The LXRβ/NF-κB axis reprograms CAR-T cells to resist exhaustion in the tumor microenvironment.

Liver X receptor β (LXRβ) is a key transcription factor involved in lipid metabolism and immune regulation, yet its functional role in tumor-infiltrating T cells remains largely unresolved. While LXRβ has been shown to suppress NF-κB target gene expression, the mechanistic interaction between LXRβ and NF-κB signaling in the tumor microenvironment (TME) has not been fully established. In this study, we identify LXRβ as a critical regulator of CAR-T cell differentiation, the metabolic state, and effector function within solid tumors. LXRβ overexpression altered the transcriptional and phenotypic landscape of CAR-T cells, including the modulation of stem-like TCF1⁺ populations, proliferative capacity (Ki-67), and cytokine production (IFNγ, TNFα). Through genetic perturbation of NF-κB components, particularly RelB, we further demonstrate that disrupting non-canonical NF-κB signaling enhances CAR-T cell cytotoxicity and attenuates exhaustion-related features such as TOX upregulation. Notably, combined targeting of LXRβ and RelB produced additive and, in some settings, synergistic benefits, improving metabolic fitness, reducing terminal exhaustion, and augmenting anti-tumor activity in vivo. Together, these findings define an LXRβ-NF-κB regulatory axis that shapes CAR-T cell fate and function in the TME and highlight this pathway as a promising target for improving CAR-T cell-based therapies against solid tumors.