Abstract Body: Immune checkpoint inhibitors (ICIs) targeting PD-L1, particularly in combination with CTLA-4 blockade, have become standard-of-care therapies for advanced malignancies. Dual checkpoint inhibition significantly improves overall survival in patients with advanced cancers and represents one of the most transformative advances in oncology. However, its success is offset by the emergence of immune-related adverse events (irAEs). These toxicities arise from aberrant immune activation and affect multiple organs, including the heart. Despite increasing recognition of ICI-associated cardiotoxicities, the molecular mechanisms underlying these events remain poorly understood. Myeloid cells in the heart express PD-L1, whereas CTLA-4 is primarily expressed by T cells. The contribution of their interplay to cardiac pathology during dual checkpoint blockade in colorectal cancer remains undefined, representing a critical gap in understanding ICI-mediated cardiotoxicity. To inhibit PD-L1 in myeloid cells, we generated myeloid-specific PD-L1 knockout mice. Preliminary studies demonstrate that mPD-L1 KO models combined with CTLA-4 blockade enhance antitumor efficacy in colorectal cancer and reduce tumor fibrosis, while promoting innate and adaptive immune activation within the tumor microenvironment. In contrast, echocardiographic assessment revealed a detrimental cardiac phenotype in colorectal cancer bearing mice subjected to myeloid PD-L1 inhibition and anti–CTLA-4 treatment, indicating dissociation between tumor control and cardiac outcomes. Echocardiographic findings were validated by qRT-PCR analysis of heart failure markers, and Masson’s trichrome staining revealed increased myocardial fibrosis, supporting maladaptive cardiac remodeling. Immunophenotyping of the heart, spleen, and tumor by flow cytometry revealed pronounced myocardial inflammation in combination therapy groups, implicating excessive immune activation as a driver of cardiac dysfunction. Transcriptomic analysis of whole-heart RNA revealed a cardiomyocyte-specific MHC class I–restricted immune response in the heart. In summary, dual inhibition of myeloid PD-L1 and CTLA-4 enhances antitumor efficacy in colorectal cancer but disrupts cardiac repair mechanisms, leading to cardiotoxicity. Targeting cardiomyocyte specific MHC-I dependent pathways may help mitigate cardiac adverse events while preserving the antitumor activity of immune checkpoint blockade.