Protein S-palmitoylation in cancer progression and therapeutic resistance

Protein S-palmitoylation is a reversible lipid post-translational modification (PTM) that controls protein localization, stability, trafficking, and signaling. In cancer, this modification does not act as a simple oncogenic switch. Its effects depend on the substrate, the palmitoyltransferase or depalmitoylase involved, the tumor lineage, and the immune context. In some settings, palmitoylation sustains oncogenic signaling, metabolic rewiring, stemness, ferroptosis resistance, and immune escape. In others, it restrains tumor growth or improves therapeutic sensitivity by limiting key signaling pathways or preserving antigen presentation. This context dependence is especially important in the tumor microenvironment (TME), where palmitoylation can shape T cell exhaustion, natural killer (NK) cell cytotoxicity, macrophage polarization, myeloid-derived suppressor cell (MDSC) expansion, and immune checkpoint protein stability. This mini-review summarizes the enzymatic regulation and detection of protein S-palmitoylation, highlights its roles in tumor progression and immune regulation, and discusses how palmitoylation-targeted strategies may improve cancer therapy. Rather than viewing global inhibition as a universal solution, we emphasize the need to define substrate-specific and cell type-specific palmitoylation programs. Such precision will be critical for translating this dynamic PTM into rational combinations with chemotherapy, radiotherapy, targeted therapy, and immune checkpoint inhibitors (ICIs).