Cytoplasmic DNA emerges as a consequence of genomic instability. However, its potential role in disease diagnosis has yet to be fully explored. Here we analyzed DNA remnants in mature red blood cells (rbcDNA) from both healthy individuals and cancer patients. Our study unveiled distinct genomic profiles in rbcDNA from cancer patients with early-stage solid tumors compared to those of healthy donors. Significant changes in read counts at specific genomic regions within rbcDNA were identified in patients, which were termed tumor-associated rbcDNA features. These features demonstrated potential for highly accurate early-stage cancer detection, proposing a novel approach for cancer detection. Moreover, tumor-associated rbcDNA features were observed in tumor mouse models, with some features being conserved between mice and humans. Chronic, but not transient, up-regulation of interleukin-18 is essential for the development of these features by promoting DNA damage in bone marrow hematopoietic cells through the up-regulation of NR4A1. These results underscore the remote regulation of chromosomal stability in hematopoietic cells by solid tumors and propose tumor-associated rbcDNA features as a promising strategy for early cancer detection.