{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T06:10:22Z","timestamp":1790403022460,"version":"4.1.0"},"reference-count":45,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T00:00:00Z","timestamp":1761696000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cervical cancer remains a significant public health priority, particularly in low- and middle-income countries. In this context, liquid biopsy has emerged as a minimally invasive method for detecting and monitoring molecular biomarkers, offering advantages over traditional screening approaches. This systematic review included 21 studies published between 2015 and 2025 and was conducted in accordance with the PRISMA 2020 statement. The analysis examined the role of serum cytokines, circulating microRNAs (miRNAs), and circulating cell-free HPV DNA (cfHPV-DNA) in patients with cervical cancer or high-grade intraepithelial lesions. Circulating miRNAs\u2014particularly miR-21, miR-29a, and miR-34a\u2014are consistently associated with recurrence, tumor progression, and reduced survival. However, their immediate clinical translation remains limited by methodological variability and the lack of universal normalizers. In contrast, cfHPV-DNA, especially with ddPCR, exhibited the best study-level performance, with a specificity of 100% and a sensitivity of approximately 80\u201388%, across heterogeneous endpoints and analytic conditions. Consequently, cfHPV-DNA represents a promising tool for post-treatment surveillance and early detection of recurrence. Serum cytokines, such as TNF-\u03b1, IL-6, and IL-10, reflect inflammation and the tumor microenvironment. Nevertheless, their lack of standardization and variability across detection platforms restricts their reproducibility, positioning them as complementary rather than stand-alone markers. In conclusion, the evidence supports liquid biopsy as a promising tool in cervical cancer management; nonetheless, only cfHPV-DNA is currently ready for clinical application, whereas miRNAs and cytokines require multicenter validation and technical standardization before implementation.<\/jats:p>","DOI":"10.3390\/ijms262110503","type":"journal-article","created":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T17:38:22Z","timestamp":1761759502000},"page":"10503","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Liquid Biopsy Biomarkers for Cervical Cancer: A Systematic Review"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-6498-6684","authenticated-orcid":false,"given":"Jes\u00fas Alejandro","family":"Pineda-Migranas","sequence":"first","affiliation":[{"name":"Escuela Superior de Medicina, Instituto Polit\u00e9cnico Nacional (IPN), Salvador D\u00edaz Mir\u00f3n esq. Plan de San Luis y D\u00edaz Mir\u00f3n s\/n, Col. Casco de Santo Tom\u00e1s, Mexico City 11340, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3585-0051","authenticated-orcid":false,"given":"Juan Carlos","family":"Bravata-Alc\u00e1ntara","sequence":"additional","affiliation":[{"name":"Health Research Unit, Hospital de Alta Especialidad Ixtapaluca, Servicios de Salud del Instituto Mexicano del Seguro Social para el Bienestar (IMSS-BIENESTAR), Carr Federal M\u00e9xico-Puebla Km 34.5, Ixtapaluca 56530, Mexico"},{"name":"Facultad de Medicina y Cirug\u00eda, Universidad Aut\u00f3noma \u201cBenito Ju\u00e1rez\u201d de Oaxaca (UABJO), Oaxaca 68020, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9409-5896","authenticated-orcid":false,"given":"Iliana Alejandra","family":"Cort\u00e9s-Ort\u00edz","sequence":"additional","affiliation":[{"name":"Molecular Genetics and Diagnostic Laboratory, Hospital Ju\u00e1rez de M\u00e9xico, Instituto Polit\u00e9cnico Nacional, 5160, Col. Magdalena de las Salinas, Mexico City 07760, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6240-3468","authenticated-orcid":false,"given":"Enoc Mariano","family":"Cort\u00e9s-Malag\u00f3n","sequence":"additional","affiliation":[{"name":"Research Division, Hospital Ju\u00e1rez de M\u00e9xico, Instituto Polit\u00e9cnico Nacional, 5160, Col. 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Clin."