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The development of tumor biomarkers derived from blood, or its components, has become pivotal in advancing early cancer diagnosis. Malignant transformations induce cancer-specific alterations in the transcriptome, proteome, and secretome of tumor cells. Recent studies highlighted similar alterations in peripheral blood mononuclear cells (PBMCs) in cancer patients, which appear to mirror the state of transformation in tumor cells. These findings suggest an intercellular communication-driven mechanism rather than a systemic inflammatory response and, in addition to current ctDNA-based liquid biopsy biomarkers, point to a novel, simple, and highly robust approach for the early detection of cancer. Using this phenomenon to advance PBMC-based biomarker development, it will be essential to achieve 3D in vitro tumor models that reproduce a highly physiological tumor microenvironment (TME). In this study, an innovative modular 3D co-culturing approach was used to expose PBMCs to lung tumoroids under physiologically relevant conditions. Changes in DNA fragmentation of PBMCs in the presence of lung cancer were quantified and used as a biomarker, and validated against clinical data. Similar to the clinical observations, PBMCs exposed to lung tumoroids showed a significantly lower level of DNA fragmentation, demonstrating the model’s power to monitor cell-to-cell communication effects and support the development of blood-based biomarkers.

Melanoma treatment has improved significantly with the development of immune checkpoint inhibition (ICI), which has greatly enhanced the survival rates of patients with metastatic melanoma. However, a significant number of patients do not respond well to ICI treatment and experience progression, highlighting the critical need for practical means to track response. To address this, patterns of circulating miRNAs were studied in liquid biopsies of melanoma patients. A flow-cytometric test measured up to 63 different miRNAs at once. The study identified a combination of nine miRNAs capable of distinguishing between different stages of melanoma, particularly stage IV. Additionally, five miRNAs were pinpointed which are downregulated in patients who do not respond to ICI treatment; two miRNAs were found that correlate to the level of PD-L1 in tumor tissue, and low levels of miR-150-5p were linked to poorer overall survival. These findings suggest circulating miRNAs could serve as valuable markers to predict the effectiveness of ICI and inform treatment decisions, though further research is needed to confirm their clinical usefulness.