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Background: Cachexia is a systemic disease manifested with muscle atrophy and appetite loss, especially in patients with pancreatic cancer. Emerging evidence showed that cachexia is an inflammation-associated disease. But the role of tumor immune microenvironment in cachexia remains elusive. ZIP4, a zinc transporter, plays a critical role in promoting pancreatic cancer cachexia. We aimed to study how ZIP4 promotes cancer cachexia via interacting with immune microenvironment. Methods: We evaluated the association between cachexia and several major immune cell types in the tumor tissue of patients with cancer. Genetically engineered mouse models and clodronate treatment were used to establish the mouse models with macrophage depletion. Flow cytometry, western blotting, chromatin immunoprecipitation assay and luciferase assay were used to study the underlying mechanism. Results: We found that macrophage infiltration level in tumor tissue is associated with the prevalence and severity of cancer cachexia. Depletion of macrophage using Ccr2 knockout mice (Ccr2-/- mice) or clodronate treatment ameliorated cancer cachexia. Cytokine array identified TWEAK (also known as TNFSF12) as a key player in cancer cachexia. The basal level of TWEAK is low in macrophages and tumor cells. However, TWEAK level drastically increased in tumor cells when cocultured with macrophages. Mechanistically, macrophage-derived CCL5 upregulates TWEAK expression in cancer cells through p65 signaling axis. On the other end, ZIP4 induced CCL2 secretion from cancer cells through ZXDC, a zinc dependent transcription factor, leading to the recruitment and activation of macrophages. Overexpression of TWEAK restored the cachexia phenotype of cancer cells with low cachexia potential. Blocking ZIP4-TWEAK signaling axis restored appetite and muscle mass in pancreatic cancer mouse models. Conclusion: This study identified an uncharacterized role of tumor immune microenvironment in promoting cancer cachexia through increasing TWEAK secretion from tumor cells. Specifically, ZIP4 increased CCL2 secreting from tumor cells, which recruits and activates macrophages. The activated macrophages secreted CCL5, upregulating TWEAK expression in cancer cells through TRAF6/NF-κB axis, thus forming a feedforward loop to promote cancer cachexia. Citation Format: Zhijun Zhou, Mingyang Liu, Yu Ren, Jingxuan Yang, Xiuhui Shi, Yang Cai, Alex X. Arreola, Wenyi Luo, Kar-Ming Fung, Chao Xu, Ryan D. Nipp, Michael S. Bronze, Lei Zheng, Yi-Ping Li, Courtney W. Houchen, Yuqing Zhang, Min Li. A zinc transporter drives pancreatic cancer cachexia via the crosstalk between tumor cells and immune microenvironment abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts) ; 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85 (8Suppl₁): Abstract nr 5262.
Zhou et al. (Mon,) studied this question.