Protein S‑palmitoylation in T cell‑mediated antitumor immunity: Context‑dependent mechanisms and therapeutic opportunities (Review)

S-palmitoylation is a critical post-translational regulator of protein function; however, its role in T cell-mediated antitumor immunity remains unclear.The present review summarizes emerging evidence that redefines T cell biology and its implications for antitumor immunity.The regulatory functions of S-palmitoylation in T cell receptor signaling, activation, proliferation, differentiation, exhaustion and apoptosis are first outlined, highlighting the distinct roles of the zinc finger Asp-His-His-Cystype family of palmitoyl acyltransferases and depalmitoylating enzymes in modulating the membrane localization, stability and signal transduction of key T cell signaling regulators.How S-palmitoylation of immune checkpoints, such as programmed death-ligand 1, and the components of antigen presentation shape the tumor immune microenvironment were further examined.Additionally, the recent advances in therapeutic strategies targeting S-palmitoylation, including small-molecule inhibitors, peptide-based interventions and nanoparticle delivery systems, were highlighted, and their potential to enhance T cell antitumor immunity, particularly in combination with immune checkpoint blockade, was discussed.Finally, the current challenges, including the suboptimal selectivity of pharmacological agents, technical limitations of existing delivery systems and the intrinsic heterogeneity and immunosuppressive nature of the tumor microenvironment were discussed, and future directions for advancing S-palmitoylation-targeted immunotherapies were proposed.collectively, the present review highlights S-palmitoylation as a promising regulatory axis for antitumor immunity and provides a foundation for the future development of targeted immunotherapies. Contents Introduction 2. Fundamentals and methodological considerations in protein S-palmitoylation 3. T cell-intrinsic S-palmitoylation during TcR signaling, activation, differentiation, exhaustion and apoptosis 4. Tumor-cell-intrinsic S-palmitoylation regulating T cell immunity 5. S-palmitoylation in dendritic cells (dcs) and otherantigen-presenting or myeloid cells 6. Metabolism-S-palmitoylation crosstalk in the TME 7. Therapeutic strategies, supporting evidence and translational barriers 8. conclusions and perspectives Protein S-palmitoylation in T cell-mediated antitumor immunity: Context-dependent mechanisms and therapeutic opportunities (Review)