Pathophysiological remodeling of the skeletal muscle microenvironment in patients with lung cancer

Cancer-associated cachexia is characterized by weight loss, muscle wasting, systemic inflammation, and functional decline. This multifactorial syndrome is highly prevalent and detrimental in patients with advanced-stage non–small cell lung cancer (NSCLC). To investigate the cellular and molecular underpinnings of muscle wasting, we analyzed skeletal muscle biopsies from NSCLC patients and healthy matched controls using quantitative proteomics, histology, fluorescence-activated cell sorting, gene expression profiling, and high-resolution respirometry. Skeletal muscle from patients was characterized by type II muscle fiber atrophy, greater collagen deposition, and redistribution of lipids to the extracellular matrix. This coincided with a shift in fibro-adipogenic progenitors (FAPs), favouring the CD90⁻ subtype, and experiments using conditioned media indicated a catabolic secretory phenotype from patient-derived FAPs. Proteomic and functional analyses revealed dysregulated calcium handling, downregulation of key mitochondrial proteins, and altered respiratory capacity in muscle samples from patients with NSCLC. These alterations, along with fiber-type specific mitochondrial remodelling, were accompanied by STAT3 activation and immune cell infiltration, suggesting a link between mitochondrial dysfunction and local inflammation. These results provide the first human evidence that altered FAP composition, mitochondrial homeostasis, calcium handling, and immune cell landscape coincide with muscle wasting in NSCLC, highlighting potential therapeutic targets to treat patients with cancer-associated cachexia.