<p>Current liquid-biopsy technologies predominantly rely on genomic and proteomic analyses to detect tumor-derived signals in blood. However, the extremely low abundance of tumor secretome components remains a major limitation for reliable detection. Here, we introduce an AI-driven imaging framework that leverages chromatin-based cellular fingerprints as functional biosensors to detect cancer-associated blood-derived secretome signals. As a proof of concept, we demonstrate that human stromal fibroblasts exhibit a higher signal-to-noise ratio for detecting prostate cancer-derived secretomes isolated from whole blood compared with immune cells. Notably, aged fibroblasts display enhanced sensitivity relative to their young counterparts and T cells. To achieve a fully integrated sample-to-sensing workflow, we combined this imaging approach with a micropillar-guided secretome/plasma isolation platform coupled to an on-chip cell-culture chamber, enabling rapid exposure of sensor cells to tumor-derived secretome factors. Together, our results establish a proof-of-concept exploratory study demonstrating the feasibility of chromatin-based functional biosensing of cancer-associated blood-derived secretome signals.</p>