Myeloid-derived immunosuppressive PD-1/PD-L1 signaling is essential to maintain adult heart homeostasis.

Immune checkpoint inhibitors (ICIs) have transformed cancer therapy by enhancing antitumor immunity but are associated with immune-related adverse events, including myocarditis. Although T cell involvement in ICI-associated myocarditis is well established, the contribution of myeloid-specific programmed death-ligand 1 (PD-L1) signaling to cardiac immune regulation remains unclear. To investigate the role of myeloid-specific PD-L1 in maintaining cardiac immune homeostasis, we generated a myeloid-specific PD-L1 conditional knockout (KO) mouse model using LysMCre-driven deletion. Cardiac function was assessed by echocardiography. Immune profiling of cardiac and systemic compartments was performed using flow cytometry, quantitative PCR, ELISA, and histological analyses. In vitro coculture assays were conducted to assess macrophage-fibroblast (FB) and macrophage-T cell interactions. Myeloid PD-L1 KO mice exhibited early-onset cardiac dysfunction, reduced left ventricular ejection fraction, left ventricular fractional shortening, and upregulated heart failure markers. Immune profiling revealed systemic and myocardial inflammation, with increased C-C chemokine receptor type 2 macrophages and activated T cells. Coculture assays confirmed that PD-L1-deficient myeloid cells enhance T cell activation, Th17 polarization, and FB-mediated fibrotic gene expression. Myeloid-specific PD-L1 plays a critical role in limiting inflammation and maintaining cardiac integrity. Its deficiency promotes a proinflammatory microenvironment, contributing to cardiac dysfunction and implicating it as a key player in ICI-associated myocarditis. These findings identify myeloid PD-L1 as a potential therapeutic target to mitigate immune-mediated cardiotoxicity.NEW & NOTEWORTHY Immune checkpoint inhibitor-associated myocarditis is incompletely understood beyond T cell-driven mechanisms. This study identifies myeloid-specific PD-L1 as a critical regulator of cardiac immune homeostasis. Loss of myeloid PD-L1 triggers early myocardial inflammation, immune cell infiltration, FB activation, and subsequent cardiac dysfunction. These findings uncover a previously unrecognized myeloid checkpoint pathway contributing to immune-mediated cardiotoxicity and highlight myeloid PD-L1 as a potential therapeutic target.