{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T09:08:13Z","timestamp":1788944893307,"version":"build-2803163510"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:p>Molecular residual disease (MRD) refers to occult cancer persisting below the detection limit of conventional imaging and is a major source of later relapse. Circulating tumor DNA (ctDNA) provides a minimally invasive molecular surrogate of residual disease, but its interpretation is influenced by tumor burden, shedding, anatomic site, treatment-related cell death, sampling time, and analytical sensitivity. Immune biomarkers provide complementary information on whether residual disease is being recognized, contained, or permitted to escape by the host immune system. This Mini Review examines how ctDNA and immune biomarker testing can be integrated for MRD surveillance and immune stratification across solid tumors. We summarize tumor-informed and tumor-na\u00efve ctDNA approaches, including mutation-, methylation-, fragmentomic-, and whole-genome-based assays; discuss tissue and blood immune biomarkers such as PD-L1, mismatch repair status, tumor mutational burden, antigen-presentation integrity, T-cell receptor repertoires, cytokines, and suppressive myeloid populations; and review recent evidence from colorectal, lung, urothelial, breast, and melanoma studies. We propose a conceptual, hypothesis-generating framework in which ctDNA reports tumor-derived molecular signal and shedding, whereas immune assays report immune pressure and escape. Joint interpretation may, if prospectively validated, distinguish biologically different MRD states, improve longitudinal risk assessment, and provide a laboratory foundation for biomarker-oriented immunotherapy and cell-therapy studies. However, clinical implementation requires standardized preanalytics, explicit assay limits, paired leukocyte controls, serial sampling, harmonized immune assays, and prospective trials demonstrating clinical utility rather than prognostic association alone.<\/jats:p>","DOI":"10.3389\/fmed.2026.1942673","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T08:34:41Z","timestamp":1788942881000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["ctDNA and immune biomarker testing for molecular residual disease surveillance and immune stratification in cancer"],"prefix":"10.3389","volume":"13","author":[{"given":"Ning","family":"Cui","sequence":"first","affiliation":[{"name":"Huanghe Science and Technology University","place":["Zhengzhou, Henan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongying","family":"Hao","sequence":"additional","affiliation":[{"name":"Huanghe Science and Technology University","place":["Zhengzhou, Henan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaofeng","family":"Hu","sequence":"additional","affiliation":[{"name":"Huanghe Science and Technology University","place":["Zhengzhou, Henan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaxuan","family":"Li","sequence":"additional","affiliation":[{"name":"Huanghe Science and Technology University","place":["Zhengzhou, Henan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"498","DOI":"10.1038\/s41568-024-00705-7","article-title":"Defining clinically useful biomarkers of immune checkpoint inhibitors in solid tumours","volume":"24","author":"Holder","year":"2024","journal-title":"Nat Rev Cancer"},{"key":"B2","doi-asserted-by":"publisher","first-page":"101621","DOI":"10.1016\/j.xcrm.2024.101621","article-title":"Advances and prospects of biomarkers for immune checkpoint inhibitors","volume":"5","author":"Yamaguchi","year":"2024","journal-title":"Cell Rep Med"},{"key":"B3","doi-asserted-by":"publisher","first-page":"5309","DOI":"10.1016\/j.cell.2021.09.020","article-title":"Hallmarks of response, resistance, and toxicity to immune checkpoint blockade","volume":"184","author":"Morad","year":"2021","journal-title":"Cell"},{"key":"B4","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1038\/s41568-021-00347-z","article-title":"Systemic immunity in cancer","volume":"21","author":"Hiam-Galvez","year":"2021","journal-title":"Nat Rev Cancer"},{"key":"B5","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1038\/s41392-022-01136-2","article-title":"Therapeutic