Plasma proteomics identifies an IL-6 -associated SAA axis linked to muscle wasting and survival in patients with cancer cachexia

Cachexia affects nearly half of patients with lung- and pancreatic cancer and worsens prognosis, yet factors driving muscle wasting remain poorly defined. We performed longitudinal clinical and plasma proteomic profiling of 67 patients with non-small cell lung cancer, with and without cachexia, during first-line treatment. At diagnosis, cachectic patients showed 128 upregulated and 67 downregulated plasma proteins relative to non-cachectic patients. Longitudinal body composition, physical performance, clinical outcome, and nutritional risk assessments revealed distinct fat- and muscle-wasting trajectories: 71 proteins tracked with fat loss, 92 with muscle loss, and 177 with concurrent muscle and weight loss. Patients with concurrent loss had 68% shorter median overall survival than those who preserved mass (239 vs. 740 days). Among proteins associated with both muscle loss and adverse outcomes, we prioritized eight candidates and screened their recombinant forms, where serum amyloid A (SAA) produced a 47% reduction in myotube width and impaired contractile function in human 2D and 3D myotubes. In an independent cohort of 146 patients with advanced pancreatic cancer, pharmacological blockade of IL-6 signaling with tocilizumab normalized circulating SAA levels, establishing a cancer-driven IL-6-SAA axis that promotes muscle wasting. In both lung and pancreatic cancer, elevated SAA was associated with reduced overall survival. Together, these findings identify SAA1 and SAA2 as IL-6-driven, cachexia-associated factors that impair muscle mass and function and predict survival, nominating the IL-6-SAA axis as a therapeutic target for cancer cachexia.