Wnt signaling as a regulator of memory T cells: implications for CAR-T cell therapy

Chimeric antigen receptor T-cell (CAR-T) therapy has achieved impressive remission rates in hematologic cancers, but long-term efficacy remains limited by insufficient CAR-T cell persistence. T cell factor 1 (TCF1) and lymphoid enhancer binding factor 1 (LEF1), transcription factors well known for their role in downstream Wnt/β-catenin signaling, have been found to regulate transcriptional and epigenetic memory programming important for CAR-T cell persistence and favorable patient outcomes. Activation of the Wnt/β-catenin in endogenous T cells was found to arrest effector differentiation and promote the formation of cluster of differentiation (CD) 8+ memory stem cells, characterized by strong proliferative and recall potential, key traits of persisting memory cells. Genetically engineered CAR-T cells are subject to the same transcriptional and epigenetic factors that govern memory development in endogenous T cells, providing a strong rationale for applying scientific findings from basic T cell biology to CAR-T cell engineering. With this in mind, recent studies have shown that there is clinical potential for Wnt-directed approaches to improve CAR-T cell memory phenotypes, persistence, and exhaustion. Here we review the role of Wnt/β-catenin signaling in T cell development and memory formation, examine clinical evidence linking Wnt/TCF1 activity to CAR-T cell persistence and patient outcomes, and discuss emerging genetic, epigenetic, and pharmacological strategies used to target this pathway in CAR-T cell manufacturing.