The LXRß/NF-?B Axis Reprograms CAR-T Cells to Resist Exhaustion in the Tumor Microenvironment

Liver X Receptor ß (LXRß) is a pivotal transcription factor regulating lipid metabolism and immune cell function. Although LXRß has been implicated in T cell homeostasis, its role within the tumor microenvironment (TME) remains poorly understood. Notably, LXRß can inhibit NF-?B target gene expression, yet the functional interplay between LXRß and NF-?B signaling in tumor-infiltrating CD8? T cells has not been fully elucidated. Here, we demonstrate that LXRß modulates the differentiation and functional state of CAR-T cells within the TME. LXRß overexpression reshaped the phenotypic landscape of CAR-T cells, including altered expression of the progenitor marker TCF1, proliferation marker Ki-67, and effector cytokines IFN? and TNFa. Furthermore, perturbation of NF-?B signaling, particularly through RelB deletion, enhanced CAR-T cell cytotoxicity and mitigated exhaustion-associated features such as TOX expression. Combined modulation of LXRß 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 LXRß and NF-?B 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. Overall design: RNA-seq profiling was performed on hCD19 CAR-T cells engineered to overexpress LXRß (LbOE) and on control CAR-T cells transduced with an empty vector (pMIG).