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<p>Anemia is one of the most prevalent systemic complications in patients with cancer, substantially impairing quality of life and limiting the safe administration of cytoreductive therapies. Despite its clinical significance, the mechanisms by which tumors disrupt erythroid homeostasis remain incompletely understood. Here, we identify a previously unrecognized mechanism by which tumor-derived DNA directly drives cancer-associated anemia through pathological interaction with circulating red blood cells (RBCs). Specifically, we show that circulating tumor-derived DNA binds to lon peptidase 1 (LONP1), a mitochondrial protease aberrantly expressed on the surface of peripheral blood reticulocytes in tumor-bearing hosts. This interaction induces morphological alterations and apoptosis in reticulocytes, thereby triggering their premature clearance via erythrophagocytosis and contributing to anemia progression. Therapeutically, the enzymatic degradation of surface-bound DNA using Deoxyribonuclease I (DNase I) restores reticulocyte morphology, diminishes erythrophagocytic clearance, and alleviates anemia in tumor-bearing models. Moreover, combining DNase I with erythropoietin-driven stimulation of erythropoiesis produces synergistic hematologic improvement, simultaneously limiting pathological RBC clearance and enhancing RBC production. Together, these findings reveal a previously unappreciated DNA-mediated axis linking tumor burden to systemic erythroid dysfunction. This work establishes circulating tumor-derived DNA as an active pathogenic mediator in cancer-associated anemia and provides a mechanistically grounded combinatorial therapeutic strategy targeting both erythrocyte destruction and impaired erythropoiesis.</p>

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Tumor-derived DNA drives cancer-associated anemia by promoting reticulocyte clearance

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月24日

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  • Ting Yuan,
  • Xuebing Liu,
  • Yucui Wu,
  • Shanshan Li,
  • Han Chu,
  • Qing Li,
  • Zefang Chen,
  • Haichuan Liu,
  • Tao Mao,
  • Haoran Zha,
  • Xiaoming Cheng,
  • Jing Jing,
  • Chengmu Li,
  • Lina Peng,
  • Xiaoxing Chen,
  • Qian Liao,
  • Renren Yu,
  • Hao Lv,
  • Junwei Zhang,
  • Zhongyu Wang,
  • Qingzhu Jia,
  • Haixia Long,
  • Degao Chen,
  • Bo Zhu

摘要

Anemia is one of the most prevalent systemic complications in patients with cancer, substantially impairing quality of life and limiting the safe administration of cytoreductive therapies. Despite its clinical significance, the mechanisms by which tumors disrupt erythroid homeostasis remain incompletely understood. Here, we identify a previously unrecognized mechanism by which tumor-derived DNA directly drives cancer-associated anemia through pathological interaction with circulating red blood cells (RBCs). Specifically, we show that circulating tumor-derived DNA binds to lon peptidase 1 (LONP1), a mitochondrial protease aberrantly expressed on the surface of peripheral blood reticulocytes in tumor-bearing hosts. This interaction induces morphological alterations and apoptosis in reticulocytes, thereby triggering their premature clearance via erythrophagocytosis and contributing to anemia progression. Therapeutically, the enzymatic degradation of surface-bound DNA using Deoxyribonuclease I (DNase I) restores reticulocyte morphology, diminishes erythrophagocytic clearance, and alleviates anemia in tumor-bearing models. Moreover, combining DNase I with erythropoietin-driven stimulation of erythropoiesis produces synergistic hematologic improvement, simultaneously limiting pathological RBC clearance and enhancing RBC production. Together, these findings reveal a previously unappreciated DNA-mediated axis linking tumor burden to systemic erythroid dysfunction. This work establishes circulating tumor-derived DNA as an active pathogenic mediator in cancer-associated anemia and provides a mechanistically grounded combinatorial therapeutic strategy targeting both erythrocyte destruction and impaired erythropoiesis.