Tumor immune microenvironment delineates progression trajectories of distinct nasopharyngeal carcinoma phenotypes.

We investigate the molecular landscape of locally advanced nasopharyngeal carcinoma (LA-NPC) subtypes: limited (L), ascending (A), descending (D), and ascending-descending (AD). Using a cohort of 994 patients, we perform germline and somatic whole-exome sequencing (WES), transcriptomic profiling, multiplex immunohistochemistry (mIHC), and spatial histopathological analyses of tumor whole-slide images (WSIs). Germline WES reveals the most variants in AD subtypes, but somatic WES shows no subtype-specific mutations. Transcriptomics reveals higher extracellular matrix (ECM) gene expression in A and AD subtypes and higher immune gene expression in D and AD subtypes, agreeing with deconvolution and mIHC. Tumor immune microenvironment (TIME) of node-negative (N0) and node-positive (N+) L subtypes, considered early nasopharyngeal carcinoma (NPC), resembles A and D subtypes, respectively, suggesting distinct evolutionary trajectories. Spatial WSI analyses identify the most immune-dense tumors among D subtypes and association of TIME with disease-free survival in AD subtypes. These findings highlight the TIME's role in LA-NPC progression and its potential impact on treatment strategies.