AbstractThe heterogeneous nature of tumour microenvironment (TME) underlying diverse treatment responses remains unclear in nasopharyngeal carcinoma (NPC). Here, we profile 176,447 cells from 10 NPC tumour-blood pairs, using single-cell transcriptome coupled with T cell receptor sequencing. Our analyses reveal 53 cell subtypes, including tumour-infiltrating CD8+T, regulatory T (Treg), and dendritic cells (DCs), as well as malignant cells with different Epstein-Barr virus infection status. Trajectory analyses reveal exhausted CD8+T and immune-suppressive TNFRSF4+Treg cells in tumours might derive from peripheral CX3CR1+CD8+T and naïve Treg cells, respectively. Moreover, we identify immune-regulatory and tolerogenic LAMP3+DCs. Noteworthily, we observe intensive inter-cell interactions among LAMP3+DCs, Treg, exhausted CD8+T, and malignant cells, suggesting potential cross-talks to foster an immune-suppressive niche for the TME. Collectively, our study uncovers the heterogeneity and interacting molecules of the TME in NPC at single-cell resolution, which provide insights into the mechanisms underlying NPC progression and the development of precise therapies for NPC.