Cellular origins and evolutionary dynamics of plasma cfDNA in solid tumors: integrating germline, tumor-derived, and hematopoietic variation for MRD and treatment guidance

Plasma cell-free DNA (cfDNA) is a heterogeneous and rapidly changing biological pool derived from malignant cells, normal tissues, and hematopoietic cells. The abundance and molecular composition of circulating tumor DNA (ctDNA) are determined not only by tumor burden but also by tissue architecture, vascular access, cell-death programs, chromatin organization, nuclease processing, systemic clearance, treatment exposure, and clonal evolution. These biological determinants shape the mutation, methylation, fragmentation, nucleosomal, and temporal features exploited by contemporary liquid-biopsy assays. Accurate clinical interpretation therefore requires both sensitive detection and reliable source attribution, particularly the distinction of tumor-derived variants from constitutional germline alterations and clonal hematopoiesis. In this review, we integrate the biological origins and processing of plasma cfDNA with analytical strategies for low-tumor-fraction detection and critically evaluate the evidence supporting postoperative molecular residual disease (MRD), recurrence surveillance, treatment-response assessment, resistance monitoring, and ctDNA-guided therapy across solid tumors. Particular emphasis is placed on distinguishing prognostic validity, treatment-predictive value, and demonstrated clinical utility. Current evidence is strongest in colorectal cancer and, more recently, ctDNA-selected urothelial cancer, whereas routine ctDNA-directed intervention in resected non-small cell lung cancer and breast cancer remains insufficiently validated. By linking cfDNA biology to an explicit hierarchy of clinical evidence, this review defines both the established applications and the major limitations that must be addressed before broader implementation of ctDNA-guided precision oncology.