Abstract 5870: Blocking cadherin-11 activates pyroptosis-mediated antitumor immunity via the PD-L1/GSDMD/CCL3 axis in bladder cancer

Abstract Introduction: Pyroptosis, a form of programmed cell death driven by proinflammatory signals, plays a dual role in inflammation and cancer progression. Cadherin-11 (CDH-11), a type II cadherin, is known to mediate cell-cell and cell-extracellular matrix adhesion. Emerging evidence suggests that CDH-11 contributes to tumor progression and metastasis, making it a potential therapeutic target. In this study, we investigate whether targeting CDH-11 can suppress bladder cancer (BC) cell invasiveness and activate pyroptosis-mediated antitumor immunity. Materials & Methods: Transwell assays were conducted to evaluate cell migration and invasion abilities. Pyroptosis was measured using lactate dehydrogenase (LDH) assays, while calcein AM staining-based cytotoxicity assays were employed to measure natural killer (NK) cell-mediated cytotoxicity. Inflammatory cytokine levels in BC tissues were determined using a human antibody array. To investigate the role of CDH-11 in tumor progression, a subcutaneous tumor model and a popliteal lymph node model were established to evaluate tumor growth and lymphatic metastasis in vivo. Immunohistochemistry staining was utilized to assess CDH-11 protein expression in human BC tissues. Results: Elevated CDH-11 expression was observed in BC patients compared to healthy individuals, with a positive correlation to advanced clinical stages, lymphatic metastasis, and poor overall survival. In vitro analyses demonstrated that blocking CDH-11 significantly reduced BC cell invasiveness. Notably, CDH-11 blockade induced bubble-like protrusions on the cell surface and increased LDH release, indicative of enhanced pyroptosis. Mechanistically, CDH-11 inhibition activated PD-L1-mediated GSDMD expression, with the GSDMD N-terminal domain forming membrane pores to initiate pyroptosis. Further analysis revealed that CDH-11-induced pyroptosis elevated the release of the proinflammatory cytokine CCL3 within the tumor microenvironment, thereby enhancing natural killer (NK) cell-mediated cytotoxicity against BC cells. In vivo, CDH-11 blockade effectively suppressed tumor growth, lymphatic metastasis, and lung metastasis, highlighting its therapeutic potential. Conclusions: These findings reveal a novel role of CDH-11, demonstrating that its inhibition suppresses cell invasion and enhances pyroptosis-mediated antitumor immunity through CCL3 in BC. Targeting CDH-11 represents a promising therapeutic strategy for the management of BC. Citation Format: Thomas I-Sheng Hwang, An-Chen Chang. Blocking cadherin-11 activates pyroptosis-mediated antitumor immunity via the PD-L1/GSDMD/CCL3 axis in bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5870.