Bridging metabolic reprogramming and targeted therapy: the critical role of S-palmitoylation in cancer

Metabolic reprogramming provides cancer cells with excess fatty acids (FA) to adapt to metabolic stress; however, the precise mechanisms by which these lipid substrates are converted into sustained oncogenic signaling outputs remain incompletely elucidated. This article highlights S-palmitoylation, a reversible post-translational modification (PTM), as a critical molecular bridge linking substrate supply to protein membrane anchoring, stability, and activity. Notably, this interaction forms a malignant positive feedback loop: metabolic reprogramming expands the substrate pool, while aberrant S-palmitoylation conversely stabilizes metabolic enzymes, further exacerbating metabolic disruption. Mechanistically, dysregulated S-palmitoylation not only directly sustains key signaling pathways (RAS/MAPK, PI3K/AKT, and Hippo pathways) to promote stress tolerance but also regulates epigenetic plasticity, synergistically driving tumorigenesis, metastasis, and drug resistance. Beyond intracellular signaling, S-palmitoylation reshapes the tumor microenvironment (TME) by regulating the transport and degradation of immunomodulatory factors, notably promoting immune evasion by inhibiting the lysosomal degradation of programmed death-ligand 1 (PD-L1). This review synthesizes recent advances through three unique organizing pillars: (i) the bidirectional metabolic-palmitoylation feedback loops, (ii) palmitoylation-driven epigenetic plasticity, and (iii) the paradigm shift toward substrate-centric therapeutic designs, aiming to overcome current clinical challenges and enhance the efficacy of immunotherapy.