Cancer-associated adipocytes: metabolic reprogramming, crosstalk and therapeutic implications in tumor progression

Abstract

Adipose tissue, once considered a passive fuel store, is now recognized as a dynamic endocrine organ that shapes cancer behavior. Within the tumor microenvironment (TME), cancer-associated adipocytes (CAAs) undergo marked reprogramming—losing large lipid droplets, adopting fibroblast-like features, and intensifying lipolysis—while releasing proinflammatory mediators that accelerate proliferation, invasion, and therapy resistance. This interaction is bidirectional: through cytokines, adipokines, and extracellular vesicles (including exosomal microRNAs), CAAs coordinate immune recruitment, extracellular matrix (ECM) remodeling, and angiogenesis. Mechanistically, several pathways converge at this interface. YAP/TAZ, STAT3, and PI3K/AKT integrate mechanical stress, inflammatory tone, and nutrient cues; metabolic symbiosis—enhanced fatty acid oxidation alongside glycolytic rewiring—supplies energy and redox support. CAAs also amplify metastasis and chemoresistance, particularly in triple-negative breast (TNBC) and pancreatic cancers, via effectors such as CXCL8, FAM3C, and SAA1. Systemic axes also matter in cancer cachexia, adipocyte-derived lipocalin-2 (LCN2) promotes tissue wasting and dampens thermogenesis, while obesity’s chronic inflammation further biases the TME toward tumor promotion. This review synthesizes how CAAs and adipose dynamics drive oncogenesis, progression and therapeutic failure and highlights actionable nodes within the adipose–tumor axis for precision oncology.