Single-cell and spatial transcriptomics reveal mechanisms of radioresistance and immune escape in recurrent nasopharyngeal carcinoma.

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-SIRPalpha 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.