Spatial Plasticity and Multidirectional Crosstalk of Cancer-Associated Adipocytes in Therapy-Remodeled Niches.

Abstract

Cancer-associated adipocytes (CAAs) are increasingly recognized as active and heterogeneous components of the tumor microenvironment. Initially defined as tumor-adjacent adipocytes characterized by lipid depletion, reduced expression of mature adipocyte markers, and inflammatory activation, CAAs are now understood to encompass a spectrum of context-dependent states. These states are shaped by anatomical location, preexisting adipocyte properties, tumor-derived signals, and therapeutic exposure. Through metabolic exchange, paracrine signaling, direct cell contact, extracellular-vesicle communication, and matrix remodeling, CAAs influence tumor-cell plasticity, metastatic colonization, immune dysfunction, stromal organization, and treatment response. In turn, signals from tumor, immune, and stromal cells continuously reshape adipocyte identity and function, placing CAAs within reciprocal multicellular networks. This review examines the evolving criteria used to identify CAAs, their lineage origins and plasticity, their spatial organization, and their interactions with tumor, immune, and stromal compartments. The contribution of CAAs to therapeutic adaptation is also discussed, together with potential intervention points involving CAA-derived outputs and the metabolic dependencies induced in recipient cells. Finally, major methodological challenges are considered. Adipocyte-resolved profiling, lineage tracing, spatial multiomics, lipid flux analysis, and physiologically relevant models will be needed to distinguish transient remodeling from stable state transitions and to identify context-specific therapeutic vulnerabilities.