Abstract Body: Immune checkpoint modulators have revolutionized tumor therapy with significant therapeutic benefits. However, immune-related adverse events, especially cardiovascular sequelae have been documented in clinical use. Current studies have focused on conventional immune checkpoint inhibitors (anti-PD-1/PD-L1, anti-CTLA-4), which are associated with severe myocarditis in ~1-2% of patients. There is an increasing need to understand whether emerging immune checkpoint modulators contribute to cardiovascular risk and the progression of chronic cardiovascular diseases. Such agents target different mechanisms and are often used in combination with conventional immune checkpoint inhibitors. For example, combination of OX40 agonist and PD-1 inhibitor demonstrates promising anti-tumor effects in pre-clinical and early clinical studies. Here, we employed single-cell RNA-sequencing, lineage tracing, immunostaining, flow cytometry and antibody neutralization studies to explore the cardiac effects of combined OX40 activation and PD-1 inhibition. We observed that combined PD1 inhibition and OX40 activation increased the recruitment of monocytes and CCR2+ macrophages into the heart, and the frequency of cardiac effector memory T-cells along with elevated pro-inflammatory chemokines and cytokines in both naïve and tumor bearing mice. These changes persisted at chronic time points highlighting the long-term effects of combined OX40-PD1 therapy on cardiac immune niches. Unlike conventional immune checkpoint inhibition, these changes were independent of CD8+ T-cell mediated IFN-γ signaling. Instead, monocyte recruitment depended on signals generated by CD4⁺ T-cells and the effector memory phenotype of T-cells induced by OX40 agonist relied on TNF-α signaling. From a clinical perspective, prior OX40 agonism aggravated ischemia reperfusion injury and angiotensin II and phenylephrine infusion induced cardiac hypertrophy, fibrosis and inflammation in Pdcd1^-/- mice establishing the functional relevance of shifts in the cardiac immune landscape induced by combined PD-1 inhibition and OX40 agonism. Collectively, these findings indicate that combined OX40 activation and PD1 inhibition reshape the cardiac immune environment, promote myocardial inflammation, and vulnerability.