ZDHHC3 is a zinc finger DHHC-type palmitoyltransferase that catalyzes S-palmitoylation of multiple substrates, functioning primarily as a protein lipidation enzyme 1. This post-translational modification stabilizes target proteins by blocking their ubiquitination and subsequent degradation 12. In cancer immunity, ZDHHC3 mediates palmitoylation of immune checkpoint proteins including PD-L1 and B7-H4, preventing their lysosomal degradation and sustaining tumor immune evasion 13. ZDHHC3 also promotes cholesterol biosynthesis through SCAP S-acylation, creating a positive feedback loop with SREBP2 that reprograms metabolism and restrains anti-tumor T cell responses in hepatocellular carcinoma 4. Outside oncology, ZDHHC3-mediated palmitoylation of Cadm4 is essential for its plasma membrane localization and CNS myelination; ZDHHC3 disruption causes demyelination and neuroinflammation 5. In liver pathology, ZDHHC3 palmitoylates IRHOM2, promoting fatty acid-induced hepatosteatosis and nonalcoholic steatohepatitis progression 2. In antiviral immunity, ZDHHC3 suppresses innate antiviral signaling by promoting MAVS degradation through K48-linked ubiquitination 6. ZDHHC3 inhibition via 2-bromopalmitate or ZDHHC3 knockdown enhances anti-tumor immunity and chemotherapy efficacy across pancreatic cancer and colorectal cancer models 78, establishing ZDHHC3 as an emerging therapeutic target.