Decoding Protein–Phospholipid Interaction Networks in Cancer: The Role of Acyl-Chain Remodeling

Abstract

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, positioning acyl-chain remodeling as a core molecular hallmark of cancer. Distinct tumor types exhibit characteristic acyl chain profiles, often shifting toward shorter, more saturated chains that alter physical and functional interactions in model systems. 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 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 chemical biology challenge, requiring new probe design and integrative data frameworks to decode protein–lipid interaction networks in cancer. Finally, we discuss how new tools for acyl chain–resolved lipid analysis and targeted modulation reveal how membrane remodeling rewires signaling pathways and reshapes the tumor protein–lipid interactome, opening new opportunities for cancer diagnosis and therapeutic intervention.