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22 reviewsSUMMARYTo identify nasopharyngeal carcinoma (NPC)-relevant T cell receptors (TCRs), we profile the repertoires ofperipheral blood TCRβ chains from 228 NPC patients, 241 at-risk controls positive for serum Epstein-Barr virus (EBV) VCA-IgA antibody, and 251 seronegative controls. We develop a TCR-based signature (T-score)based on 208 NPC-enriched CDR3β sequences, which accurately diagnoses NPC in both the original andindependent validation cohorts. Notably, a higher T-score, associated with a shorter time interval to NPCdiagnosis, effectively identifies early-stage NPC among EBV-seropositive at-risk individuals prior to clinicaldiagnosis. These NPC-enriched TCRs react against not only EBV-specific antigens but also non-EBV antigens expressed by NPC cells, indicating a broad range of specificities. Moreover, the abundance of NPC-enriched CD8+ T cells in blood correlates with the infiltration of non-exhausted T cell counterparts in tumors andpredicts prolonged survival, suggesting that these NPC-enriched T cells have significant potential for diseasemonitoring and therapeutic applications.