CAR-M2 immunotherapy resolves renal fibrosis via revascularization and apoptosis of profibrotic Cxcr2+ endothelial cells

  • Cell Rep Med. 2026 Apr 21;7(4):102698. doi: 10.1016/j.xcrm.2026.102698.
Wenyan Zhao  1 ,  Xin Zhou  2 ,  Xingli Zhao  2 ,  Hao Tian  2 ,  Yang Su  2 ,  Shanlan Zhao  2 ,  Min Liu  2 ,  Qiao Zhang  2 ,  Lin Chen  2 ,  Xiaochen Li  2 ,  Di Liu  2 ,  Junxuan Li  2 ,  Lang Li  2 ,  Yanhong Wang  2 ,  Xingtong Li  2 ,  Jin Yan  3 ,  Wen Chen  4 ,  Bing Liu  5 ,  Chuhong Zhu  6 ,  Wen Zeng  7
Affiliations
  • 1. Department of Cell Biology, Army Medical University, Chongqing 400038, China; Department of Pain and Rehabilitation, Xinqiao Hospital, Third Military Medical University, Chongqing 400038, China.
  • 2. Department of Cell Biology, Army Medical University, Chongqing 400038, China.
  • 3. Jinfeng Laboratory, Chongqing 401329, China.
  • 4. Department of Pathology, The 8th Medical Center, Chinese PLA General Hospital, Beijing 100091, China. Electronic address: [email protected].
  • 5. State Key Laboratory of Experimental Hematology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China. Electronic address: [email protected].
  • 6. Department of Anatomy, Engineering Research Center for Organ Intelligent Biological Manufacturing of Chongqing, Key Lab for Biomechanics and Tissue Engineering of Chongqing, Third Military Medical University, Chongqing 400038, China; Engineering Research Center of Tissue and Organ Regeneration and Manufacturing, Ministry of Education, Chongqing 400038, China; State Key Laboratory of Trauma and Chemical Poisoning, Chongqing, China. Electronic address: [email protected].
  • 7. Department of Cell Biology, Army Medical University, Chongqing 400038, China; Jinfeng Laboratory, Chongqing 401329, China; State Key Laboratory of Trauma and Chemical Poisoning, Chongqing, China. Electronic address: [email protected].
PMID: 41887221 DOI: 10.1016/j.xcrm.2026.102698
Abstract

Renal fibrosis is a common outcome of chronic kidney disease (CKD), forming a fibrotic niche characterized by fibroblast activation and vascular rarefaction. Currently, there are no effective treatment strategies targeting fibrotic niche. Here, we show that chimeric antigen receptor-modified M2 macrophages (CAR-M2) targeting FAP and secreting interleukin (IL)-4 are delivered via an injectable HAMA-CS hydrogel beneath the renal subcapsule and attenuate renal fibrosis while promoting renal revascularization. The single-cell RNA Sequencing reveals the heterogeneity and interaction of stroma and endothelial cells (ECs). A fibrosis-related CXCR2+ EC subset is identified, and its specific depletion effectively mitigates renal fibrosis. Further results reveal that CAR-M2 can release matrix metalloproteinase 2 (MMP2) in close proximity to activate retinoid X receptor alpha (Rxra) in the CXCR2+ ECs and further triggers its mitochondrial Autophagy, leading to Apoptosis. Our research provides innovative strategies and proof of principle for the immunotherapy of organ fibrosis.

Keywords
CAR-M2; Cxcr2(+) ECs; FAP(+) fibroblasts; HAMA-CS hydrogel; renal fibrosis; revascularization.
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