You Rui, Shen Qunlun, Lin Chao, Dong Kangning, Liu Xiao, Xu Hanshi, Hu Wanming, Xie Yulong, Xie Ruoqi, Song Xiaoyi, Huang Chunliu, Wu Jinhui, Yu Tao, Li Huifeng, Wang Zining, Chen Keming, Zou Xiong, Huang Peiyu, Hua Yijun, Liu Youping, Xia Tianliang, Zhang Shihua, Chen Mingyuan
Nasopharyngeal Cancer Center, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, The People's Republic of China.
Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, The People's Republic of China.
Nat Genet. 2025 Jul 21. doi: 10.1038/s41588-025-02253-8.
Radiotherapy resistance and immune evasion are prominent features of recurrent nasopharyngeal carcinoma (rNPC). However, their mechanisms remain incompletely understood. Here, we conducted single-cell and spatial transcriptomics analysis of 39 tumors from 24 patients to reveal the microenvironmental differences between primary and rNPC. Specific MCAM cancer-associated fibroblasts are significantly enriched in rNPC, where they promote tumor radioresistance through the collagen IV-ITGA2-FAK-AKT axis. Furthermore, we found that collagen IV suppresses the infiltration of T cells, and we identified mechanisms of immune escape in rNPC. We uncovered the presence and function of CD8 ZNF683 cells in rNPC with lower cytotoxicity. The abundance of B cells and tertiary lymphoid structures significantly diminishes in rNPC. Finally, we confirmed that CD47-SIRPα commonly existed between myeloid and malignant cells in rNPC. This study provides an in-depth understanding of the mechanism of radioresistance and immune evasion in rNPC as well as highlighting critical preliminary targets for curing rNPC.
放射治疗抵抗和免疫逃逸是复发性鼻咽癌（rNPC）的突出特征。然而，它们的机制仍未完全明确。在此，我们对24例患者的39个肿瘤进行了单细胞和空间转录组学分析，以揭示原发性和复发性鼻咽癌之间的微环境差异。特定的MCAM癌症相关成纤维细胞在复发性鼻咽癌中显著富集，它们通过IV型胶原-整合素α2-黏着斑激酶-蛋白激酶B轴促进肿瘤的放射抗性。此外，我们发现IV型胶原抑制T细胞浸润，并确定了复发性鼻咽癌的免疫逃逸机制。我们发现细胞毒性较低的复发性鼻咽癌中存在CD8 ZNF683细胞并明确了其功能。复发性鼻咽癌中B细胞和三级淋巴结构的丰度显著降低。最后，我们证实CD47-信号调节蛋白α在复发性鼻咽癌的髓系细胞和恶性细胞之间普遍存在。本研究深入了解了复发性鼻咽癌的放射抗性和免疫逃逸机制，并突出了治愈复发性鼻咽癌的关键初步靶点。
