Nasopharyngeal carcinoma (NPC) is an aggressive malignancy with extremely skewed ethnic and geographic distributions. Increasing evidence indicates that targeting the tumor microenvironment (TME) represents a promising therapeutic approach in NPC, highlighting an urgent need to deepen the understanding of the complex NPC TME. Here, we generated single-cell transcriptome profiles for 7581 malignant cells and 40,285 immune cells from fifteen primary NPC tumors and one normal sample. We revealed malignant signatures capturing intratumoral transcriptional heterogeneity and predicting aggressiveness of malignant cells. Diverse immune cell subtypes were identified, including novel subtypes such as CLEC9A⁺ dendritic cells (DCs). We further revealed transcriptional regulators underlying immune cell diversity, and cell–cell interaction analyses highlighted promising immunotherapeutic targets in NPC. Moreover, we established the immune subtype-specific signatures, and demonstrated that the signatures of macrophages, plasmacytoid dendritic cells (pDCs), CLEC9A⁺ DCs, natural killer (NK) cells, and plasma cells were significantly associated with improved survival outcomes in NPC. Taken together, our findings represent a unique resource providing in-depth insights into the cellular heterogeneity of NPC TME and highlight potential biomarkers for anticancer treatment and risk stratification, laying a new foundation for precision therapies in NPC.

鼻咽癌 (NPC) 是一种侵袭性恶性肿瘤，种族和地理分布极为倾斜。越来越多的证据表明，靶向肿瘤微环境 (TME) 代表了一种有前途的 NPC 治疗方法，突出了加深对复杂 NPC TME 的理解的迫切需要。在这里，我们从 15 个原发性 NPC 肿瘤和 1 个正常样本中生成了 7581 个恶性细胞和 40,285 个免疫细胞的单细胞转录组谱。我们揭示了捕捉肿瘤内转录异质性和预测恶性细胞侵袭性的恶性特征。鉴定了多种免疫细胞亚型，包括新的亚型，例如CLEC9A ⁺树突状细胞 (DC)。我们进一步揭示了免疫细胞多样性背后的转录调节因子，细胞间相互作用分析突出了 NPC 中有希望的免疫治疗靶点。此外，我们建立了免疫亚型特异性特征，并证明巨噬细胞、浆细胞样树突状细胞 (pDC)、CLEC9A ⁺ DC、自然杀伤 (NK) 细胞和浆细胞的特征与改善的 NPC 生存结果显着相关。总之，我们的研究结果代表了一种独特的资源，可以深入了解 NPC TME 的细胞异质性，并突出潜在的抗癌治疗和风险分层的生物标志物，为 NPC 的精准治疗奠定新的基础。