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Zhou, L., Li, Y., Wang, H., Qin, R., Han, Z., and Li, R. (2025). Global cervical cancer elimination: Quantifying the status, progress, and gaps. BMC Med., 23.","DOI":"10.1186\/s12916-025-03897-3"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Cruz-Valdez, A., Palacio-Mejia, L.S., Quezada-Sanchez, A.D., Hernandez-Avila, J.E., Galicia-Carmona, T., Cetina-Perez, L.D.C., Arango-Bravo, E.A., Isla-Ortiz, D., Aranda-Flores, C.E., and Uscanga-Sanchez, S.R. (2023). Cervical cancer prevention program in Mexico disrupted due to COVID-19 pandemic: Challenges and opportunities. Front. Oncol., 13.","DOI":"10.3389\/fonc.2023.1008560"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Garrido, F., Wild, C.M., Mittelberger, J., Dobler, F., Schneider, M., Ansorge, N., Kopke, M., Strieder, A., Ditsch, N., and Jeschke, U. (2021). The Role of Chemokines in Cervical Cancers. Medicina, 57.","DOI":"10.3390\/medicina57111141"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Millan-Catalan, O., Perez-Yepez, E.A., Martinez-Gutierrez, A.D., Rodriguez-Morales, M., Lopez-Urrutia, E., Coronel-Martinez, J., Cantu de Leon, D., Jacobo-Herrera, N., Peralta-Zaragoza, O., and Lopez-Camarillo, C. (2024). A microRNA Profile Regulates Inflammation-Related Signaling Pathways in Young Women with Locally Advanced Cervical Cancer. Cells, 13.","DOI":"10.3390\/cells13110896"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2297","DOI":"10.3892\/or.2016.4583","article-title":"Methylation and expression of miRNAs in precancerous lesions and cervical cancer with HPV16 infection","volume":"35","year":"2016","journal-title":"Oncol. Rep."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Agorastos, T., Chatzistamatiou, K., Katsamagkas, T., Koliopoulos, G., Daponte, A., Constantinidis, T., Constantinidis, T.C., and HERMES Study Group (2015). Primary screening for cervical cancer based on high-risk human papillomavirus (HPV) detection and HPV 16 and HPV 18 genotyping, in comparison to cytology. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0119755"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1823","DOI":"10.2147\/RMHP.S296914","article-title":"An Overview of HPV Screening Tests to Improve Access to Cervical Cancer Screening Among Underserved Populations: From Development to Implementation","volume":"15","author":"Okunade","year":"2022","journal-title":"Risk Manag. Healthc. Policy"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"80","DOI":"10.26444\/jpccr\/126432","article-title":"High-risk HPV test in cervical cancer prevention\u2014Present and future","volume":"14","author":"Zarankiewicz","year":"2020","journal-title":"J. Pre-Clin. Clin. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2097","DOI":"10.1038\/s41416-023-02233-x","article-title":"Detection of circulating cell-free HPV DNA of 13 HPV types for patients with cervical cancer as potential biomarker to monitor therapy response and to detect relapse","volume":"128","author":"Mittelstadt","year":"2023","journal-title":"Br. J. Cancer"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Poinho, M., Dias, L., Pinheiro, L.S., Gomes, F.N.O., Rondon, H., de Oliveira, M.P., Souza, J.S., Figueiredo, H.F., Lira, D.L., and Levi, J.E. (2025). The Role of cf-HPV DNA as an Innovative Biomarker for Predicting the Recurrence or Persistence of Cervical Cancer. Viruses, 17.","DOI":"10.3390\/v17030409"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1080\/1547691X.2020.1755397","article-title":"Circulating inflammatory markers in cervical cancer patients and healthy controls","volume":"17","author":"Vitkauskaite","year":"2020","journal-title":"J. Immunotoxicol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Kepsha, M.A., Timofeeva, A.V., Chernyshev, V.S., Silachev, D.N., Mezhevitinova, E.A., and Sukhikh, G.T. (2024). MicroRNA-Based Liquid Biopsy for Cervical Cancer Diagnostics and Treatment Monitoring. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms252413271"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2795","DOI":"10.1111\/cas.16214","article-title":"Performance of an ancillary test for cervical cancer that measures miRNAs and cytokines in serum and cervical mucus","volume":"115","author":"Fujii","year":"2024","journal-title":"Cancer Sci."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Gonzalez-Ramirez, M.I., Cardona, Y.T., Agudelo, M.C., Lopez, C., Florez-Acosta, J.J., Agudelo-Gamboa, S., Garai, J., Li, L., Orozco-Castano, C.A., and Zabaleta, J. (2023). miRNAs signature as potential biomarkers for cervical precancerous lesions in human papillomavirus positive women. Sci. Rep., 13.","DOI":"10.1038\/s41598-023-36421-9"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Aranda Flores, C.E., Gomez Gutierrez, G., Ortiz Leon, J.M., Cruz Rodriguez, D., and Sorbye, S.W. (2021). Self-collected versus clinician-collected cervical samples for the detection of HPV infections by 14-type DNA and 7-type mRNA tests. BMC Infect. Dis., 21.","DOI":"10.1186\/s12879-021-06189-2"},{"key":"ref_17","first-page":"100593","article-title":"Performance of cervical cytology and HPV testing for primary cervical cancer screening in Latin America: An analysis within the ESTAMPA study","volume":"26","author":"Ramirez","year":"2023","journal-title":"Lancet Reg. Health Am."