In parallel, we used engineered heart tissues in which mechanical load can be controlled at will. In these models, mechanical load inhibited, whereas tissue unloading promoted the proliferation of lung adenocarcinoma, colon carcinoma, and melanoma cells within the myocardium. To investigate the mechanisms underlying these effects, we used spatial transcriptomics to analyze samples of human cancers that gave rise to both cardiac and extracardiac metastases. We found that cardiac metastases shared a common transcriptional profile, independent from the origin of the primary tumor. Among the most up-regulated genes in cardiac metastases were histone demethylases. Consistently, cardiac metastases showed reduced histone 3 lysine 9 trimethylation and reduced chromatin compaction. Similar findings were observed in our experimental models of cardiac load modulation in which chromatin accessibility and histone methylation were altered at sites controlling cancer cell proliferation, as determined by single-nuclei assay for transposase-accessible chromatin with sequencing and chromatin immunoprecipitation sequencing. Nesprin-2, a protein known to mediate mechanotransduction from the cytoplasm to the nucleus, emerged as a key molecule sensing mechanical forces operating in beating hearts and translating them into reduced cell proliferation. Silencing of Nesprin-2 in lung cancer cells prior to their implantation in the heart in vivo restored the capacity of the cells to proliferate in the presence of physiological mechanical load, resulting in the formation of large tumors.