Therapy-induced senescent cancer cells contribute to cancer progression by promoting ribophorin 1-dependent PD-L1 upregulation

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, Jong-Ho Cha () and Jae-Seon Lee ()
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Hyun Jung Hwang: Inha University
Donghee Kang: Inha University
Jisoo Shin: Inha University
Jonghun Jung: Inha University
Soyeon Ko: Inha University
Kyung Hee Jung: Inha University
Soon-Sun Hong: Inha University
Ji Eun Park: Chungnam National University
Myung Jin Oh: Chungnam National University
Hyun Joo An: Chungnam National University
Wen-Hao Yang: China Medical University
Young-Gyu Ko: Korea University
Jong-Ho Cha: Inha University
Jae-Seon Lee: Inha University

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract Conventional chemotherapy- and radiotherapy-induced cancer senescence, which is characterized by poor proliferation, drug resistance, and senescence-associated secretory phenotype, has gained attention as contributing to cancer relapse and the development of an immunosuppressive tumor microenvironment. However, the association between cancer senescence and anti-tumor immunity is not fully understood. Here, we demonstrate that senescent cancer cells increase the level of PD-L1 by promoting its transcription and glycosylation. We identify ribophorin 1 as a key regulator of PD-L1 glycosylation during cancer senescence. Ribophorin 1 depletion reduces this elevated level of PD-L1 through the ER-lysosome-associated degradation pathway, thereby increasing the susceptibility of senescent cancer cells to T-cell-mediated killing. Consistently, ribophorin 1 depletion suppresses tumor growth by decreasing PD-L1 levels and boosting cytotoxic T lymphocyte activity in male mice. Moreover, ribophorin 1-targeted or anti-PD-1 therapy reduces the number of senescent cancer cells in irradiated tumors and suppresses cancer recurrence through the activation of cytotoxic T lymphocytes. These results provide crucial insights into how senescent cancer cells can escape T-cell immunity following cancer treatment and thereby contribute to cancer recurrence. Our findings also highlight the therapeutic promise of targeting senescent cancer cells for cancer treatment.

Date: 2025
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DOI: 10.1038/s41467-024-54132-1

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