Cardiac immunity and heart repair: Mechanism, challenge, and future direction

Figure 1. Immune cells in cardiac homeostasis and disease. This schematic summarizes the key immune cell populations present in the heart under homeostatic conditions (left) and during pathological states (right). Under homeostatic conditions, the heart maintains a balanced milieu comprising resident macrophages, fibroblasts, and cardiomyocytes, alongside circulating monocytes, neutrophils, and lymphocytes. During disease, the cardiac immune response initiates with early neutrophil infiltration and degranulation, followed by monocyte recruitment and their differentiation into inflammatory M1-like macrophages, which amplify tissue damage via cytokine release and phagocytosis. Concurrently, dendritic cells become activated and prime adaptive immunity by recruiting and stimulating T cells: CD8+ cytotoxic T cells directly induce apoptosis, while CD4+ T cells enhance inflammatory signaling. B cells further contribute through differentiation into antibody-producing plasma cells. Throughout this process, mast cells degranulate and stimulate collagen production by fibroblasts, promoting the accumulation of activated myofibroblasts and pathological fibrosis. Counter-regulatory mechanisms also…

Figure 2. Schematic illustration of immune cell orchestration during cardiac injury and regeneration: neonatal vs. adult heart comparison. Cardiac injury elicits a temporally ordered immune cascade with distinct outcomes in adult and neonatal hearts. In adults, necrotic cardiomyocytes and resident mast cells release DAMPs, which trigger early neutrophil infiltration that peaks at 1–3 days and transitions from proinflammatory N1 to reparative N2 states after day 3. CCR2+ cardiac macrophages amplify inflammation by secreting chemokines that recruit circulating monocytes, which differentiate into inflammatory macrophages (M1-like) and subsequently shift to reparative phenotypes (M2-like) over days 3–7. Although this phase shift contributes to partial resolution, cardiomyocyte proliferation remains minimal, and subsequent fibroblast and lymphocyte activity drives pathological remodeling and fibrotic scar formation. By contrast, neonatal hearts are dominated by self-renewing CCR2– resident macrophages, which persist locally after DAMP activation rather than being replaced by massive monocyte recruitment. During the regenerative window (days 3–7), various immune cells, including Tregs,…

Figure 3. Schematic illustration of representative mechanisms of cardiac regeneration. Cardiac regeneration is regulated by the immune system through different mechanisms. Upper Left (Cardiomyocyte proliferation):YAP5SA-expressing cardiomyocytes recruit C3+ fibroblasts and macrophages, driving anti-inflammatory macrophage phenotypes that secrete molecules to promote cardiomyocyte proliferation. Lower Left (ECM remodeling): Immune-derived cytokines activate fibroblasts to synthesize collagens, while macrophages degrade ECM via MMP9/ADAM15 or produce collagens themselves, thereby shaping regenerative capacity. Upper Right (vascular and lymphatic regeneration): Regenerative macrophages secrete METRNL to stimulate angiogenesis, and LECs release RELN to facilitate lymphangiogenesis and macrophage phenotype switching. Lower Right (Immunometabolic reprogramming): Signals from the ischemic myocardium rewire macrophages, shifting metabolism from glycolysis to OXPHOS/FAO and generating reparative macrophages that secrete proregenerative mediators. ADAM15: A disintegrin and metalloproteinase 15; BRD4: Bromodomain-containing protein 4; C3: Complement component 3; C3aR1: Complement C3a receptor 1;…

Figure 4. Therapeutic targeting of immune responses in cardiac regeneration and repair. Immune cell-targeted drug delivery: Immune cells loaded with therapeutic agents or nanoparticles are recruited specifically to myocardial injury sites to modulate post-injury inflammatory responses. Engineered cell therapy: Patient-derived T cells and macrophages are engineered to express chimeric antigen receptors (CAR-T and CAR-M, respectively). These modified cells specifically target activated cardiac fibroblasts, ameliorating cardiac dysfunction. Transplantation strategies: Allogeneic or xenogeneic heart transplantation is performed for end-stage heart failure patients, followed by immunosuppressive therapy to control post-transplant immune responses. Cardiac patch implantation: Engineered cardiac patches, comprising iPSC-CMs integrated with biomaterial scaffolds (e.g., hydrogels), are implanted at injury sites. Functional recovery is mediated through paracrine signaling from the transplanted cardiomyocytes. CAR-M: Chimeric antigen receptor macrophages; CAR-T: Chimeric antigen receptor T cell; iPSC-CMs: Induced pluripotent stem cell-derived cardiomyocytes. Created in BioRender. Liu, Y. (2026)…

Figure 5. Overview of modern cytometry technologies used in cardiac immune profiling. Flow cytometry and its derivatives (mass, spectral, and imaging-based platforms) offer complementary capabilities for analyzing immune phenotypes, function, and spatial context in the heart. While conventional flow cytometry provides high-throughput, multiparameter profiling, spectral cytometry overcomes fluorescence spillover. Mass cytometry allows simultaneous quantification of >40 markers. Imaging modalities (ImFC and IMC) add morphological and spatial resolution, enabling comprehensive cellular characterization in both suspension and tissue contexts. ImFC: Imaging flow cytometry; IMC: Imaging mass cytometry. Created in BioRender. Liu, Y. (2026) https://BioRender.com/gb0r3nm.