Protein palmitoylation and immune regulation in pancreatic ductal adenocarcinoma: Integrating insights from cross-cancer studies.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by an immunologically "cold" tumor microenvironment (TME), marked by a dense stromal barrier, impaired antigen presentation, and extensive infiltration of immunosuppressive cells. In recent years, protein S-palmitoylation, a reversible lipid modification, has emerged as a critical mechanism regulating immune signaling, receptor trafficking, and membrane localization of immune-related proteins. This review highlights the multifaceted roles of S-palmitoylation in shaping the immunological landscape of PDAC. We systematically discuss its involvement in immune checkpoint regulation, T-cell activation, antigen presentation, and the function of myeloid-derived suppressor cells (MDSCs), integrating evidence from both PDAC and other cancer types. Special attention is given to key palmitoylated molecules, including programmed death-ligand 1 (PD-L1), cluster of differentiation 80 (CD80), lymphocyte-specific protein tyrosine kinase (LCK), linker for activation of T cells (LAT), interferon-induced transmembrane proteins (IFITMs), and major histocompatibility complex class I (MHC-I), and their potential roles in the immunosuppressive network of PDAC. Moreover, we explore therapeutic strategies targeting palmitoylation, such as the use of selective palmitoyltransferase inhibitors, the design of palmitoylation-deficient CAR-T cells, and the development of nanotechnology-based delivery platforms. By incorporating cross-cancer insights, we propose that palmitoylation is a promising regulatory axis for reprogramming the PDAC immune microenvironment and overcoming resistance to immunotherapy.