A plasma proteomic signature of cancer-related sarcopenia implicates the IGFBP axis in muscle dysfunction

Background Cancer-related sarcopenia is associated with poor clinical outcomes but remains difficult to define and quantify in routine oncology practice. Current assessments rely on imaging and functional scales that are time-consuming and provide limited biological insight. We aimed to identify a plasma proteomic signature of cancer-related sarcopenia and to uncover circulating mediators involved in its pathophysiology. Methods Patients were included from two cohorts of the MATCH-R study (NCT02517892): a discovery cohort of advanced cancer patients treated with immunotherapy and an independent validation cohort of metastatic castration-resistant prostate cancer (mCRPC) patients treated with androgen-receptor pathway inhibitors. External validation was performed in the TRACERx cohort of non–small cell lung cancer. Skeletal muscle index at L3 was quantified using imaging, and ECOG performance status served as a functional proxy. Plasma proteomics was performed using the Olink Explore platform. An extreme gradient boosting (XGBoost) model was trained on a high-contrast subset using a neuromuscular-focused protein panel and validated across cohorts. Functional effects of candidate mediators were assessed in differentiating human myoblasts. Results The model generated a continuous sarcopenia probability (SP) score that correlated with muscle mass and functional status and consistently stratified overall survival across cohorts. A reduced four-protein model retained comparable performance, supporting translational applicability. Proteins associated with SP included IGFBP1, IGFBP2, and IL6. IGFBP1 and IGFBP2 impaired myoblast differentiation, while IL6 induced IGFBP1 expression in liver cells. Conclusions Plasma proteomics enables scalable and biologically informed assessment of cancer-related sarcopenia, identifies tumor–host mediators of muscle dysfunction, and supports objective patient stratification for therapeutic intervention.