Succinate dehydrogenase B palmitoylation promotes T cell exhaustion through the H3K27ac-PD1 axis in pancreatic cancer.

Palmitoyltransferase ZDHHC5 (DHHC5) is a palmitoylation regulator that adds palmitate to various protein substrates. Its role in pancreatic cancer (PC) remains unclear, thus posing significant challenges to the promotion of the "cold tumor" immune microenvironment, the development of new drugs, and targeted therapy. In this study, through comprehensive bioinformatics analysis, we determined the association between DHHC5 and various immune and metabolic components which we refer to as post-translational modification checkpoint of palmitoylation (Palm-PTM-checkpoint). We found that in pancreatic cancer, DHHC5 upregulates the palmitoylation of succinate dehydrogenase B (SDHB), stabilizes the SDHB protein, inhibits lysosomal degradation, and increases fumarate production by promoting succinate dehydrogenase activity. This process suppresses the overall immune microenvironment, especially the anti-tumor immunity of T cells. Mechanistically, the excessive fumarate produced by the palmitoylation cycle of SDHB in cancer cells increases the production of acetyl-CoA in T cells and promotes T-cell exhaustion by upregulating the H3K27 acetylation (H3K27ac) -PD1 axis. Additionally, based on the sequence near the palmitoylation site of SDHB, we designed an intracellular penetrating peptide CPP-S1 targeting SDHB palmitoylation. As a competitive inhibitor, CPP-S1 inhibits the palmitoylation modification of SDHB, reduces the SDHB protein level, and suppresses the tumor growth of pancreatic cancer cells, with enhanced effects when used in combination with anti-PD1 therapy. These findings reveal a new strategy to overcome the immune escape mediated by the DHHC5-SDHB axis in pancreatic cancer immunotherapy.