox homeostasis. The metabolic exchanges supply both ATP and biosynthetic precursors, enabling tumor cells to adapt to fluctuating nutrient and oxygen availability within the TME.
CAAs contribute to metastatic dissemination and resistance to therapy. The review emphasizes particular relevance in triple-negative breast cancer (TNBC) and pancreatic cancer, where adipocyte–tumor interactions are pronounced. Specific effectors implicated in promoting invasion, metastasis and chemoresistance include CXCL8, FAM3C, and SAA1, which act within the TME to support aggressive phenotypes. The adipose-driven microenvironment therefore represents a contributor to poor therapeutic outcomes in these contexts.
Beyond local effects, adipose tissue influences systemic cancer biology. Cancer-associated changes in adipose signaling contribute to cancer cachexia and whole-body metabolic dysfunction. The adipokine lipocalin-2 (LCN2) is identified as a mediator that promotes tissue wasting and reduces thermogenesis in cachexia. In addition, chronic inflammation associated with obesity further skews the TME toward tumor promotion, linking systemic metabolic state to local tumor-supportive conditions.
The adipose–tumor crosstalk presents multiple potential therapeutic targets. Nodes highlighted include signaling hubs (YAP/TAZ, STAT3, PI3K/AKT), mediators of metabolic exchange (lipolysis and fatty acid oxidation pathways), and secreted effectors such as cytokines, adipokines and extracellular vesicles. Targeting these components could disrupt metabolic symbiosis, blunt pro-tumor inflammation, or sensitize tumors to standard therapies. The review frames these nodes as opportunities for precision oncology approaches that consider adipose dynamics when designing interventions.
This synthesis underscores that CAAs are active drivers of oncogenesis, progression and therapeutic failure through coordinated changes in phenotype, signaling and metabolism. The adipose compartment shapes immune recruitment, ECM remodeling and angiogenesis while supplying metabolic substrates to cancer cells. Actionable nodes within this adipose–tumor axis merit further translational exploration to improve outcomes, particularly for cancers where adipocyte interactions are prominent. The abstract reports these overarching mechanisms and therapeutic implications; details on specific experimental data, quantitative measures, or clinical trial results were not provided in the abstract and would require consultation of the full article for comprehensive actionable guidance.