Tumor cells impair immunological synapse formation via central nervous system-enriched metabolite

Tumors employ various strategies to evade immune surveillance. Central nervous system (CNS) has multiple features to restrain immune response，because cranial inflammation can rapidly develop into lethal brain edema. However, whether tumors and CNS share similar programs of immune tolerance is elusive. Here, we analyzed transcriptomic and metabolomic profiles of tumors from patients with HER2+ breast cancer, who received trastuzumab, anti-PD-L1 antibodies and docetaxel (KN035-TH-HER2 study). We found that a neuronal metabolite N-acetylaspartate (NAA) and its synthetase N-acetyltransferase 8-like (NAT8L) are enriched in resistant tumors. In CNS, NAA is released during brain inflammation. We showed that NAT8L attenuates brain inflammation in experimental autoimmune encephalomyelitis (EAE) and impairs anti-tumor immunity by inhibiting cytotoxicity of NK cells and CD8+ T cells via NAA. Mechanistically, NAA disrupts the formation of immunological synapse by inducing K542 acetylation of lamin A, which inhibits the integration between lamin A and SUN2 and consequently impairs polarization of lytic granules in NK cells and CD8+ T cells. Our study uncovered that tumor cells mimic the anti-inflammatory protective barrier of CNS to evade from anti-tumor immunity and NAT8L is a potential target to enhance efficacy of anti-cancer agents