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.
Zhao et al. (Sun,) studied this question.