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

Sep 30, 2026

Liver X receptor β (LXRβ) acts as a transcription factor in lipid metabolism and immune regulation, but its role in tumor-infiltrating T cells remains unclear. This study identifies LXRβ as a regulator of CAR-T differentiation, metabolic state, and effector function in solid tumors. LXRβ overexpression reprograms CAR-T transcription and phenotype, including stem-like TCF1+ populations, Ki-67 proliferation, and IFNγ/TNFα cytokine output. Genetic disruption of NF-κB components, especially RelB, enhances cytotoxicity and reduces exhaustion features such as TOX upregulation, with additive or synergistic effects, improving metabolic fitness and anti-tumor activity in vivo.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages21

Reading Time53 min

AccessFree to download

Introduction

T cell exhaustion in the tumor microenvironment

Transcriptional regulation of effector versus exhaustion states

Metabolism–immune connections and the role of LXRβ

Complexity of NF-κB signaling and the relevance of RelB

ONCOIMMUNOLOGY 2026, VOL. 15, NO. 1, 2611615 [https://doi.org/10.1080/2162402X.2025.261](https://doi.org/10.1080/2162402X.2025.261)1615 RESEARCH ARTICLE The LXRβ/NF-κB axis reprograms CAR-T cells to resist exhaustion in the tumor microenvironment Minji Lima, b, 1, Sang-Eun Junga, b, 1, Choong-Hyun Koha,c, Hyungwoo Jeonga, b, Youngchae Moona, b and Hyungseok Seoa, b aResearch Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea; bLaboratory of Cell & Gene Therapy, College of Pharmacy, Seoul National University, Seoul, Republic of Korea; cLaboratory of Immune Regulation, College of Pharmacy, Seoul National University, Seoul, Republic of Korea ABSTRACT 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. ARTICLE HISTORY Received 29 June 2025 Revised 18 November 2025 Accepted 28 December 2025 KEYWORDS Chimeric Antigen Receptor T-cell (CAR-T); LXRβ; NF-κB; cancer immunotherapy CONTACT Hyungseok Seo [h.seo@snu.ac.kr](h.seo@snu.ac.kr) Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea 1These authors contributed equally to this work. Supplemental data for this article can be accessed online at [https://doi.org/10.1080/2162402X.2025.261](https://doi.org/10.1080/2162402X.2025.261)1615. © 2026 The Author(s) . Published with license by Taylor & Francis Group, LLC. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License ([http://creativecommons.org/licenses/by-nc/4](http://creativecommons.org/licenses/by-nc/4)[ ](http://creativecommons.org/licenses/by-nc/4)[.0/](.0/)), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent. 2 M. LIM ET AL. Introduction CD8⁺ T cells encountering tumor antigens within a chronically inflamed microenvironment, often without adequate costimulatory signals, frequently adopt a dysfunctional state known as T cell exhaustion. 1,2 These exhausted T cells exhibit impaired cytotoxicity, reduced cytokine secretion (such as IFNγ and TNFα), and sustained expression of inhibitory receptors like PD-1 and TIM3 . Critically, this state involves broad transcriptional and epigenetic reprogramming, often enforced by key transcription factors including TOX and NR4A.3,4 Such exhaustion significantly limits both endogenous anti-tumor immunity and the ther

FAQs

What problem does the study address in CAR-T therapy for solid tumors?

Solid-tumor settings often induce T cell exhaustion, which impairs cytotoxicity, cytokine secretion, and the therapeutic efficacy of CAR-T cells. Reversing or preventing this exhausted state is a major goal in cancer immunotherapy.

How does LXRβ influence CAR-T cell function according to the abstract?

LXRβ overexpression alters CAR-T transcriptional and phenotypic programs, including effects on stem-like TCF1+ populations, Ki-67 proliferation, and cytokine production such as IFNγ and TNFα.

What is the role of NF-κB signaling components, especially RelB, in exhaustion?

Disrupting non-canonical NF-κB signaling, particularly RelB, enhances CAR-T cytotoxicity and attenuates exhaustion-associated features, including TOX upregulation. Combined LXRβ and RelB targeting yields additive or synergistic benefits in certain settings.

Sep 30, 2026

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