Abstract Body: Immune checkpoint blockade targeting the PD-1/PD-L1 axis is an effective cancer immunotherapy. However, its use is associated with immune-related adverse events (irAEs), including rare but potentially fatal cardiotoxicities. Despite their significant clinical impact, the molecular mechanisms underlying immune checkpoint inhibitor (ICI)-mediated cardiotoxicity remain poorly understood. Although PD-L1 is expressed in all major cardiac cell types, its cell-specific roles in the heart and in the cardiac pathology remain unclear. Post-myocardial infarction (MI) cardiac remodeling is characterized by sustained inflammation, immune cell infiltration, and progressive fibrosis. Given the role of fibroblast (FB)-immune crosstalk in ischemic heart repair and remodeling, we examined FB-specific PD-L1 in regulating these processes. Indeed, PD-L1 was significantly up-regulated in FBs of the ischemic hearts as early as 3 days post-MI. To evaluate the role of FB-PD-L1 in post-MI fibrotic remodeling, we generated tamoxifen-inducible FB-specific PD-L1 knockout (KO) mice (PD-L1^fl/fl; Tcf21MCM). At 12 weeks of age, FB-PD-L1-KO and littermate controls were placed on a continuous tamoxifen chow diet (40 mg/kg). At 3 weeks post-tamoxifen treatment, mice underwent sham or MI surgeries, and cardiac function was assessed by echocardiography. Pre-MI, controls, and FB-PD-L1-KO hearts had comparable chamber dimensions and ventricular function. Interestingly, LV function in FB-PD-L1-KO mice became significantly detrimental at 4 weeks post-MI. Echocardiographic data are validated by qRT-PCR analysis of heart failure markers. Additionally, Deletion of fibroblast PD-L1 leads to maladaptive cardiac remodeling, evidenced by increased myocardial fibrosis on Masson’s trichrome staining. Comprehensive immune profiling of fibroblast-specific PD-L1 knockout and control hearts revealed a robust cardiac immune response in FB-PD-L1-deficient mice, suggesting that PD-L1-mediated fibroblast-immune cell crosstalk restrains myocardial inflammation and its loss promotes cardiac dysfunction and adverse remodeling. These findings identify fibroblast PD-L1 as a critical regulator of post-MI cardiac remodeling and immune fibroblast crosstalk.