A defined cytokine regimen drives durable cardioprotection and fibrosis reversal in experimental heart failure

Background Heart failure remains a leading cause of mortality worldwide, and current therapies largely provide symptomatic benefit without reversing fibrosis or cardiac dysfunction. Tumour-associated immune signalling has been shown to exert cardioprotective effects; however, the mechanisms required for sustained cardiac recovery remain unknown. Purpose To define the cytokine requirements necessary to achieve durable cardioprotection and fibrosis suppression in experimental heart failure. Methods Murine models of heart failure, including dystrophin-deficient cardiomyopathy and pressure overload–induced disease, were treated with immune-derived cytokines identified from tumour-associated serum. Cardiac function was assessed by echocardiography, and myocardial fibrosis was quantified histologically. Single versus repeated cytokine administration strategies were compared to evaluate durability of response. Results Interferon-gamma and tumour necrosis factor-alpha transiently improved ventricular function and reduced myocardial fibrosis but failed to confer sustained benefit upon repeated dosing. Interleukin-13 similarly induced short-lived functional improvement when administered alone. In contrast, repeated co-administration of interferon-gamma, tumour necrosis factor-alpha, and interleukin-13 produced a sustained increase in ventricular contractility and persistent suppression of myocardial fibrosis. This defined cytokine triad fully recapitulated the durable cardioprotective phenotype observed with tumour-derived serum. Conclusion Durable cardiac recovery requires coordinated activation of complementary immune cytokine pathways. A defined cytokine-based regimen comprising interferon-gamma, tumour necrosis factor-alpha, and interleukin-13 induces sustained cardioprotection and fibrosis reversal in heart failure models, providing a translational framework for immune-modulatory therapies in acquired and muscular dystrophy–associated cardiomyopathies.