Targeting palmitoylation: A novel frontier in cancer biology and immunotherapy.

Protein palmitoylation, a dynamic post-translational modification involving the reversible attachment of palmitic acid to cysteine residues, has emerged as a pivotal regulator of tumor biology. This review synthesizes the latest insights into palmitoylation's contributions to cancer, emphasizing its roles in metabolic reprogramming, oncogenic signaling, immune modulation, and therapeutic responsiveness. The ZDHHC family of palmitoyltransferases, in concert with depalmitoylases, coordinates intricate regulatory networks that govern protein localization, stability, and interactions essential for tumor proliferation, invasion, and immune evasion. Driven by dysregulated lipid metabolism, aberrant palmitoylation modulates key pathways such as AKT-mTOR and Wnt/β-catenin, while also stabilizing immune checkpoints like PD-L1 and TIM-3 to sculpt an immunosuppressive tumor microenvironment. Advances in multi-omics integration and detection technologies, including high-resolution mass spectrometry and imaging modalities, have deepened our mechanistic understanding of these processes. Preclinical evidence underscores the promise of small-molecule inhibitors like 2-bromopalmitate and TVB-3166, which disrupt palmitoylation to inhibit tumor growth and potentiate immunotherapy. Nonetheless, hurdles in selectivity, toxicity, and resistance demand further optimization for clinical translation. Future research should focus on unraveling palmitoylation's interplay with immune dynamics and advancing biomarker-guided, personalized therapies to elevate cancer outcomes.