Complement C1q drives skeletal muscle wasting in pancreatic cancer

Abstract Cancer cachexia, defined by involuntary skeletal muscle loss, affects ~ 70% of pancreatic ductal adenocarcinoma (PDAC) patients at diagnosis and independently worsens survival. Here, we identify complement component 1q (C1q) as a driver of PDAC-induced muscle wasting, with coordinated effects across muscle, tumor, and systemic inflammatory compartments. In cachectic PDAC patient muscle, C1q partially co-deposits with IgM, and C1q mRNA correlates with reduced muscle radiation attenuation, a CT-derived measure of muscle quality. In PDAC tumors, C1q protein correlates with immunosuppressive programs and independently predicts poor survival. These findings are recapitulated in orthotopic KPC mice, where C1q mRNA is upregulated in respiratory muscle before cachexia onset, and C1q deposits in tumors and co-deposits with IgM in muscles of cachectic mice. C1qa deletion reduced systemic inflammatory mediators, blocked muscle atrophy, and improved activity and grip strength in KPC mice, while attenuating immune cell infiltration and extracellular matrix remodeling in respiratory muscle. Host C1qa deletion also suppressed angiogenic and immunosuppressive programs in KPC tumors, while increasing intratumoral CD8⁺ T cell density and Granzyme B production. These findings position C1q as a driver of cancer-induced muscle wasting and tumor immunosuppression, supporting C1q inhibition as a potential therapeutic strategy targeting pathological features of poor-prognosis PDAC.