This study investigates the role of macrophages in promoting muscle wasting in pancreatic cancer through a crosstalk with tumor cells. Key findings include: 1. **Macrophages and Muscle Wasting**: Macrophages are significantly associated with cancer cachexia and muscle wasting in pancreatic cancer. Depletion of macrophages by *Ccr2* knockout or Clodronate treatment reduces muscle atrophy and body weight loss in mouse models. 2. **TWEAK Secretion**: Macrophages induce non-autonomous secretion of TWEAK from tumor cells via the CCL5/TRAF6/NF-κB pathway. TWEAK promotes muscle atrophy by activating MuRF1, leading to muscle remodeling. 3. **CCL2 Recruitment**: Tumor cells recruit macrophages via the CCL2/CCR2 axis. This recruitment is crucial for the activation of TWEAK in tumor cells, forming a feedforward loop that enhances muscle wasting. 4. **Clinical Significance**: TWEAK expression is associated with cancer cachexia in patients with pancreatic cancer. The combination of TWEAK expression and macrophage infiltration can predict the risk of muscle wasting. 5. **Mechanisms**: The study identifies a critical role for the NF-κB signaling pathway in the activation of TWEAK by macrophages. TRAF6 acts as an upstream regulator, facilitating the activation of NF-κB and TWEAK expression. 6. **Therapeutic Targets**: The findings suggest that targeting the CCL2-TWEAK signaling axis may be a promising therapeutic approach for treating pancreatic cancer cachexia. Overall, this study provides new insights into the interplay between macrophages and tumor cells in promoting muscle wasting in pancreatic cancer, highlighting potential therapeutic targets for this debilitating condition.This study investigates the role of macrophages in promoting muscle wasting in pancreatic cancer through a crosstalk with tumor cells. Key findings include: 1. **Macrophages and Muscle Wasting**: Macrophages are significantly associated with cancer cachexia and muscle wasting in pancreatic cancer. Depletion of macrophages by *Ccr2* knockout or Clodronate treatment reduces muscle atrophy and body weight loss in mouse models. 2. **TWEAK Secretion**: Macrophages induce non-autonomous secretion of TWEAK from tumor cells via the CCL5/TRAF6/NF-κB pathway. TWEAK promotes muscle atrophy by activating MuRF1, leading to muscle remodeling. 3. **CCL2 Recruitment**: Tumor cells recruit macrophages via the CCL2/CCR2 axis. This recruitment is crucial for the activation of TWEAK in tumor cells, forming a feedforward loop that enhances muscle wasting. 4. **Clinical Significance**: TWEAK expression is associated with cancer cachexia in patients with pancreatic cancer. The combination of TWEAK expression and macrophage infiltration can predict the risk of muscle wasting. 5. **Mechanisms**: The study identifies a critical role for the NF-κB signaling pathway in the activation of TWEAK by macrophages. TRAF6 acts as an upstream regulator, facilitating the activation of NF-κB and TWEAK expression. 6. **Therapeutic Targets**: The findings suggest that targeting the CCL2-TWEAK signaling axis may be a promising therapeutic approach for treating pancreatic cancer cachexia. Overall, this study provides new insights into the interplay between macrophages and tumor cells in promoting muscle wasting in pancreatic cancer, highlighting potential therapeutic targets for this debilitating condition.