2. Academic Validation
  3. Cathepsin L as a dual-target to mitigate muscle wasting while enhancing anti-tumor efficacy of anti-PD-L1

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

  • Nat Commun. 2025 Nov 28;16(1):10706. doi: 10.1038/s41467-025-64500-0.
Se-Young Park # 1 2,  Kyuwon Son # 3,  Jiwoo Kim 1 2,  Kyeongah Kim 1,  Sungmin Joo 1 2,  Bomi Kim 1,  Myunggyo Lee 3,  Wankyu Kim 4,  Won-Jung Jung 3,  Byung Kwan Choi 5,  Nakyung Jeon 3,  Won-Yoon Chung 1 2 6,  Yinling Hu 7,  Haeseung Lee 8,  Na-Young Song 9 10 11
Affiliations

Affiliations

  • 1 Department of Oral Biology, BK21 Four Project, Yonsei University College of Dentistry, Seoul, Republic of Korea.
  • 2 Department of Applied Life Science, The Graduate School, Yonsei University, Seoul, Republic of Korea.
  • 3 Department of Pharmacy, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, Republic of Korea.
  • 4 Department of Life Sciences, College of Natural Science, Ewha Womans University, Seoul, Republic of Korea.
  • 5 Department of Neurosurgery, Pusan National University College of Medicine, Yangsan, Republic of Korea.
  • 6 Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul, Republic of Korea.
  • 7 Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA.
  • 8 Department of Pharmacy, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, Republic of Korea. [email protected].
  • 9 Department of Oral Biology, BK21 Four Project, Yonsei University College of Dentistry, Seoul, Republic of Korea. [email protected].
  • 10 Department of Applied Life Science, The Graduate School, Yonsei University, Seoul, Republic of Korea. [email protected].
  • 11 Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul, Republic of Korea. [email protected].
  • # Contributed equally.
PMID: 41315185 DOI: 10.1038/s41467-025-64500-0
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.

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