Protein acylation in cancer: from regulatory networks to precision therapeutics

Abstract Protein acylation comprises a diverse class of metabolite-responsive post-translational modifications that links cellular metabolic states to protein function and signaling. Beyond canonical acetylation, emerging acylation marks are dynamically controlled by acyl-donor availability and writer–eraser–reader systems, forming regulatory networks that reshape chromatin, metabolism, protein stability and localization, cytoskeletal dynamics, and immune responses. In cancer, dysregulated acylation enables tumor cells to adapt to metabolic and environmental stress, thereby promoting malignant progression, metastasis, immune escape, and therapeutic resistance. This Review examines the chemical and enzymatic principles of major protein acylations and integrates their roles across metabolic, epigenetic, signaling, and tumor-immune networks. We further discuss acylation-based biomarkers, patient stratification, pharmacological targeting, and mechanism-guided combination strategies, while highlighting challenges in modification specificity and clinical validation. Together, these advances position protein acylation as a regulatory interface between tumor plasticity and therapeutic response, providing a framework for biomarker-guided precision therapeutics.