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

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<sup>+</sup> T cells in muscle. Single-cell RNA sequencing identifies these cells as tissue-resident memory-like CD49a<sup>+</sup> CD8<sup>+</sup> T cells. While CD8<sup>+</sup> 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<sup>+</sup> 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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Publication Details

Journal
Nature Communications
Published
2025-11-28
DOI
https://doi.org/10.1038/s41467-025-64500-0
Citations
1
Primary Topic
Cancer Immunotherapy and Biomarkers
Type
article
Field-Weighted Citation Impact
1.05

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

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

Sungmin Joo, Wonguen Jung, Yinling Hu, Haeseung Lee, Na‐Young Song, Wankyu Kim, Won‐Yoon Chung, Myunggyo Lee, Jiwoo Kim, Nakyung Jeon, Byung Kwan Choi, Bomi Kim, Se-Young Park, Kyuwon Son, Kyeongah Kim
article en
1 citations

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<sup>+</sup> T cells in muscle. Single-cell RNA sequencing identifies these cells as tissue-resident memory-like CD49a<sup>+</sup> CD8<sup>+</sup> T cells. While CD8<sup>+</sup> 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<sup>+</sup> 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.

Nature CommunicationsVol. 16(1)
National Institutes of Health (US), Ewha Womans University (KR), Yonsei University (KR), Frederick National Laboratory for Cancer Research (US), National Cancer Institute (US), Pusan National University Yangsan Hospital (KR), Center for Cancer Research (US), Yonsei University Health System (KR), Yonsei University College of Dentistry, Pusan National University (KR)
National Research Foundation, National Research Foundation of Korea
Openalex Percentile: Top 15%
Cancer Immunotherapy and Biomarkers
1.05
DOIOpen Access PDFOpenAlex
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