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"n71","DOI":"10.1136\/bmj.n71","article-title":"The PRISMA 2020 statement: An updated guideline for reporting systematic reviews","volume":"372","author":"Page","year":"2021","journal-title":"BMJ"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.jclinepi.2016.01.021","article-title":"PRESS Peer Review of Electronic Search Strategies: 2015 Guideline Statement","volume":"75","author":"McGowan","year":"2016","journal-title":"J. Clin. Epidemiol."},{"key":"ref_20","unstructured":"Higgins, J., Thomas, J., Chandler, J., Cumpston, M., Li, T., Page, M., and Welch, V. (Cochrane Handbook for Systematic Reviews of Interventions, 2023). Cochrane Handbook for Systematic Reviews of Interventions, version 6.4 (Updated August 2023)."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"i4919","DOI":"10.1136\/bmj.i4919","article-title":"ROBINS-I: A tool for assessing risk of bias in nonrandomized studies of interventions","volume":"355","author":"Sterne","year":"2016","journal-title":"BMJ"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"l4898","DOI":"10.1136\/bmj.l4898","article-title":"RoB 2: A revised tool for assessing risk of bias in randomized trials","volume":"366","author":"Sterne","year":"2019","journal-title":"BMJ"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"j4008","DOI":"10.1136\/bmj.j4008","article-title":"AMSTAR 2: A critical appraisal tool for systematic reviews that include randomized or nonrandomized studies of healthcare interventions, or both","volume":"358","author":"Shea","year":"2017","journal-title":"BMJ"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1001\/jama.2017.19163","article-title":"Preferred Reporting Items for a Systematic Review and Meta-analysis of Diagnostic Test Accuracy Studies: The PRISMA-DTA Statement","volume":"319","author":"McInnes","year":"2018","journal-title":"JAMA"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"13","DOI":"10.3892\/mco.2023.2609","article-title":"Circulating cervical cancer biomarkers potentially useful in medical attention (Review)","volume":"18","author":"Gutierrez","year":"2023","journal-title":"Mol. Clin. Oncol."},{"key":"ref_26","first-page":"104","article-title":"An increase of microRNA-16-1 is associated with the high proliferation of squamous intraepithelial lesions in the presence of the integrated state of HR-HPV in liquid cytology samples","volume":"20","author":"Patino","year":"2020","journal-title":"Oncol. Lett."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Bonin-Jacob, C.M., Almeida-Lugo, L.Z., Puga, M.A.M., Machado, A.P., Padovani, C.T.J., Noceti, M.C., Ferreira, A.M.T., Fernandes, C., Resende, J.C.P., and Bovo, A.C. (2021). IL-6 and IL-10 in the serum and exfoliated cervical cells of patients infected with high-risk human papillomavirus. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0248639"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"491","DOI":"10.3233\/CBM-190256","article-title":"Circulating plasma microRNA signature for the diagnosis of cervical cancer","volume":"26","author":"Ma","year":"2019","journal-title":"Cancer Biomark."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Du, S., Zhao, Y., Lv, C., Wei, M., Gao, Z., and Meng, X. (2020). Applying Serum Proteins and MicroRNA as Novel Biomarkers for Early-Stage Cervical Cancer Detection. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-65850-z"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1177\/1933719115570902","article-title":"Plasma miR-127 and miR-218 Might Serve as Potential Biomarkers for Cervical Cancer","volume":"22","author":"You","year":"2015","journal-title":"Reprod. