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

Area of Science:

• Immunology
• Molecular Biology
• Oncology

Background:

• Liver X receptor beta (LXRβ) influences lipid metabolism and immune responses.
• The role of LXRβ in tumor-infiltrating T cells, particularly CAR-T cells, is not well understood.
• The interplay between LXRβ and NF-κB signaling in the tumor microenvironment (TME) requires further elucidation.

Purpose of the Study:

• To investigate the role of LXRβ in CAR-T cell differentiation, metabolism, and function within solid tumors.
• To explore the mechanistic link between LXRβ and NF-κB signaling in CAR-T cells.
• To evaluate the therapeutic potential of targeting the LXRβ-NF-κB axis for enhancing CAR-T cell therapy.

Main Methods:

• Analysis of LXRβ's impact on CAR-T cell transcriptional and phenotypic profiles.
• Genetic manipulation of NF-κB components (e.g., RelB) in CAR-T cells.
• In vivo studies assessing anti-tumor efficacy of combined LXRβ and RelB targeting.

Main Results:

• LXRβ overexpression modulated CAR-T cell stem-like populations, proliferation, and cytokine production.
• Disrupting non-canonical NF-κB signaling (RelB) improved CAR-T cell cytotoxicity and reduced exhaustion markers.
• Combined LXRβ and RelB targeting demonstrated additive/synergistic improvements in metabolic fitness, reduced exhaustion, and enhanced in vivo anti-tumor activity.

Conclusions:

• LXRβ is a critical regulator of CAR-T cell fate and function in the TME.
• The LXRβ-NF-κB axis represents a novel regulatory pathway influencing CAR-T cell performance.
• Targeting this pathway holds promise for improving CAR-T cell therapies against solid tumors.