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This study develops a circularly polarized surface-enhanced shifted-excitation Raman difference spectroscopy (SE-SERDS) system for label-free analysis of circulating cell-free DNA (cfDNA). Spectra were acquired from 90 recurrent and 90 non-recurrent NPC patients under non-polarized (NP), left-handed circularly polarized (LHCP), and right-handed circularly polarized (RHCP) excitations, alongside a fused LHCP + RHCP dataset. While the combination of circular polarization and surface-enhanced Raman scattering (SERS) uncovers hidden chiroptical signatures of cfDNA, the instrumentation-based SERDS method effectively eliminates residual fluorescence. In contrast to traditional polynomial-fitting (PF) methods, this hardware-driven approach replaces subjective algorithmic assumptions with physical wavelength modulation, improving apparent spectral resolution and enabling the extraction of subtle prognostic features at 1074 and 1147 cm\u20131 with a higher signal-to-background contrast. Furthermore, circularly polarized excitation yields more statistically significant spectral differences between groups than NP excitation, with fused LHCP + RHCP spectra providing higher discriminability by capturing complementary conformational information of the cfDNA double helix than standalone polarization data. Using 5-fold cross-validated linear discriminant analysis, SE-SERDS consistently outperformed PF-SERS across all excitation modes, with prediction accuracies rising from 71.1 vs 66.7% (NP) to a maximum of 93.9 vs 87.8% (LHCP + RHCP). Integration with a support vector machine (SVM) further enhanced the accuracy to 95.6%. These results indicate that the fused dual-polarization SE-SERDS strategy provides a powerful tool for pretreatment NPC recurrence prediction to support clinical intervention.<\/jats:p>","DOI":"10.1021\/acssensors.6c02119","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T13:13:43Z","timestamp":1785849223000},"page":"7531-7546","source":"Crossref","is-referenced-by-count":0,"title":["Circularly Polarized SE-SERDS of Circulating cfDNA for Pretreatment Prediction of Nasopharyngeal Carcinoma Recurrence"],"prefix":"10.1021","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8228-3339","authenticated-orcid":true,"given":"Jinyong","family":"Lin","sequence":"first","affiliation":[{"name":"Fujian Cancer Hospital , , ,","place":["Fuzhou, China, 350014"]},{"name":"NHC Key Laboratory of Cancer and Metabolism (Fujian Cancer Hospital) , ,","place":["Fuzhou, China, 350014"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingna","family":"Wang","sequence":"additional","affiliation":[{"name":"Fujian Normal University , , ,","place":["Fuzhou, China, 350007"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuduo","family":"Wu","sequence":"additional","affiliation":[{"name":"University at Buffalo , , ,","place":["Buffalo, New York, United States, 14260"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueliang","family":"Lin","sequence":"additional","affiliation":[{"name":"Quanzhou Normal University , , ,","place":["Quanzhou, China, 362000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-0524-1951","authenticated-orcid":true,"given":"Weilin","family":"Wu","sequence":"additional","affiliation":[{"name":"Fujian Normal University , , ,","place":["Fuzhou, China, 350007"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanji","family":"Xu","sequence":"additional","affiliation":[{"name":"Fujian Cancer Hospital , , ,","place":["Fuzhou, China, 350014"]},{"name":"NHC Key Laboratory of Cancer and Metabolism (Fujian Cancer Hospital) , ,","place":["Fuzhou, China, 350014"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaobin","family":"Huang","sequence":"additional","affiliation":[{"name":"Fujian Cancer Hospital , , ,","place":["Fuzhou, China, 350014"]},{"name":"NHC Key Laboratory of Cancer and Metabolism (Fujian Cancer Hospital) , ,","place":["Fuzhou, China, 350014"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Lin","sequence":"additional","affiliation":[{"name":"Fujian Cancer Hospital , , ,","place":["Fuzhou, China, 350014"]},{"name":"NHC Key Laboratory of Cancer and Metabolism (Fujian Cancer Hospital) , ,","place":["Fuzhou, China, 350014"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junxin","family":"Wu","sequence":"additional","affiliation":[{"name":"Fujian Cancer Hospital , , ,","place":["Fuzhou, China, 350014"]},{"name":"NHC Key Laboratory of Cancer and Metabolism (Fujian Cancer Hospital) , ,","place":["Fuzhou, China, 350014"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shangyuan","family":"Feng","sequence":"additional","affiliation":[{"name":"Quanzhou Normal University , , ,","place":["Quanzhou, China, 362000"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,28]]},"reference":[{"key":"2026090201430224100_cit1","doi-asserted-by":"publisher","first-page":"1423","DOI":"10.1016\/j.ccell.2025.04.009","article-title":"Immunosequencing identifies signatures of T cell responses for early detection of nasopharyngeal carcinoma","author":"Zhang","year":"2025","journal-title":"Cancer Cell"},{"key":"2026090201430224100_cit2","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2021.693199","article-title":"Failure patterns of recurrence and metastasis after intensity-modulated radiotherapy in patients with nasopharyngeal carcinoma: results of a multicentric clinical study","volume":"11","author":"Chen","year":"2022","journal-title":"Front. 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