Protein palmitoylation in hematological malignancies: mechanistic links to lipid metabolic reprogramming and therapy resistance.

Protein palmitoylation has emerged as a central post-translational mechanism governing protein localization, stability, and signal transduction. In hematological malignancies, this dynamic modification lies at the intersection of lipid metabolic reprogramming, tumor-immune interactions, and therapeutic resistance. Here, we review how dysregulated palmitoyltransferases and depalmitoylases modify metabolic enzymes, lipid transporters, lipid-droplet proteins, oncogenic signaling components, and immune-regulatory molecules, thereby creating self-reinforcing circuits that sustain tumor growth and treatment failure. We further discuss the contribution of macrophage and myeloid-cell lipid metabolism, the potential roles of palmitoylation in non-malignant cells of the tumor microenvironment, and the underexplored relevance of palmitoylation to multiple myeloma. Particular attention is given to crosstalk with phosphorylation and ubiquitination, as well as to the distinction between direct evidence from hematological malignancies and cross-tumor mechanistic inferences. Finally, we evaluate emerging therapeutic strategies, including selective enzyme inhibitors, proteolysis-targeting chimeras, metabolic modulation, and immunotherapy combinations. This evidence-calibrated framework highlights both the translational potential of targeting palmitoylation and the need for cell-type-resolved validation in blood cancers.