Decoding protein-phospholipid interaction networks in cancer: the role of acyl-chain remodeling

Lipids, particularly phosphoinositides, are increasingly recognized as important markers and causal regulators in cancer progression. Less appreciated, however, are the functional consequences of changes in phospholipid acyl chain length and saturation. These alterations reshape membrane biophysics and rewire membrane-associated signaling complexes, suggesting that acyl-chain remodeling represents an emerging regulatory layer in cancer biology. Distinct tumor types or their models exhibit characteristic acyl chain profiles, often shifting toward shorter, more saturated chains that alter physical and functional interactions. Stress conditions and the tumor microenvironment further diversify these profiles, linking acyl chain composition to cellular plasticity, invasiveness, and metastatic potential. In this review, we summarize the molecular factors and enzymatic pathways that govern phospholipid acyl chain remodeling in cancer and examine their relevance to dynamic protein interaction networks. We describe how dysregulated lipid metabolism at the fatty acid level intersects with oncogenic signaling and highlight emerging chemical biology and multi-omics approaches that enable interrogation of protein-phospholipid interaction networks in physiological contexts. Together, these developments position acyl chain-resolved lipid analysis as a central challenge in chemical biology, requiring new probe design and integrative data frameworks to decode lipid-protein interaction networks in cancer. Finally, we discuss how emerging tools for acyl chain-resolved lipid analysis and targeted modulation reveal how membrane remodeling rewires signaling pathways and reshapes the tumor lipid-protein interactome, opening new opportunities for cancer diagnosis and therapeutic intervention.