C3a–C3aR1–mediated crosstalk between cardiac fibroblasts and macrophages drives the progression of ICI-associated myocarditis

Objective Immune checkpoint inhibitor (ICI)–associated myocarditis carries high mortality, but its organ-specific drivers remain undefined. We examined whether cardiac fibroblast–mediated complement activation contributes to local inflammatory injury. Methods Single-cell RNA sequencing of murine ICI myocarditis was used to identify key intercellular signaling pathways. Mechanistic studies in primary cardiac fibroblasts and macrophages defined upstream regulators of complement activation. Pharmacologic C3aR1 inhibition was evaluated in vivo for therapeutic efficacy and impact on antitumor response. Results Inflammatory cardiac fibroblasts expanded significantly in ICI myocarditis and preferentially expressed complement C3, whereas C3aR1 was enriched in macrophages. Cardiac, but not circulating, C3/C3a levels were elevated and inversely associated with ventricular function, supporting local complement activation. IFN-γ induced fibroblast C3 expression and cathepsin L–dependent C3a generation, which enhanced macrophage TNF-α production. In vivo C3aR1 blockade reduced myocardial inflammation, improved cardiac function, and did not diminish antitumor efficacy. Conclusion Local C3a–C3aR1 signaling between cardiac fibroblasts and macrophages represents a cardiac-specific inflammatory mechanism in ICI-associated myocarditis and a potential therapeutic target that may preserve anticancer benefit while mitigating cardiotoxicity.