Macrophages play a critical role in promoting pancreatic cancer-induced muscle wasting through the non-autonomous activation of TWEAK secretion from tumor cells. This study reveals a feedforward loop between pancreatic cancer cells and macrophages, where tumor cells recruit and reprogram macrophages via the CCL2/CCR2 axis, leading to increased TWEAK secretion. TWEAK promotes muscle atrophy by activating MuRF1, a key muscle atrophy marker. Macrophages induce TWEAK secretion through the CCL5/TRAF6/NF-κB pathway. Depletion of macrophages or inhibition of TWEAK reduces muscle wasting, suggesting that targeting macrophages or TWEAK could be promising therapeutic strategies for pancreatic cancer cachexia. The study also identifies the role of CCL5 in promoting TWEAK expression via the p65 signaling pathway, and highlights the importance of TRAF6 in activating NF-κB signaling to upregulate TWEAK. These findings provide new insights into the mechanisms underlying pancreatic cancer cachexia and suggest potential therapeutic targets for its treatment.Macrophages play a critical role in promoting pancreatic cancer-induced muscle wasting through the non-autonomous activation of TWEAK secretion from tumor cells. This study reveals a feedforward loop between pancreatic cancer cells and macrophages, where tumor cells recruit and reprogram macrophages via the CCL2/CCR2 axis, leading to increased TWEAK secretion. TWEAK promotes muscle atrophy by activating MuRF1, a key muscle atrophy marker. Macrophages induce TWEAK secretion through the CCL5/TRAF6/NF-κB pathway. Depletion of macrophages or inhibition of TWEAK reduces muscle wasting, suggesting that targeting macrophages or TWEAK could be promising therapeutic strategies for pancreatic cancer cachexia. The study also identifies the role of CCL5 in promoting TWEAK expression via the p65 signaling pathway, and highlights the importance of TRAF6 in activating NF-κB signaling to upregulate TWEAK. These findings provide new insights into the mechanisms underlying pancreatic cancer cachexia and suggest potential therapeutic targets for its treatment.