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Zhang, Y., Zhang, D., Wang, F., Xu, D., Guo, Y., and Cui, W. (2015). Serum miRNAs panel (miR-16-2*, miR-195, miR-2861, miR-497) as novel noninvasive biomarkers for detection of cervical cancer. Sci. Rep., 5.","DOI":"10.1038\/srep17942"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Aftab, M., Poojary, S.S., Seshan, V., Kumar, S., Agarwal, P., Tandon, S., Zutshi, V., and Das, B.C. (2021). Urine miRNA signature as a potential noninvasive diagnostic and prognostic biomarker in cervical cancer. Sci. Rep., 11.","DOI":"10.1038\/s41598-021-89388-w"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"5106","DOI":"10.7150\/jca.51141","article-title":"6 Circulating miRNAs can be used as Noninvasive Biomarkers for the Detection of Cervical Lesions","volume":"12","author":"Ning","year":"2021","journal-title":"J. Cancer"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1002\/cjp2.47","article-title":"Circulating human papillomavirus DNA detected using droplet digital PCR in the serum of patients diagnosed with early stage human papillomavirus-associated invasive carcinoma","volume":"2","author":"Jeannot","year":"2016","journal-title":"J. Pathol. Clin. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"5869","DOI":"10.1158\/1078-0432.CCR-21-0625","article-title":"Circulating HPV DNA as a Marker for Early Detection of Relapse in Patients with Cervical Cancer","volume":"27","author":"Jeannot","year":"2021","journal-title":"Clin. Cancer Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.ygyno.2022.07.028","article-title":"Circulating cell-free tumor human papillomavirus DNA is a promising biomarker in cervical cancer","volume":"167","author":"Sivars","year":"2022","journal-title":"Gynecol. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Bonlokke, S., Stougaard, M., Sorensen, B.S., Booth, B.B., Hogdall, E., Nyvang, G.B., Lindegaard, J.C., Blaakaer, J., Bertelsen, J., and Fuglsang, K. (2022). The Diagnostic Value of Circulating Cell-Free HPV DNA in Plasma from Cervical Cancer Patients. Cells, 11.","DOI":"10.3390\/cells11142170"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1002\/1878-0261.13538","article-title":"Circulating cell-free HPV DNA is a strong marker for disease severity in cervical cancer","volume":"18","author":"Bonlokke","year":"2024","journal-title":"Mol. Oncol."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Lalondrelle, S., Lee, J., Cutts, R.J., Garcia Murillas, I., Matthews, N., Turner, N., Harrington, K., Vroobel, K., Moretti, E., and Bhide, S.A. (2023). Predicting Response to Radical Chemoradiotherapy with Circulating HPV DNA (cHPV-DNA) in Locally Advanced Uterine Cervix Cancer. Cancers, 15.","DOI":"10.3390\/cancers15051387"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"12597","DOI":"10.1007\/s00432-023-05077-3","article-title":"Digital droplet PCR-based quantification of ccfHPV-DNA as liquid biopsy in HPV-driven cervical and vulvar cancer","volume":"149","author":"Thangarajah","year":"2023","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Beaussire-Trouvay, L., Duhamel, O., Perdrix, A., Leveque, E., Vion, R., Rovelet-Lecrux, A., Sarafan-Vasseur, N., Di Fiore, F., Crouzet, A., and Leheurteur, M. (2024). Prognostic value of HPV circulating tumor DNA detection and quantification in locally advanced cervical cancer. Front. Oncol., 14.","DOI":"10.3389\/fonc.2024.1382008"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"655","DOI":"10.2147\/IJWH.S347740","article-title":"Serum IL-6 Level Predicts the Prognosis and Diagnosis in Cervical Cancer Patients","volume":"14","author":"Cai","year":"2022","journal-title":"Int. J. Womens Health"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Vitkauskaite, A., Urboniene, D., Celiesiute, J., Jariene, K., Paskauskas, S., Vaitkiene, D., and Vitkauskiene, A. (2024). Expression of Inflammation Depending on the Stage of Cervical Cancer. Medicina, 60.","DOI":"10.3390\/medicina60030349"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1159\/000517320","article-title":"Inflammatory Biomarkers as Promising Predictors of Prognosis in Cervical Cancer Patients","volume":"99","author":"Domenici","year":"2021","journal-title":"Oncology"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Nascimento, N.P.G., Gally, T.B., Borges, G.F., Campos, L.C.G., and Kaneto, C.M. (2022). Systematic review of circulating MICRORNAS as biomarkers of cervical carcinogenesis. BMC Cancer, 22.","DOI":"10.1186\/s12885-022-09936-z"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/21\/10503\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T17:42:30Z","timestamp":1761759750000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/21\/10503"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,29]]},"references-count":45,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["ijms262110503"],"URL":"https:\/\/doi.org\/10.3390\/ijms262110503","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,29]]}}}