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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE299958 | GEO | 2026/01/14

REPOSITORIES: GEO

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Project description:Mesenchymal stem cells (MSCs) are known to induce the conversion of activated T-cells into regulatory T-cells in vitro. The marker CD69 is a target of canonical NF-κB signaling and is transiently expressed upon activation; however, stable CD69 expression defines cells with immunoregulatory properties. Given its enormous therapeutic potential, we explored the molecular mechanisms underlying the induction of regulatory cells by MSCs. Peripheral blood CD3+ T-cells were activated and cultured in the presence or absence of MSCs. CD4+ cell mRNA expression was then characterized by microarray analysis. The drug BAY11-7082 and a siRNA against RELB were used to explore the differential roles of canonical and non-canonical NF-κB signaling, respectively. Flow cytometry and real-time PCR were used for analyses. Genes with immunoregulatory functions, CD69 and non-canonical NF-κB subunits (RELB and NFKB2) were all expressed at higher levels in lymphocytes co-cultured with MSCs. The frequency of CD69+ cells among lymphocytes cultured alone progressively decreased after activation. In contrast, the frequency of CD69+ cells increased significantly following activation in lymphocytes co-cultured with MSCs. Inhibition of canonical NF-κB signaling by BAY immediately following activation blocked the induction of CD69; however, inhibition of canonical NF-κB signaling on the 3rd day further induced the expression of CD69. Furthermore, late expression of CD69 was inhibited by RELB siRNA. These results indicate that the canonical NF-κB pathway controls the early expression of CD69 after activation; however, in an immunoregulatory context, late and sustained CD69 expression is promoted by the non-canonical pathway and is inhibited by canonical NF-κB signaling. In order to study the molecular basis by which Multipotent Mesenchymal Stromal/Stem Cells (MSC) exert their immune regulatory function, immunomagnetically purified CD3+ T-cells from the peripheral blood of 3 individuals were activated and cultured in the presence or absence of MSCs. Following 5 days, CD4+ and CD8+ T-cells were further immunomagnetically selected and their gene expression profiles were obtained by microarrays and compared. Paired samples from 3 individuals were used for this analysis.

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

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