Mantle cell lymphoma (MCL) is a rare and aggressive B-cell malignancy accounting for approximately 6% of non-Hodgkin lymphoma cases and associated with poor clinical outcomes. Despite therapeutic advances, frequent relapse and limited treatment durability highlight the need for novel therapeutic strategies. Here, we evaluated the therapeutic effects and mechanisms of TS156, an inhibitor targeting the EP300/CREBBP histone acetyltransferase (HAT) domain. TS156 induced cytotoxic effects in MCL cell lines, accompanied by cell-cycle arrest and a dose-dependent increase in apoptosis. Transcriptome profiling and subsequent analyses revealed that TS156 activates the PERK–eIF2α–ATF4–CHOP axis, indicating ER stress–mediated apoptosis. Notably, PERK-driven ER stress has been recognized as a key trigger of immunogenic cell death (ICD), a form of regulated cell death that stimulates antitumor immune responses through the release of damage-associated molecular patterns (DAMPs) and the cell surface exposure of calreticulin. Consistent with this mechanism, TS156-treated MCL cells exhibited hallmarks of ICD, including increased DAMP release and surface translocation of calreticulin. These ICD-associated features were accompanied by immune activation in vivo, as evidenced by reduced tumor volume and enhanced dendritic cell maturation and CD8⁺ T-cell activation following TS156 treatment. These findings indicate that TS156 is a potential ICD-inducing agent and represents a promising therapeutic strategy for MCL.