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Current methods require targeted labels, extensive processing, and provide only static snapshots of cell identity and activation. Here, we introduce a surface-enhanced Raman spectroscopy (SERS) and machine learning (ML) approach that enables single-cell identification of engineered CAR T cells without molecularly-targeted labels and time-resolved, semi-continuous monitoring of their functional activation state through a single physical readout spanning donor-derived cells and patient blood. From intrinsic vibrational signatures of live cells, we detect spectral differences resulting from engineered receptor expression in donor-derived CD19- and GD2-targeted CAR T cells (nine and five donors, respectively) with 81-85% donor-level accuracy, and resolve dynamic antigen-specific activation trajectories with temporal precision. Applying this same SERS-ML method to longitudinal samples from a four-patient CD19-CAR T therapy cohort, we classify patient peripheral blood mononuclear cells across pre-and post-infusion timepoints with a mean patient-level accuracy of 84%, and show that isolated CAR-positive T cells are distinguishable from both CAR-negative T cells and background populations with average 86-88% accuracies. These capabilities stem from biochemical signatures consistent with processes such as receptor expression, tonic signalling, and immune synapse formation, demonstrating a single method that reports both cellular identity and activation state with biochemical specificity across cell engineering and clinical monitoring contexts. Our results extend CAR T cell monitoring beyond static phenotyping and support the potential of SERS-ML analysis for rapid, point-of-care assessment of engineered immune cells across the therapeutic lifecycle.<\/jats:p>","DOI":"10.64898\/2026.02.22.707331","type":"posted-content","created":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T05:30:12Z","timestamp":1771911012000},"source":"Crossref","is-referenced-by-count":0,"title":["Dynamic, single-cell monitoring of CAR T cell identity and activation with Raman spectroscopy"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8694-1930","authenticated-orcid":false,"given":"Ariel","family":"Stiber","sequence":"first","affiliation":[{"name":"Department of Materials Science and Engineering, Stanford University, Stanford, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boi","family":"Quach","sequence":"additional","affiliation":[{"name":"Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA"},{"name":"Division of Computational Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA"},{"name":"Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University, Stanford, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Babatunde","family":"Ogunlade","sequence":"additional","affiliation":[{"name":"Department of Materials Science and Engineering, Stanford University, Stanford, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antony","family":"Georgiadis","sequence":"additional","affiliation":[{"name":"Department of Materials Science and Engineering, Stanford University, Stanford, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Electrical Engineering, Stanford University, Stanford, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanwei","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Materials Science and Engineering, Stanford University, Stanford, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Quinn","sequence":"additional","affiliation":[{"name":"Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University, Stanford, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoqing","family":"Wang","sequence":"additional","affiliation":[{"name":"Stanford Cryo-EM Microscopy Center, Stanford University, Stanford, California, USA"},{"name":"Cryoelectron Microscopy, Nucleus at Sarafan ChEM-H, Stanford University, Stanford, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristin C. Y.","family":"Tsui","sequence":"additional","affiliation":[{"name":"Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA"},{"name":"Division of Computational Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA"},{"name":"Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University, Stanford, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charm","family":"Ang","sequence":"additional","affiliation":[{"name":"Department of Materials Science and Engineering, Stanford University, Stanford, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Sotillo","sequence":"additional","affiliation":[{"name":"Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University, Stanford, California, USA"},{"name":"Weill Cancer Hub West, Stanford University, Stanford, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David B.","family":"Miklos","sequence":"additional","affiliation":[{"name":"Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University, Stanford, California, USA"},{"name":"Division of Blood and Marrow Transplantation and Cellular Therapy, Department of Medicine, Stanford University, Stanford, California, USA"},{"name":"Weill Cancer Hub West, Stanford University, Stanford, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Crystal","family":"Mackall","sequence":"additional","affiliation":[{"name":"Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University, Stanford, California, USA"},{"name":"Division of Hematology and Oncology, Department of Pediatrics, Stanford University, Stanford, CA, USA"},{"name":"Division of Blood and Marrow Transplantation and Cellular Therapy, Department of Medicine, Stanford University, Stanford, California, USA"},{"name":"Parker Institute for Cancer Immunotherapy, Stanford University, Stanford, California, US"},{"name":"Weill Cancer Hub West, Stanford University, Stanford, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zinaida","family":"Good","sequence":"additional","affiliation":[{"name":"Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA"},{"name":"Division of Computational Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA"},{"name":"Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University, Stanford, California, USA"},{"name":"Parker Institute for Cancer Immunotherapy, Stanford University, Stanford, California, US"},{"name":"Weill Cancer Hub West, Stanford University, Stanford, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer A.","family":"Dionne","sequence":"additional","affiliation":[{"name":"Department of Materials Science and Engineering, Stanford University, Stanford, California, USA"},{"name":"Department of Radiology, Stanford University School of Medicine, Stanford, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026072217151881000_2026.02.22.707331v2.1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-05707-3"},{"key":"2026072217151881000_2026.02.22.707331v2.2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2116133"},{"key":"2026072217151881000_2026.02.22.707331v2.3","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0006-x"},{"key":"2026072217151881000_2026.02.22.707331v2.4","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1215134"},{"key":"2026072217151881000_2026.02.22.707331v2.5","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(18)30864-7"},{"key":"2026072217151881000_2026.02.22.707331v2.6","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-023-00615-w"},{"key":"2026072217151881000_2026.02.22.707331v2.7","doi-asserted-by":"crossref","first-page":"1770","DOI":"10.3389\/fimmu.2020.01770","article-title":"The chimeric antigen receptor detection toolkit","volume":"11","year":"2020","journal-title":"Front. 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