LXRβ/NF-κB 轴重编程 CAR-T 细胞以抵抗肿瘤微环境中的耗竭

Liver X receptor (LXR ) 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 LXR has been shown to suppress NF- B target gene expression, the mechanistic interaction between LXR and NF- B signaling in the tumor microenvironment (TME) has not been fully established. In this study, we identify LXR as a critical regulator of CAR-T cell differentiation, the metabolic state, and effector function within solid tumors.

LXR 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 (IFN , TNF ). Through genetic perturbation of NF- B components, particularly RelB, we further demonstrate that disrupting non-canonical NF- B signaling enhances CAR-T cell cytotoxicity and attenuates exhaustion-related features such as TOX upregulation.

Notably, combined targeting of LXR 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 LXR -NF- B 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.