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Nat. Commun., Nov 28 2025, 16 (1) 10706 | https://doi.org/10.1038/s41467-025-64500-0 Cathepsin L as a dual-target to mitigate muscle wasting while enhancing anti-tumor efficacy of anti-PD-L1

Se-Young Park^1,2,8, Kyuwon Son^3,8, Jiwoo Kim^1,2, Kyeongah Kim¹, Sungmin Joo^1,2, Bomi Kim¹, Myunggyo Lee³, Wankyu Kim⁴, Won-Jung Jung³, Byung Kwan Choi⁵, Nakyung Jeon³, Won-Yoon Chung^1,2,6, Yinling Hu⁷, Haeseung Lee^3,9 & Na-Young Song^1,2,6,9

¹Department of Oral Biology, BK21 Four Project, Yonsei University College of Dentistry, Seoul, Republic of Korea.
²Department of Applied Life Science, The Graduate School, Yonsei University, Seoul, Republic of Korea.
³Department of Pharmacy, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, Republic of Korea.
⁴Department of Life Sciences, College of Natural Science, Ewha Womans University, Seoul, Republic of Korea.
⁵Department of Neurosurgery, Pusan National University College of Medicine, Yangsan, Republic of Korea.
⁶Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul, Republic of Korea.
⁷Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA.
⁸These authors contributed equally: Se-Young Park, Kyuwon Son.
⁹These authors jointly supervised this work: Haeseung Lee, Na-Young Song.

Corresponding authors
Correspondence to Haeseung Lee or Na-Young Song.

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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