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Archive > Volume 33 Issue 5 > 2026,33(5):521-527. DOI:10.3872/j.issn.1007-385X.2026.05.006 Prev Next
Basic Research
Mesenchymal stromal cell-derived extracellular vesicles alleviate immune checkpoint inhibitor-related pneumonitis by regulating macrophage inflammasome activation
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Abstract:
[Abstract] Objective：To investigate the therapeutic effect and molecular mechanism of mesenchymal stromal cell-derived extracellular vesicles (MSC-EV) on immune checkpoint inhibitor-related pneumonitis (CIP) in a mouse model. Methods: Foxp3 DTR mice were inoculated with MC38 mouse colon cancer cells and randomly divided into 3 groups (n = 6 per group): ① control group (MC38 inoculation only); ② CIP model group (inoculated with MC38 cells, intraperitoneally injected with diphtheria toxin [DT] and anti-PD-1 antibody); ③ MSC-EV intervention group (based on the CIP model, intranasally administered with MSC-EV [dose 10 9 particles/mouse, every 3 days, 2 times in total]). A mouse CIP model induced by Treg depletion combined with anti-PD-1 antibody was established. In vivo, H-E staining was used to observe lung pathological injury, lung wet/dry ratio was measured to assess pulmonary edema, ELISA was used to detect IL-1β, IL-6, and TNF- α levels in bronchoalveolar lavage fluid (BALF), and flow · · 521 中国肿瘤生物治疗杂志, 2026, 33(5) cytometry was used to detect the proportion of Ly6G ? granulocyte infiltration in BALF. Tumor volume was monitored to evaluate antitumor efficacy. In vitro, DiO fluorescent labeling was used to observe the uptake of extracellular vesicles (EVs) by bone marrow- derived macrophages, and WB assay was used to detect the expression levels of key NLRP3 inflammasome proteins (cleaved GSDMD and mature IL-1β). Potential mechanisms were explored using GEO database miRNA sequencing data (GSE69909), Dicer knockdown, and miR-21/miR-125 inhibitor intervention. Results: Intranasal administration of MSC-EV alleviated lung inflammatory injury in CIP model mice, reduced IL-1β, IL-6, and TNF-α levels and the proportion of Ly6G? granulocyte infiltration in BALF (P < 0.05), without compromising the antitumor efficacy of anti-PD-1 antibody therapy. In vitro DiO labeling tracing showed that MSC-EV could be taken up by macrophages. WB assay showed that MSC-EV decreased the levels of key activated proteins (cleaved GSDMD and mature IL- 1β) of the NLRP3 inflammasome (P < 0.05). In vitro, after Dicer knockdown, the MSC-EV showed a weakened downregulation effect on IL-1β in macrophages (P < 0.05). miRNA sequencing (GEO database, GSE69909) showed high expression of miR-21 and miR-125 in MSC-EV, and inhibition of miR-21 or miR-125 reduced the inhibitory effect of the corresponding MSC-EV on IL-1β cleavage in macrophages (P < 0.05). Conclusion: MSC-EV exert anti-inflammatory effects through their carried miRNAs such as miR-21 and miR- 125, and the mechanism may be related to inhibition of NLRP3 inflammasome activation in macrophages, thereby effectively alleviating CIP without compromising the antitumor efficacy of immune checkpoint inhibitor.
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