{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T06:05:43Z","timestamp":1792130743341,"version":"4.4.0"},"posted":{"date-parts":[[2026,7,16]]},"group-title":"Bioengineering","reference-count":65,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T00:00:00Z","timestamp":1784160000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,28]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Clinical studies of chimeric antigen receptor (CAR)-T therapy generate diverse molecular and clinical evidence that remains fragmented across publications, public repositories and patient-derived datasets, limiting systematic therapeutic discovery. Here we present BioPathfinder, an evidence-guided multi-agent workflow for closed-loop biomedical discovery. BioPathfinder constructs a provenance-aware knowledge resource linking publications with patient single-cell RNA sequencing (scRNA-seq) datasets and clinical metadata, and uses role-specialized large language model agents to generate, review and prioritize diverse, falsifiable and dataset-aware mechanistic hypotheses for computational and experimental validation. Applied to a curated corpus of CAR-T-treated patient studies and matched scRNA-seq datasets, BioPathfinder identified candidate mechanisms underlying CAR-T persistence, dysfunction and therapeutic resistance. The workflow prioritized the hypothesis that genes associated with an NK-like transition programme could be targeted to reduce CAR-T exhaustion and improve persistence. Analysis of patient scRNA-seq datasets showed enrichment of this programme in exhausted post-infusion CAR-T cells. Virtual perturbation prioritized transition-associated receptor genes, including\n                  <jats:italic>KLRC1<\/jats:italic>\n                  ,\n                  <jats:italic>KLRD1<\/jats:italic>\n                  and\n                  <jats:italic>KLRG1<\/jats:italic>\n                  , and expert review selected\n                  <jats:italic>KLRC1<\/jats:italic>\n                  , encoding NKG2A, for experimental validation.\n                  <jats:italic>In vitro<\/jats:italic>\n                  and\n                  <jats:italic>in vivo<\/jats:italic>\n                  chronic-stimulation models showed that NKG2A marked activated, exhaustion-associated CD8\u207a CAR-T cells, whereas NKG2A blockade enhanced antitumour activity and persistence-associated functional readouts\n                  <jats:italic>in vivo<\/jats:italic>\n                  . BioPathfinder establishes a generalizable framework that transforms fragmented clinical single-cell evidence into experimentally validated therapeutic hypotheses, providing a scalable strategy for AI-guided biomedical discovery.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>HIGHLIGHTS<\/jats:title>\n                  <jats:list list-type=\"order\">\n                    <jats:list-item>\n                      <jats:p>BioPathfinder integrates fragmented CAR-T clinical studies, patient scRNA-seq datasets and metadata into a provenance-aware evidence resource for AI-guided hypothesis discovery.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>A multi-agent workflow generates, critiques and prioritizes diverse, falsifiable, dataset-aware mechanisms underlying CAR-T persistence, dysfunction and therapeutic resistance.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>BioPathfinder prioritizes KLRC1\/NKG2A as a therapeutic target, and experimental validation demonstrates that NKG2A blockade enhances CAR-T persistence and antitumour function.<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.64898\/2026.07.15.738646","type":"posted-content","created":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T13:55:14Z","timestamp":1784210114000},"source":"Crossref","is-referenced-by-count":2,"title":["BioPathfinder: Evidence-guided multi-agent platform enables hypothesis discovery for CAR-T engineering"],"prefix":"10.64898","author":[{"given":"Shubing","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA 90095, 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USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhoulin","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yichen","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoyan","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA 90095, USA"},{"name":"Biomedical Imaging 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