The LXRβ/NF-κB Axis Reprograms CAR-T Cells to Resist Exhaustion in the Tumor Microenvironment

Liver X Receptor β (LXRβ) is a pivotal transcription factor regulating lipid metabolism and immune cell function. Although LXRβ has been implicated in T cell homeostasis, its role within the tumor microenvironment (TME) remains poorly understood. Notably, LXRβ can inhibit NF-κB target gene expression, yet the functional interplay between LXRβ and NF-κB signaling in tumor-infiltrating CD8⁺ T cells has not been fully elucidated. Here, we demonstrate that LXRβ modulates the differentiation and functional state of CAR-T cells within the TME. LXRβ overexpression reshaped the phenotypic landscape of CAR-T cells, including altered expression of the progenitor marker TCF1, proliferation marker Ki-67, and effector cytokines IFNγ and TNFα. Furthermore, perturbation of NF-κB signaling, particularly through RelB deletion, enhanced CAR-T cell cytotoxicity and mitigated exhaustion-associated features such as TOX expression. Combined modulation of LXRβ and RelB synergistically improved the functional fitness of CAR-T cells and their anti-tumor efficacy in vivo. These findings reveal a critical regulatory axis between LXRβ and NF-κB that governs CAR-T cell exhaustion and effector function in solid tumors. Targeting this pathway may provide a novel strategy to enhance CAR-T cell–based immunotherapies.