Palmitoylation-dependent regulation of innate and adaptive immunity: molecular insights and translational opportunities

Immune cells orchestrate organismal defense through pathogen surveillance, tissue homeostasis, and immune tolerance, with innate and adaptive subsets coordinating context-specific responses. The dynamic lipid modification, S-palmitoylation (often referred to simply as palmitoylation), regulates membrane trafficking, signal transduction, and protein–protein interactions by spatiotemporally controlling the localization, stability, and activity of immune mediators. Dysregulation of this process in immune cells contributes to pathologies including immunosuppression, chronic inflammation, and autoimmunity. This review synthesizes current knowledge on how palmitoylation governs immune cell development, subset-specific functions, and immune-mediated pathologies—encompassing metabolic disorders, infectious diseases, autoimmune disorders, and cancer. We further explore the diagnostic and therapeutic potential of targeting palmitoyltransferases, depalmitoylases, and palmitoylation-dependent immune checkpoints to restore immune equilibrium. By integrating mechanistic insights into palmitoylation-dependent immune regulation with translational applications, this work underscores the potential of palmitoylation-centric biomarkers and therapies to transform immunological diagnostics and treatment.