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 advances in targeted therapies and CAR-T cell treatments, limited response rates and poor survival after relapse underscore the urgent need for novel therapeutic strategies. Because CRISPR-based knockout screening identified EP300 as a therapeutic vulnerability, we evaluated the therapeutic effects and mechanisms of TS156, a novel inhibitor targeting the EP300/CREBBP HAT domain. TS156 induced the cytotoxic effects accompanied by G1 cell cycle arrest in MCL cell lines. 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). Consistent with this mechanism, TS156-treated MCL cells exhibited hallmarks of ICD, including DAMP release and surface translocation of calreticulin, suggesting that TS156 not only induces tumor cell apoptosis but also promotes immunogenic signaling that may enhance antitumor immunity. These findings indicate that TS156 functions as a potential ICD-inducing agent and represents a promising therapeutic strategy for MCL.