Abstract 2556: Therapy-induced senescent cancer cells facilitate immune evasion in cancer by promoting PD-L1 upregulation through a ribophorin 1-dependent pathway

Abstract Cancer senescence induced by conventional chemotherapy and radiotherapy, characterized by limited proliferation, drug resistance, and a senescence-associated secretory phenotype, is increasingly recognized as a contributor to cancer relapse and the development of an immunosuppressive tumor microenvironment. However, the relationship between cancer senescence and anti-tumor immunity remains poorly understood. In this study, we demonstrate that senescent cancer cells upregulate PD-L1 expression by enhancing its transcription and glycosylation. We identify ribophorin 1 as a key regulator of PD-L1 glycosylation during cancer senescence. Ribophorin 1 depletion significantly reduces PD-L1 levels through the ER-lysosome-associated degradation pathway, rendering senescent cancer cells more susceptible to T-cell-mediated killing. Furthermore, ribophorin 1 depletion suppresses tumor growth by decreasing PD-L1 levels and enhancing cytotoxic T lymphocyte (CTL) activity. Additionally, targeting ribophorin 1 or using anti-PD-1 therapy effectively reduces the number of senescent cancer cells in irradiated tumors and suppresses cancer recurrence by activating CTLs. These findings clarify how senescent cancer cells evade T-cell immunity following treatment, contributing to cancer recurrence. Our results highlight the therapeutic potential of targeting senescent cancer cells as a strategy in cancer treatment. Citation Format: Hyun Jung Hwang, Donghee Kang, Jisoo Shin, Jonghun Jung, Soyeon Ko, Kyung Hee Jung, Soon-Sun Hong, Ji Eun Park, Myung Jin Oh, Hyun Joo An, Wen-Hao Yang, Young-Gyu Ko, Minji Choi, Jong-Ho Cha, Jae-Seon Lee. Therapy-induced senescent cancer cells facilitate immune evasion in cancer by promoting PD-L1 upregulation through a ribophorin 1-dependent pathway [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 2556.