Single-cell profiling of natural killer/T-cell lymphoma reveals stratified immune features and potential therapeutic implications

作者：Yi Cao, Jun Cai, Danling Dai, Jinni Wang, Yuchen Zhang, Jie Xiong, Huiqiang Huang, Yan Gao, Yi Xia, Fang Liu, Xinna Gao, Shenrui Bai, Qihua Zou, Jiahui Wang, Shuyun Ma, Junfeng Jiang, Weili Zhao, Wenlong Zhong, Qingqing Cai · 发表于：Nature Communications · 年份：2026 · DOI：10.1038/s41467-026-76152-9 · 研究领域：Lymphoma Diagnosis and Treatment、Immune Cell Function and Interaction、CAR-T cell therapy research

Tumor cell heterogeneity and interactions with the immune microenvironment play a key role in the progression and therapeutic efficacy of natural killer/T-cell lymphoma (NKTCL). We perform single-cell RNA sequencing analysis of 63 samples, integrating spatial transcriptomics, bulk transcriptomics, proteomics, and metabolomics to dissect inter- and intra-tumoral heterogeneity. Four meta-programs (MP) are identified, including MP1 (immune-responsive), MP2 (proliferative), MP3 (inflammatory), and MP4 (metabolic), each linked to distinct molecular and immune features. MP1 exhibits an immune-exhausted tumor microenvironment and high programmed death-ligand 1 expression, suggesting a potential response to immune checkpoint blockade. MP2 shows an immune-desert phenotype with elevated HDAC2 and MKI67 expression, indicating epigenetic regulation in tumor proliferation. MP3 is characterized by a myeloid-dominant tumor microenvironment, JAK/STAT pathway activation, and an aggressive clinical course. MP4 exhibits a distinct amino acid metabolic profile and enriched tertiary lymphoid structures. Collectively, our study provides a high-resolution molecular atlas of NKTCL heterogeneity, offering insights into patient stratification and potential avenues for future therapeutic development. Tumor cell heterogeneity and interactions with the immune microenvironment play a key role in natural killer/T-cell lymphoma (NKTCL). Here, the authors characterize 63 NKTCL samples using single-cell, spat...