Dasatinib ameliorates immune checkpoint inhibitor-associated myocarditis in mice

Introduction Immune checkpoint inhibitor-associated myocarditis (ICIM) is a rare but life-threatening complication of cancer immunotherapy. Current management strategies, which are primarily based on glucocorticoids, are often limited by suboptimal efficacy and side effects. This study investigated the therapeutic potential and mechanism of action of dasatinib in a murine model of ICIM. Methods An ICIM model was established in male A/J mice by intraperitoneal injection of anti-PD-L1 and anti-CTLA-4 antibodies. The treatment group received dasatinib (50 mg/kg/d) via intragastric administration. Cardiac histopathology was assessed by H&E staining. The infiltration of CD4 + and CD8 + T lymphocytes and expression of IFN-γ and IL-6 were evaluated by immunohistochemistry. Transcriptome sequencing and bioinformatics analysis were performed to explore the underlying mechanisms involved. Results Dasatinib treatment significantly alleviated disruption of the myocardial architecture and inflammatory cell infiltration. It markedly reduced the infiltration of CD4 + and CD8 + T cells and suppressed the production of IFN-γ and IL-6 in cardiac tissues. Transcriptomic analysis revealed that dasatinib reversed ICI-induced differential gene expression, with enrichment in possible pathways such as the G2M checkpoint. Key genes such as Hmmr and Ttk were identified as potential targets. Conclusion Dasatinib protects against ICIM by mitigating T lymphocyte infiltration and proinflammatory cytokine release, potentially through modulation of cell cycle-related pathways. Our findings suggest that dasatinib is a promising repurposed therapeutic candidate for ICIM, warranting further clinical investigation.