Targeting ZDHHC15-mediated S-acylation of CD155 reactivates anti-tumor immunity

The immune checkpoint CD155 is frequently upregulated across multiple malignancies and drives tumor progression and immune evasion, yet the posttranslational mechanisms regulating its stability and activity remain unclear. Here, we identify S-acylation as a key regulator of CD155 stability and immunosuppressive function. Using chemical reporters, we demonstrate that CD155 is S-acylated at three cytoplasmic cysteines by the acyltransferase ZDHHC15 and deacylated by the thioesterases PPT1/APT1. S-acylation protects CD155 from lysosomal degradation and promotes its interaction with Sprouty2 to sustain oncogenic ERK signaling. Genetic inhibition of ZDHHC15 disrupts CD155 S-acylation, triggering CD155 degradation, enhancing CD8⁺ T cell infiltration, and suppressing tumor growth in syngeneic models. We further show that the FDA-approved CDK4/6 inhibitor abemaciclib promotes CD155 degradation by upregulating PPT1 and enhancing lysosome biogenesis. Our work identifies reversible CD155 S-acylation as a druggable regulatory mechanism that links protein lipidation to immune checkpoint stability and reveals an unexpected immune-potentiating mechanism of abemaciclib.