Cathepsin L as a dual-target to mitigate muscle wasting while enhancing anti-tumor efficacy of anti-PD-L1

Se-Young Park, Kyuwon Son, Jiwoo Kim, Kyeongah Kim, Sungmin Joo, Bomi Kim, Myunggyo Lee, Wankyu Kim, Won-Jung Jung, Byung Kwan Choi, Nakyung Jeon, Won-Yoon Chung, Yinling Hu, Haeseung Lee () and Na-Young Song ()
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Se-Young Park: Yonsei University College of Dentistry, Department of Oral Biology, BK21 Four Project
Kyuwon Son: Pusan National University, Department of Pharmacy, College of Pharmacy and Research Institute for Drug Development
Jiwoo Kim: Yonsei University College of Dentistry, Department of Oral Biology, BK21 Four Project
Kyeongah Kim: Yonsei University College of Dentistry, Department of Oral Biology, BK21 Four Project
Sungmin Joo: Yonsei University College of Dentistry, Department of Oral Biology, BK21 Four Project
Bomi Kim: Yonsei University College of Dentistry, Department of Oral Biology, BK21 Four Project
Myunggyo Lee: Pusan National University, Department of Pharmacy, College of Pharmacy and Research Institute for Drug Development
Wankyu Kim: Ewha Womans University, Department of Life Sciences, College of Natural Science
Won-Jung Jung: Pusan National University, Department of Pharmacy, College of Pharmacy and Research Institute for Drug Development
Byung Kwan Choi: Pusan National University College of Medicine, Department of Neurosurgery
Nakyung Jeon: Pusan National University, Department of Pharmacy, College of Pharmacy and Research Institute for Drug Development
Won-Yoon Chung: Yonsei University College of Dentistry, Department of Oral Biology, BK21 Four Project
Yinling Hu: National Institutes of Health, Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute
Haeseung Lee: Pusan National University, Department of Pharmacy, College of Pharmacy and Research Institute for Drug Development
Na-Young Song: Yonsei University College of Dentistry, Department of Oral Biology, BK21 Four Project

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy; however, their use is frequently associated with immune-related adverse events (irAEs). In this study, anti-PD-L1 therapy exacerbates muscle wasting in tumor-bearing male mice despite its anti-tumor efficacy, accompanied by an accumulation of CD8+ T cells in muscle. Single-cell RNA sequencing identifies these cells as tissue-resident memory-like CD49a+ CD8+ T cells. While CD8+ T cell depletion prevents muscle wasting, it compromises the anti-tumor efficacy of anti-PD-L1. To resolve this paradox, we identify cathepsin L (CTSL) as a dual-target capable of suppressing both tumor progression and CD8+ T cell-mediated muscle wasting, through integrative transcriptomic analysis. Pharmacological inhibition of CTSL not only mitigates anti-PD-L1-induced muscle wasting but also further suppresses tumor growth, potentially via downregulation of BNIP3. Here, we show that CTSL is a dual-action target to uncouple anti-tumor efficacy from muscle-specific irAEs, offering a strategy to improve clinical outcomes of ICIs.

Date: 2025
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DOI: 10.1038/s41467-025-64500-0

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