2. Academic Validation
  3. CAR-M2 immunotherapy resolves renal fibrosis via revascularization and apoptosis of profibrotic Cxcr2+ endothelial cells

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

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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