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This review charts the evolution of LTBI diagnosis from the tuberculin skin test (TST) and interferon-gamma release assays (IGRAs) to a new molecular\u2013intelligent paradigm. At the clinical level, we propose a CD4\/age-stratified, resource-matched decision framework that delivers actionable screening and sequencing strategies for people living with HIV, children, the immunosuppressed, and pregnant women. At the biomarker level, we integrate host-derived analytes (CXCL1, CCL8, IP-10, CD38\n                    <jats:sup>+<\/jats:sup>\n                    CD27\u207b T cells, and Fc-glycosylated antibodies) with pathogen-derived antigens (dormancy survival regulator [DosR], resuscitation-promoting factor [Rpf], heparin-binding hemagglutinin [HBHA], and PE\/PPE) to create a three-tier index: single-analyte triage, multi-analyte confirmation, and dynamic treatment monitoring. At the technology level, we benchmark multi-omics-plus-AI models, single-molecule Simoa arrays, and microfluidic point-of-care testing (POCT) platforms for sensitivity, accessibility, and cost. High-quality cross-population validation, standardized thresholds, and resource-tiered deployment remain the principal translational bottlenecks. We call for integrated programs that combine key-population multicenter cohorts, explainable AI, and ASSURED criteria to propel LTBI management from the T-cell-sensitization era into the molecular\u2013intelligent age. Achieving this vision within 5 years is technically feasible and will accelerate global elimination targets by enabling precision preventive therapy at an unprecedented scale.\n                  <\/jats:p>","DOI":"10.1128\/cmr.00258-25","type":"journal-article","created":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T13:00:23Z","timestamp":1774875623000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":2,"title":["From T-cell sensitization to molecular\u2013intelligent stratification: a roadmap for precision diagnosis of latent tuberculosis infection"],"prefix":"10.1128","volume":"39","author":[{"given":"Ruizi","family":"Ni","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04gw3ra78","id-type":"ROR","asserted-by":"publisher"}],"name":"Senior Department of Tuberculosis, Chinese PLA General Hospital","place":["Beijing, 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