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Recent Advances in Liquid Biopsy Biomarkers of Cancer

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Biomarkers".

Deadline for manuscript submissions: 15 July 2026 | Viewed by 6491

Editor

National Institute of Standards and Technology, Gaithersburg, MD, USA
Interests: cancer biomarker; standards development; assay standardization; liquid biopsy; regenerative medicine
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Liquid biopsy has emerged as a minimally invasive method for cancer detection, prognosis, treatment decision guidance, and monitoring. It detects cancer-related biomarkers, including circulating tumor cells, cell-free DNA, cell-free RNA, miRNA, extracellular vesicles, proteins, lipids, and metabolites present in the bodily fluids of patients. These biospecimens can be easily and reproducibly collected for analysis. The rapid advances in sequencing technologies, AI, and other emerging technologies have the potential to enhance the utility of liquid biopsy biomarkers for early cancer detection and multi-cancer detection. However, there are still limitations and challenges in liquid biopsy, such as a lack of laboratory standardization. It is crucial to ensure the accuracy and reliability of these test results for clinical utility.

We invite you to contribute to this Special Issue, titled "Recent Advances in Liquid Biopsy Biomarkers of Cancer". It will focus not only on the discovery of novel cancer biomarkers, such as genetic, epigenetic, proteomic, circulating microbial DNA, fragmentome, and metabolic markers in liquid biopsy for clinical applications, but also on analytical assay development, validation, and reference material development for these biomarker measurements. Additionally, we will explore emerging tools and advanced computational methodologies for detecting cancer biomarkers in liquid biopsy.

For this Special Issue, we welcome original research articles, reviews, and perspective or opinion pieces discussing challenges and future directions in the field.

We look forward to receiving your contributions.

Dr. Hua-Jun He
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-anonymized peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • liquid biopsy
  • circulating tumor cells
  • circulating tumor DNA
  • extracellular vesicles
  • circulating RNA
  • cfDNA methylation
  • fragmentome
  • reference material
  • miRNA
  • multi-cancer detection

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Published Papers (3 papers)

