Abstract Angioimmunoblastic T‐cell lymphoma (AITL) exemplifies a neoplasm characterized by prominent inflammatory infiltration and robust immune responses in the tumor microenvironment (TME). The pathophysiology of refractory/recurrent (RR) AITL remains poorly understood due to profound intratumoral heterogeneity and complex TME features, contributing to limited therapeutic efficacy. Using Xenium‐based spatial transcriptomics on 10 clinical samples, we compared RR AITL with treatment‐responsive non‐refractory/recurrent event in 3 years (NR) cases to map the TME architecture. We identified a novel cluster of NEIL3 + (Nei Like DNA Glycosylase 3) T‐follicular helper (Tfh) cells, which exhibited stem‐like characteristics at the transcriptional level, featuring self‐renewal and multilineage differentiation capacity, and were highly enriched in RR tumors. Furthermore, we found major differences in immune cell organization between NR and RR microenvironments: RR cases were dominated by B cells primed for adaptive immunity and myeloid cells driving angiogenesis, whereas NR cases exhibited a chemokine‐mediated regulatory landscape. These findings provide comprehensive characterization of the TME ecosystem in AITL and reveal potential therapeutic targets for high‐risk RR AITL patients. © 2026 The Pathological Society of Great Britain and Ireland.
DONG et al. (Thu,) studied this question.