Single-cell and spatial transcriptomics reveal intratumor heterogeneity and immune evasion in natural killer/T cell lymphoma.

Natural killer/T cell lymphoma (NKTCL), an Epstein-Barr virus-associated malignancy, is a highly aggressive subtype of non-Hodgkin lymphoma. However, the intratumoral heterogeneity and the interaction within the tumor microenvironment (TME) remain insufficiently understood. Here, we utilized single-cell and spatial transcriptomics to analyze tissues from NKTCL patients, identifying five malignant meta-programs (MPs) with distinct functional pathways, differentiation trajectories, and spatial distributions. Notably, the MP3 subgroup emerges at the early stages of tumor differentiation, characterized by the hyperactivation of MYC signaling and an association with poor prognosis. Intriguingly, pharmacologic inhibition of fatty acid-binding protein 5 (FABP5) leads to the downregulation of c-Myc and significantly impairs tumor growth both in vitro and in vivo. Furthermore, ligand-receptor interaction analysis reveals that tumor-associated macrophages (TAMs) may facilitate immune evasion and suppress T cell activity within the TME. Collectively, our findings elucidate the cellular heterogeneity and immune landscape of NKTCL, offering potential targets for therapeutic intervention.