NET-Associated Transcriptional Signatures and T-Cell Functional States During Allogeneic CAR-γδT-Cell Therapy: A Longitudinal Single-Cell Analysis

Background

CAR T-cell therapy has transformed the treatment of hematologic malignancies, although conventional autologous αβ CAR-T products remain limited by complex manufacturing, variable persistence, and relapse risk. γδT cells provide a promising donor source for next-generation off-the-shelf CAR-T therapies due to their MHC-independent tumor recognition, potent cytotoxicity, and minimal risk of graft-versus-host disease; however, the determinants of treatment durability following allogeneic CAR–γδT-cell therapy remain poorly defined. NETs have recently emerged as key immunoregulatory components of the TME, where excessive NET formation sustains inflammation, reshapes immune–stromal interactions, and impairs lymphocyte function, yet their impact on CAR-T-cell fate is largely unknown.