Abstract 5576: Identification of inter-organ targets to mitigate cachexia while enhancing tumor suppression by anti-PD-L1

Immune checkpoint inhibitors (ICIs), such as anti-PD-L1, have revolutionized cancer therapy but are frequently associated with immune-related adverse events (irAEs). Here, we show a significant correlation between ICI treatment and weight loss in cancer patients. Similarly, anti-PD-L1 therapy exacerbates muscle wasting in a cancer cachexia (CAC) mouse model, despite its anti-tumor effects, suggesting that muscle atrophy may represent a potential irAE. Single-cell RNA sequencing reveals that cytotoxic T-like cells accumulate in the skeletal muscle of CAC mice, directly contributing to muscle wasting. While their depletion prevents cachexia, it compromises the anti-tumor efficacy of anti-PD-L1. To address this discrepancy, we identify cathepsin L (CTSL) as an inter-organ target capable of inhibiting both cancer and cachexia, particularly muscle wasting driven by cytotoxic T cells, through unbiased integrative transcriptome analysis. Notably, CTSL inhibition not only reduces muscle wasting but also enhances the anti-tumor efficacy of anti-PD-L1. These findings highlight CTSL as a promising therapeutic target for cancer cachexia, offering a novel strategy to prevent muscle-specific irAEs while enhancing the benefits of ICIs. Citation Format: Se-Young Park, Jiwoo Kim, Kyuwon Son, Haeseung Lee, Na-Young Song. Identification of inter-organ targets to mitigate cachexia while enhancing tumor suppression by anti-PD-L1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5576.