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Background While cardiotoxicity is a recognized risk of chemotherapy and radiation, the cardiac effects of immune checkpoint inhibitors (ICIs) remain poorly understood. [ 1 8F]F-AraG is a PET tracer that targets mitochondrial DNA synthesis, enabling visualization of activated T cells due to their elevated mitochondrial biogenesis. Importantly, this tracer also accumulates in mitochondria-rich cells such as cardiomyocytes, allowing the simultaneous assessment of target (tumor) and off target (heart) effect of immunotherapy. This study aimed to characterize cardiac [1 8F]F-AraG uptake patterns in patients with cancer receiving ICIs to identify early post-treatment changes potentially associated with immunotherapy-related cardiac effects.Methods Twenty-six healthy subjects underwent [ 1 8F]F-AraG PET imaging to establish baseline cardiac uptake. Eight treatment-naïve patients with stage III melanoma and ten patients with advanced non-small cell lung cancer (NSCLC) were scanned before and 1–4 weeks after receiving their first anti-PD-1 therapy dose. Standardized uptake values (SUVmax, SUVmean, and SUVtotal) were measured in the left and right ventricles. Regional uptake in the left ventricle (LV) was further analyzed using a standard 17-segment myocardial model.Results Healthy subjects showed consistent cardiac uptake, as measured by SUVmax and SUVmean ( figure 1A, bottom table), across sex, age, and body size (LV SUVmean COV: 11.2% LV, 12.3% RV), with higher uptake in the LV due to greater workload.Patients with melanoma exhibited similar pre-treatment uptake to controls (LV SUVmean: 3.07), but showed a significant increase post-ICI (LV SUVmean: 3.65, p = 0.008). Patients with NSCLC who had received prior therapy had higher baseline uptake (LV SUVmean: 4.23 vs. 3.47, p=0.004) than controls, and 4 of 10 patient showed >50% post-ICI increase in either ventricle. Prior to ICI treatment, patients with NSCLC showed greater inter-subject variability (SUVmean COV: 32.3% in the LV, 36.5% in the RV), while patients with melanoma had more uniform uptake. After ICI therapy, myocardial uptake variability increased in patients with melanoma (SUVmean COV: 17.6% in the LV, 23.2% in the RV). In healthy controls, 17-segment analysis showed homogenous uptake without necrotic patterns (defined as uptake <50% of maximum). In one patient with NSCLC, baseline PET showed necrotic LV segments that exhibited elevated [1 8F]F-AraG uptake post-ICI, suggesting potential T cell infiltration (figure 1).Conclusions Cardiac [ 1 8F]F-AraG PET imaging detects dynamic changes in myocardial uptake following ICI therapy, potentially reflecting immune and metabolic effects in the heart. These findings support the potential of [1 8F]F-AraG PET as a non-invasive biomarker for early detection and monitoring of ICI-related cardiac involvement.Trial Registration NCT02323893, NCT04678440, NCT04726215, NCT03618641Ethics Approval The studies were approved by the Institutional Review Boards of Stanford University, Sutter Health, the University of Pittsburgh, the University of California Davis, and the University of California San Francisco. All participants provided written informed consent.Abstract 1072 Figure 1Assessing cardiac effects of cancer immunotherapy with [18F]F-AraG PET imaging. (A) Representative maximum intensity projection and transaxial PET images from a patient with advanced NSCLC, acquired before and after initiation of Pembrolizumab. Post-ICI treatment, [18F]F-AraG uptake increased across multiple tissues—including tumor lesions, lymph nodes, salivary glands, thyroid, and heart—indicating systemic T cell activation. Notably, cardiac uptake was elevated even prior to ICI therapy, likely reflecting prior standard treatment, and further increased following immunotherapy. (B) Polar tomographic images showing FDG uptake (pre-ICI) and [18F]F-AraG uptake (pre- and post-ICI). Pre-treatment images revealed a necrotic pattern, defined as uptake <50% of the maximum, in the basal and mid-inferoseptal segments within the right coronary artery territory—mirroring FDG findings. After ICI therapy, these regions showed markedly increased [18F]F-AraG uptake