Extranodal NK/T-cell lymphoma: an update of the molecular characterization of the tumor and microenvironment, and its clinical implications

Extranodal NK/T-cell lymphoma (ENKTL) is an aggressive lymphoma associated with Epstein-Barr virus which does not respond to conventional anthracycline-based chemotherapy. Recent multi-omics studies have identified genetic and epigenetic alterations involved in the tumor pathogenesis and enabled the characterisation of distinct molecular subtypes with therapeutic and prognostic implications. Similarly, genomic and transcriptomic studies have shed new light on the tumor microenvironment (TME) and potential interactions with the EBV-infected malignant cells, as well as their potential influence on tumor development and progression. This review provides an update on the key genetic alterations and analysis of the recurrent mutations of ENKTL, the role of EBV, epigenetic modifications and emerging molecular classifications of both the tumor and the TME. We also explore the prognostic and therapeutic applications of these new insights, and how they are beginning to reshape the current understanding and future clinical management of this difficult-to-treat disease.