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19 pages, 7499 KB  
Article
Caught in the Act: Tumor-Immune Interactions in Circulation of Patients with Immune Marker Positive Circulating Tumor Cells
by Amin Naghdloo, Mohamed Kamal, Dean Tessone, Valerie Hennes, James Hicks and Peter Kuhn
Cancers 2025, 17(22), 3667; https://doi.org/10.3390/cancers17223667 - 15 Nov 2025
Cited by 1 | Viewed by 1386
Abstract
Background/Objectives: Circulating tumor cells (CTCs) and large extracellular vesicles (LEVs) are key components of the liquid biopsy that provide minimally invasive access to tumor biology. A clinically relevant subset of CTCs coexpressing epithelial and immune markers (im.CTCs) has been described, yet the origin [...] Read more.
Background/Objectives: Circulating tumor cells (CTCs) and large extracellular vesicles (LEVs) are key components of the liquid biopsy that provide minimally invasive access to tumor biology. A clinically relevant subset of CTCs coexpressing epithelial and immune markers (im.CTCs) has been described, yet the origin of this phenotype remains unclear. In this study, we investigated the cellular and molecular context underlying the emergence of immune marker expression on CTCs and LEVs. Methods: Using high-resolution immunofluorescence microscopy of patient-derived blood samples, we identified direct physical interactions between white blood cells (WBCs) and both im.CTCs and im.LEVs, exclusively in patients harboring im.CTCs. Results: In several cases, WBCs partially encapsulated CTCs and LEVs, and quantitative analysis revealed localized enrichment of immune membrane markers at the contact interface, distinguishing these events from random proximity. Proteomic profiling further identified CD4+ T cells as the predominant interacting immune cell type and confirmed the presence of CD45, CD3, and CD4 on the interacting CTCs and LEVs, matching their WBC counterparts. Conclusion: These findings support membrane transfer as a potential mechanism for the acquisition of immune markers by CTCs and LEVs and provide in vivo evidence of contact-dependent tumor-immune interactions in circulation with implications for immune modulation and clinical interpretation of the im.CTC phenotype. Full article
(This article belongs to the Special Issue Recent Advances in Liquid Biopsy Biomarkers of Cancer)
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15 pages, 3244 KB  
Article
Clinical Significance of CD90(+) Circulating Tumor Cells as Dynamic Biomarkers in Unresectable Hepatocellular Carcinoma Treated with Atezolizumab/Bevacizumab and Lenvatinib
by Takuto Nosaka, Yosuke Murata, Yu Akazawa, Tomoko Tanaka, Kazuto Takahashi, Tatsushi Naito, Masahiro Ohtani and Yasunari Nakamoto
Cancers 2025, 17(17), 2829; https://doi.org/10.3390/cancers17172829 - 29 Aug 2025
Viewed by 1294
Abstract
Background: Atezolizumab plus bevacizumab and lenvatinib are standard treatments for advanced hepatocellular carcinoma, but conventional tumor markers such as alpha-fetoprotein and des-gamma-carboxy prothrombin have a limited ability to reflect treatment responses. Circulating tumor cells with cancer stem cell characteristics have emerged as promising [...] Read more.
Background: Atezolizumab plus bevacizumab and lenvatinib are standard treatments for advanced hepatocellular carcinoma, but conventional tumor markers such as alpha-fetoprotein and des-gamma-carboxy prothrombin have a limited ability to reflect treatment responses. Circulating tumor cells with cancer stem cell characteristics have emerged as promising biomarkers. We examined the dynamics of cancer stem cell-related circulating tumor cell subsets and tumor markers at early and maximal response phases in patients with unresectable hepatocellular carcinoma undergoing systemic therapy. Methods: Sixty-two patients treated with either atezolizumab plus bevacizumab or lenvatinib were retrospectively analyzed. Peripheral blood was collected at baseline, during the early phase (during one to three months), and at maximal response. Circulating tumor cell subsets expressing cancer stem cell markers (CD90, epithelial cell adhesion molecule; CD133, vimentin) were assessed using multiparametric flow cytometry and compared with alpha-fetoprotein and des-gamma-carboxy prothrombin. Results: Early decreases in CD90-positive circulating tumor cells after therapy were associated with tumor shrinkage, longer periods of progression-free survival in both groups, and prolonged overall survival in the atezolizumab plus bevacizumab group. By contrast, early changes in alpha-fetoprotein and des-gamma-carboxy prothrombin were not consistently related to tumor size, progression-free survival, or overall survival. At maximal response, changes in CD90-positive circulating tumor cells reflected tumor burden more accurately than alpha-fetoprotein or des-gamma-carboxy prothrombin. Conclusions: These findings indicate that cancer stem cell-related circulating tumor cell subsets, particularly CD90-positive cells, may serve as valuable biomarkers for monitoring treatment response and predicting prognosis in unresectable hepatocellular carcinoma. CD90-positive circulating tumor cells perform dynamic monitoring superior to conventional markers such as alpha-fetoprotein and des-gamma-carboxy prothrombin. Full article
(This article belongs to the Special Issue Recent Advances in Liquid Biopsy Biomarkers of Cancer)
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40 pages, 1378 KB  
Systematic Review
Liquid Biopsy Biomarkers in Metastatic Castration-Resistant Prostate Cancer Treated with Second-Generation Antiandrogens: Ready for Clinical Practice? A Systematic Review
by Andrei-Vlad Badulescu, Razvan Rahota, Alon Vigdorovits and Ovidiu Laurean Pop
Cancers 2025, 17(15), 2482; https://doi.org/10.3390/cancers17152482 - 27 Jul 2025
Viewed by 3136
Abstract
Background: Second-generation androgen receptor signaling inhibitors are one of the main treatment options in metastatic castration-resistant prostate cancer (mCRPC). Nonetheless, a considerable proportion show limited response to treatment, which indicates the need for convenient, easily accessible predictor biomarkers, a role suited for [...] Read more.
Background: Second-generation androgen receptor signaling inhibitors are one of the main treatment options in metastatic castration-resistant prostate cancer (mCRPC). Nonetheless, a considerable proportion show limited response to treatment, which indicates the need for convenient, easily accessible predictor biomarkers, a role suited for liquid biopsy. Methods: We conducted a PRISMA-compliant systematic review of four databases (Embase, Medline, Scopus, Web of Science) to identify all studies (observational studies and clinical trials) investigating cell-free DNA, circulating tumor cells, exosomes, and circulating RNAs as prognostic markers in metastatic castration-resistant patients starting androgen receptor signaling inhibitors. We excluded studies that evaluated combination therapies, rare histological subtypes or included nonmetastatic or castrate-sensitive disease. We also evaluated whether published papers followed reporting guidelines (REMARK, STROBE, or CONSORT for abstracts). Results: We identified a total of 123 reports, from which we identified only a few well-studied and consistent biomarkers: androgen receptor overexpression/copy number gain and splice variant 7, as well as disease burden markers (circulating tumor DNA fraction and circulating tumor cell concentration). Alterations or copy number loss in tumor suppressors PTEN, RB1, and TP53 were second in terms of quantity and consistency of evidence. However, a large majority of identified biomarkers were relatively understudied or inconsistent. We identified two potential vulnerabilities: inconsistent adherence to reporting guidelines and the under-inclusion of patients of non-Western European ancestry. Conclusions: A large number of biomarkers were linked to worse outcomes in prostate cancer; nonetheless, in most cases, the evidence is limited or inconsistent, or even contradictory. The main exceptions pertain to androgen receptor signaling and disease burden, and, to a smaller extent, to certain tumor suppressor genes. Further studies are needed to confirm their clinical utility, using clear and consistent methodologies and including patients from currently understudied populations. Full article
(This article belongs to the Special Issue Recent Advances in Liquid Biopsy Biomarkers of Cancer)
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