targets and biomarkers of tumor immunotherapy: response versus non-response","volume":"7","author":"Wang","year":"2022","journal-title":"Signal Transduct Target Ther"},{"key":"B6","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1186\/s40364-022-00378-0","article-title":"The role of biomarkers in personalized immunotherapy","volume":"10","author":"Sankar","year":"2022","journal-title":"Biomark Res"},{"key":"B7","doi-asserted-by":"publisher","first-page":"596","DOI":"10.1016\/j.cell.2021.01.002","article-title":"Meta-analysis of tumor- and T cell-intrinsic mechanisms of sensitization to checkpoint inhibition","volume":"184","author":"Litchfield","year":"2021","journal-title":"Cell"},{"key":"B8","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1038\/s41587-021-01070-8","article-title":"Improved prediction of immune checkpoint blockade efficacy across multiple cancer types","volume":"40","author":"Chowell","year":"2022","journal-title":"Nat Biotechnol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"729","DOI":"10.1038\/s41467-021-20935-9","article-title":"Pretreatment neutrophil-to-lymphocyte ratio and mutational burden as biomarkers of tumor response to immune checkpoint inhibitors","volume":"12","author":"Valero","year":"2021","journal-title":"Nat Commun"},{"key":"B10","doi-asserted-by":"publisher","first-page":"750","DOI":"10.1016\/j.annonc.2022.05.520","article-title":"ESMO Recommendations on the use of circulating tumour DNA assays for patients with cancer: a report from the ESMO precision medicine working group","volume":"33","author":"Pascual","year":"2022","journal-title":"Ann Oncol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1115","DOI":"10.1038\/s41587-021-00857-z","article-title":"Evaluating the analytical validity of circulating tumor DNA sequencing assays for precision oncology","volume":"39","author":"Deveson","year":"2021","journal-title":"Nat Biotechnol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1080\/14737159.2021.1889371","article-title":"Ultrasensitive circulating tumor DNA analysis enables precision medicine: experimental workflow considerations","volume":"21","author":"Andersson","year":"2021","journal-title":"Expert Rev Mol Diagn"},{"key":"B13","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1093\/clinchem\/hvad203","article-title":"MAESTRO-Pool enables highly parallel and specific mutation-enrichment sequencing for minimal residual disease detection in cohort studies","volume":"70","author":"Blewett","year":"2024","journal-title":"Clin Chem"},{"key":"B14","doi-asserted-by":"publisher","first-page":"2188","DOI":"10.1038\/s44321-024-00115-0","article-title":"Ultra-sensitive molecular residual disease detection through whole genome sequencing with single-read error correction","volume":"16","author":"Li","year":"2024","journal-title":"EMBO Mol Med"},{"key":"B15","doi-asserted-by":"publisher","first-page":"114159","DOI":"10.1016\/j.ejca.2024.114159","article-title":"A review of trials investigating ctDNA-guided adjuvant treatment of solid tumors: the importance of trial design","volume":"207","author":"Verschoor","year":"2024","journal-title":"Eur J Cancer"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1200\/OP-26-00311","article-title":"Circulating tumor DNA testing in solid tumors and lymphoma: aSCO guideline","author":"Lockwood","year":"2026","journal-title":"JCO Oncol Pract"},{"key":"B17","doi-asserted-by":"publisher","first-page":"329","DOI":"10.3390\/jcm12010329","article-title":"Response to immune checkpoint inhibitors is affected by deregulations in the antigen presentation machinery: a systematic review and meta-analysis","volume":"12","author":"Rasmussen","year":"2023","journal-title":"J Clin Med"},{"key":"B18","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1002\/path.6197","article-title":"Integration of peripheral blood- and tissue-based biomarkers of response to immune checkpoint blockade in urothelial carcinoma","volume":"261","author":"Vanguri","year":"2023","journal-title":"J Pathol"},{"key":"B19","doi-asserted-by":"publisher","first-page":"1192","DOI":"10.1158\/1078-0432.CCR-21-3114","article-title":"Circulating