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Peer-reviewedCC BY 4.0Advanced Science

Loss of Lepr in Fibroblasts Drives Tumor Development by Promoting Macrophage Infiltration

  • Manyu Song1,2
  • Wuqi Yang1,2
  • Bangran Qi1,2
  • Liyuan Hou1,2
  • Xu Yang3
  • Jiuzhi Xu3
  • Shengyuan Tian3
  • Shuiling Jin4
  • Lu Yu3
  • Zhengquan Yu3,4,5
  • Min Deng3
  • Jiaqiang Huang1,2
2 more authors
  • Suoqin Jin6
  • Cong Lv1,2
6 affiliations
  1. 1Key Laboratory of Precision Nutrition and Food Quality Department of Nutrition and Health China Agricultural University Beijing China
  2. 2Beijing Advanced Innovation Center for Food Nutrition and Human Health Department of Nutrition and Health China Agricultural University Beijing China
  3. 3State Key Laboratory of Animal Biotech Breeding College of Biological Sciences China Agricultural University Beijing China
  4. 4The First Affiliated Hospital of Zhengzhou University Zhengzhou Henan China
  5. 5Tianjian Laboratory of Advanced Biomedical Sciences Academy of Medical Sciences Zhengzhou University Zhengzhou Henan China
  6. 6School of Mathematics and Statistics Wuhan University Wuhan China
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Abstract

Cancer‐associated fibroblasts (CAFs) are critical regulators of colorectal cancer (CRC) progression, yet the mechanisms governing their functional plasticity and state transitions remain incompletely understood. Here, we uncover a tumor‐driven fibroblast state transition in CRC characterized by loss of leptin receptor (Lepr) expression and acquisition of pro‐inflammatory features. We show that cooperative TNFα and TGFβ signaling drives this reprogramming, accompanied by repression of the Tcf21‐Lepr regulatory axis. Fibroblasts undergoing this transition acquire the capacity to promote macrophage recruitment and accelerate tumor development. Loss of Lepr or Tcf21 in fibroblasts upregulates Csf3, which contributes to the enhanced macrophage‐recruiting capacity of the reprogrammed fibroblasts. Consistently, blockade of TNFα and TGFβ signaling disrupts fibroblast reprogramming and attenuates macrophage infiltration. Together, our findings uncover how inflammatory signaling reshapes stromal cell states to promote macrophage accumulation, ultimately fostering a pro‐tumorigenic niche that accelerates CRC progression.

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Cite

BibTeXRIS
BibTeX
@article{song2026loss,
  title = {{Loss of Lepr in Fibroblasts Drives Tumor Development by Promoting Macrophage Infiltration}},
  author = {Manyu Song and Wuqi Yang and Bangran Qi and Liyuan Hou and Xu Yang and Jiuzhi Xu and Shengyuan Tian and Shuiling Jin and Lu Yu and Zhengquan Yu and Min Deng and Jiaqiang Huang and Suoqin Jin and Cong Lv},
  journal = {Advanced Science},
  year = {2026},
  month = oct,
  doi = {10.1002/advs.78562},
  url = {https://doi.org/10.1002/advs.78562},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Loss of Lepr in Fibroblasts Drives Tumor Development by Promoting Macrophage Infiltration
AU  - Manyu Song
AU  - Wuqi Yang
AU  - Bangran Qi
AU  - Liyuan Hou
AU  - Xu Yang
AU  - Jiuzhi Xu
AU  - Shengyuan Tian
AU  - Shuiling Jin
AU  - Lu Yu
AU  - Zhengquan Yu
AU  - Min Deng
AU  - Jiaqiang Huang
AU  - Suoqin Jin
AU  - Cong Lv
PY  - 2026
DA  - 2026/10/31
JO  - Advanced Science
DO  - 10.1002/advs.78562
UR  - https://doi.org/10.1002/advs.78562
AB  - Cancer‐associated fibroblasts (CAFs) are critical regulators of colorectal cancer (CRC) progression, yet the mechanisms governing their functional plasticity and state transitions remain incompletely understood. Here, we uncover a tumor‐driven fibroblast state transition in CRC characterized by loss of leptin receptor (Lepr) expression and acquisition of pro‐inflammatory features. We show that cooperative TNFα and TGFβ signaling drives this reprogramming, accompanied by repression of the Tcf21‐Lepr regulatory axis. Fibroblasts undergoing this transition acquire the capacity to promote macrophage recruitment and accelerate tumor development. Loss of Lepr or Tcf21 in fibroblasts upregulates Csf3, which contributes to the enhanced macrophage‐recruiting capacity of the reprogrammed fibroblasts. Consistently, blockade of TNFα and TGFβ signaling disrupts fibroblast reprogramming and attenuates macrophage infiltration. Together, our findings uncover how inflammatory signaling reshapes stromal cell states to promote macrophage accumulation, ultimately fostering a pro‐tumorigenic niche that accelerates CRC progression.
SN  - 2198-3844
ER  -