Mechanisms and biomarkers of immune checkpoint inhibitor-associated myocarditis: from T cell imbalance to multicellular crosstalk

Figure 1. Immune landscape of ICI-induced myocarditis (ICI-MC): balance between pro-inflammatory (Yang) and anti-inflammatory (Yin) immune responses. The development of ICI-MC arises from an imbalance between pro-inflammatory (yang) and anti-inflammatory (yin) immune mechanisms. On the pro-inflammatory side, CD8+ T cells serve as the primary effector cells, recognizing and attacking α-myosin antigen; CD4+ T cells amplify the inflammatory response through the NF-κB/STAT1 pathway and by secreting IFN-γ and TNF-α. 4E-BP3 deficiency reduces IL-6 and IL-1β production by dendritic cells, limiting Th1/Th17 differentiation. TEMRA induces CCL5, CCL4, and CCL21 upregulation, while TRM cells highly express CD69, exacerbating local cardiac inflammation. Regarding anti-inflammatory effects, CD4+ central memory T cells (TCM) maintain immune tolerance by reducing signals such as IL-10, CCL13, and CXCL9. Gut microbiota dysbiosis can enable Treg-mediated immunosuppression, while antibiotics can reverse this pathway. Tumor-derived extracellular vesicles (TuEVs) bioengineered to migrate to the heart induce high PD-L1 expression in cardiomyocytes, thereby mitigating immune-mediated myocardial injury. The…

Figure 2. The role of macrophages in immune checkpoint inhibitor–associated myocarditis (ICI-MC). Schematic overview of macrophage-mediated mechanisms contributing to ICI-MC pathogenesis. Under immune checkpoint blockade, macrophages undergo polarization toward the proinflammatory M1 phenotype via activation of the cGAS–STING and STAT1/NF-κB signaling pathways, resulting in the release of IL-1β, IL-6, and TNF-α. Concurrently, PD-1 inhibition impairs MerTK-dependent efferocytosis, leading to the accumulation of apoptotic debris and release of damage-associated molecular patterns (DAMPs). Macrophages further amplify inflammation by secreting CXCL9 and CXCL10 to recruit CXCR3+ T cells, establishing a feed-forward loop of immune activation. Therapeutically, interventions such as baricitinib (JAK-STAT inhibition) and mesenchymal stem cell–derived exosomes (hBMSC-Exos) promote M1-to-M2 repolarization, suppress inflammasome activation, and attenuate myocardial injury.

Figure 3. A five-phase multicellular framework of immune checkpoint inhibitor–associated myocarditis (ICI-MC). The pathogenesis of ICI-MC can be conceptualized as a dynamic, interconnected cascade encompassing five stages: (a) Baseline autoreactive reservoir – incomplete thymic deletion allows α-myosin–specific T cells to persist in the periphery; (b) Immune checkpoint blockade – disruption of the PD-1/PD-L1 axis reactivates dormant autoreactive T cells; (c) Clonal expansion – selective proliferation of autoreactive TCR clonotypes remodels the immune repertoire; (d) Effector execution – cytotoxic CD8+ T cells, B-cell–derived autoantibodies, and complement pathways mediate direct cardiomyocyte injury; and (e) Amplification of inflammation – macrophages, fibroblasts, endothelial cells, and neutrophils perpetuate tissue damage via cytokine and chemokine feedback loops. This integrative model unites adaptive and innate immunity to depict the progressive evolution of ICI-MC and identify potential points for targeted intervention.

Figure 4. Future research prospects in immune checkpoint inhibitor–associated myocarditis (ICI-MC). Schematic summary of emerging research priorities in ICI-MC. Future studies should integrate multi-omics technologies—including single-cell and spatial transcriptomics, TCR/BCR repertoire sequencing, and proteomics—to delineate the cellular and molecular mechanisms underlying myocarditis. Comparative analyses between PD-1/PD-L1 and CTLA-4 blockade are required to clarify their distinct pathogenic pathways. Translational research should focus on shifting from broad immunosuppression to precision immunomodulation through targeted therapies such as JAK-STAT inhibition, mesenchymal stem cell–derived exosomes, and microbiota modulation. Finally, a proactive clinical framework incorporating standardized diagnostic criteria, validated biomarkers, and prospective multicenter registries will be essential for optimizing patient outcomes and ensuring the safe expansion of cancer immunotherapy.