immune bioenergetic, metabolic, and genetic signatures predict melanoma patients' Response to anti-PD-1 immune checkpoint blockade","volume":"28","author":"Triozzi","year":"2022","journal-title":"Clin Cancer Res"},{"key":"B20","doi-asserted-by":"publisher","first-page":"829","DOI":"10.1080\/1750743X.2024.2379230","article-title":"Peripheral blood cytokines and outcomes with immune checkpoint blockade: a systematic review and meta-analysis","volume":"16","author":"Karol","year":"2024","journal-title":"Immunotherapy"},{"key":"B21","doi-asserted-by":"publisher","first-page":"1403771","DOI":"10.3389\/fimmu.2024.1403771","article-title":"Myeloid-derived suppressor cells in peripheral blood as predictive biomarkers in patients with solid tumors undergoing immune checkpoint therapy: systematic review and meta-analysis","volume":"15","author":"M\u00f6ller","year":"2024","journal-title":"Front Immunol"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1326083","DOI":"10.3389\/fimmu.2024.1326083","article-title":"Pan-immune inflammation value as a prognostic biomarker for cancer patients treated with immune checkpoint inhibitors","volume":"15","author":"Kuang","year":"2024","journal-title":"Front Immunol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"1862948","DOI":"10.1080\/2162402X.2020.1862948","article-title":"Peripheral T cell receptor repertoire features predict durable responses to anti-PD-1 inhibitor monotherapy in advanced renal cell carcinoma","volume":"10","author":"Kato","year":"2021","journal-title":"Oncoimmunology"},{"key":"B24","doi-asserted-by":"publisher","first-page":"1646","DOI":"10.1007\/s12094-021-02562-4","article-title":"Peripheral blood T-cell receptor repertoire as a predictor of clinical outcomes in gastrointestinal cancer patients treated with PD-1 inhibitor","volume":"23","author":"Ji","year":"2021","journal-title":"Clin Transl Oncol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"eabq5089","DOI":"10.1126\/sciadv.abq5089","article-title":"Deep learning reveals predictive sequence concepts within immune repertoires to immunotherapy","volume":"8","author":"Sidhom","year":"2022","journal-title":"Sci Adv"},{"key":"B26","doi-asserted-by":"publisher","first-page":"2261","DOI":"10.1056\/NEJMoa2200075","article-title":"Circulating tumor DNA analysis guiding adjuvant therapy in stage II colon cancer","volume":"386","author":"Tie","year":"2022","journal-title":"N Engl J Med"},{"key":"B27","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1038\/s41591-022-02115-4","article-title":"Molecular residual disease and efficacy of adjuvant chemotherapy in patients with colorectal cancer","volume":"29","author":"Kotani","year":"2023","journal-title":"Nat Med"},{"key":"B28","doi-asserted-by":"publisher","first-page":"3272","DOI":"10.1038\/s41591-024-03254-6","article-title":"ctDNA-based molecular residual disease and survival in resectable colorectal cancer","volume":"30","author":"Nakamura","year":"2024","journal-title":"Nat Med"},{"key":"B29","doi-asserted-by":"publisher","first-page":"5586","DOI":"10.1158\/1078-0432.CCR-21-0410","article-title":"Minimal residual disease detection using a plasma-only circulating tumor DNA assay in patients with colorectal cancer","volume":"27","author":"Parikh","year":"2021","journal-title":"Clin Cancer Res"},{"key":"B30","doi-asserted-by":"publisher","first-page":"3459","DOI":"10.1158\/1078-0432.CCR-24-0226","article-title":"Tissue-free liquid biopsies combining genomic and methylation signals for minimal residual disease detection in patients with early colorectal cancer from the UK TRACC part B study","volume":"30","author":"Slater","year":"2024","journal-title":"Clin Cancer Res"},{"key":"B31","doi-asserted-by":"publisher","first-page":"328","DOI":"10.1158\/1078-0432.CCR-24-2396","article-title":"A tumor-na\u00efve ctDNA assay detects minimal residual disease in resected stage II or III colorectal cancer and predicts recurrence: subset analysis from the GALAXY study in CIRCULATE-Japan","volume":"31","author":"Nakamura","year":"2025","journal-title":"Clin Cancer Res"},{"key":"B32","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1038\/s41586-023-05776-4","article-title":"Tracking