Spatial anchoring of lipid metabolism shapes immune fate in the tumor microenvironment.

Abstract

Cancer metabolic reprogramming has typically been regarded as a cell-autonomous process; however, this perspective fails to fully capture the intricacies of immunosuppression and treatment resistance within the heterogeneous and spatially organized tumor microenvironment (TME). While the metabolism of all major nutrients is subject to spatial constraints, lipid metabolism exhibits a unique and pronounced sensitivity due to the hydrophobic nature of lipids, which necessitates a specialized network of carrier proteins and organelles for their transport, storage, and signaling. We propose a model of spatio-specific lipid-immune regulatory programs that connects the intrinsic metabolic drivers of cancer cells with the spatial architecture of the TME, While grounded in existing literature, several of the mechanistic connections we describe represent a conceptual framework and working hypotheses that require direct experimental testing in the tumor microenvironment. Our investigation focuses on how three distinct spatial niches, the hypoxic core, invasive margin, and perivascular area, shape diverse lipid metabolic profiles through their unique physicochemical conditions and cellular compositions. Metabolic states specific to location determine the destiny and role of infiltrating immune cells, shaping an immune network significantly impacted by spatial positioning. Additionally, we investigate the potential of this spatial framework in identifying niche-specific biomarkers and developing novel combination therapies.