early lung cancer metastatic dissemination in TRACERx using ctDNA","volume":"616","author":"Abbosh","year":"2023","journal-title":"Nature"},{"key":"B33","doi-asserted-by":"publisher","first-page":"708","DOI":"10.1002\/cncr.33985","article-title":"Perioperative circulating tumor DNA as a potential prognostic marker for operable stage I to IIIA non-small cell lung cancer","volume":"128","author":"Li","year":"2022","journal-title":"Cancer"},{"key":"B34","doi-asserted-by":"publisher","first-page":"3308","DOI":"10.1158\/1078-0432.CCR-21-3044","article-title":"Perioperative ctDNA-based molecular residual disease detection for non-small cell lung cancer: a prospective multicenter cohort study (LUNGCA-1)","volume":"28","author":"Xia","year":"2022","journal-title":"Clin Cancer Res"},{"key":"B35","doi-asserted-by":"publisher","first-page":"500","DOI":"10.1016\/j.annonc.2022.02.007","article-title":"Residual ctDNA after treatment predicts early relapse in patients with early-stage non-small cell lung cancer","volume":"33","author":"Gale","year":"2022","journal-title":"Ann Oncol"},{"key":"B36","doi-asserted-by":"publisher","first-page":"263","DOI":"10.21037\/tlcr-22-106","article-title":"Circulating tumor DNA predicts neoadjuvant immunotherapy efficacy and recurrence-free survival in surgical non-small cell lung cancer patients","volume":"11","author":"Yue","year":"2022","journal-title":"Transl Lung Cancer Res"},{"key":"B37","doi-asserted-by":"publisher","first-page":"432","DOI":"10.1038\/s41586-021-03642-9","article-title":"ctDNA guiding adjuvant immunotherapy in urothelial carcinoma","volume":"595","author":"Powles","year":"2021","journal-title":"Nature"},{"key":"B38","doi-asserted-by":"publisher","first-page":"e005854","DOI":"10.1136\/jitc-2022-005854","article-title":"Changes in circulating tumor DNA and outcomes in solid tumors treated with immune checkpoint inhibitors: a systematic review","volume":"11","author":"Al-Showbaki","year":"2023","journal-title":"J Immunother Cancer"},{"key":"B39","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1038\/s41416-023-02285-z","article-title":"NK Cell activity and methylated HOXA9 ctDNA as prognostic biomarkers in patients with non-small cell lung cancer treated with PD-1\/PD-L1 inhibitors","volume":"129","author":"Wen","year":"2023","journal-title":"Br J Cancer"},{"key":"B40","doi-asserted-by":"publisher","first-page":"103978","DOI":"10.1016\/j.esmoop.2024.103978","article-title":"Bespoke ctDNA for longitudinal detection of molecular residual disease in high-risk melanoma patients","volume":"9","author":"Genta","year":"2024","journal-title":"ESMO Open"},{"key":"B41","doi-asserted-by":"publisher","first-page":"895","DOI":"10.1158\/1078-0432.CCR-23-2326","article-title":"Comparison of circulating tumor DNA assays for molecular residual disease detection in early-stage triple-negative breast cancer","volume":"30","author":"Coakley","year":"2024","journal-title":"Clin Cancer Res"},{"key":"B42","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1007\/s10549-024-07508-2","article-title":"Longitudinal monitoring of circulating tumor DNA to detect relapse early and predict outcome in early breast cancer","volume":"209","author":"Garcia-Murillas","year":"2025","journal-title":"Breast Cancer Res Treat"},{"key":"B43","doi-asserted-by":"publisher","first-page":"2173","DOI":"10.1158\/1078-0432.CCR-24-3145","article-title":"Detection of circulating tumor DNA using a tissue-free epigenomic assay is a highly prognostic biomarker in early-stage triple-negative breast cancer","volume":"31","author":"Ademuyiwa","year":"2025","journal-title":"Clin Cancer Res"}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2026.1942673\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T08:34:42Z","timestamp":1788942882000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2026.1942673\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,9]]},"references-count":43,"alternative-id":["10.3389\/fmed.2026.1942673"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2026.1942673","relation":{},"ISSN":["2296-858X"],"issn-type":[{"value":"2296-858X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,9]]},"article-number":"1942673"}}