Multiomic profiling reveals ligand and cell specific regulatory programs of LXR selective modulation in myeloid immune cells

Selective modulation of steroid nuclear receptors such as estrogen (ER), glucocorticoid (GR), and androgen receptors (AR) has advanced cancer therapy by enabling precise control of receptor signaling. However, selective modulation of other nuclear receptors remains underexplored. Liver X receptors (LXRs) are key regulators of cholesterol homeostasis, inflammation, and immune responses. LXR ligands have shown antiproliferative and immunomodulatory effects across multiple cancers, including prostate, breast, and colorectal cancers, as well as hematologic tumors. Certain LXR ligands also attenuate immunosuppressive cell populations in the tumor microenvironment, making LXR a promising therapeutic target. However, many synthetic LXR agonists have shown adverse metabolic and neurologic effects and their impact on tumor progression is often inconsistent, suggesting potential ligand- and cell-specific modulation. Understanding the mechanisms underlying such selective LXR modulation, inspired by established selective modulation strategies for ER and AR related cancers, may enable the development of safer and more effective LXR-directed cancer therapies.To elucidate the mechanism of selective LXR modulation in myeloid cells, we performed multi-omics profiling (RNA-seq, ATAC-seq, and RIME proteomics) on murine bone marrow derived macrophages and dendritic cells treated with seven LXR ligands. We observed both shared and ligand- or cell-specific transcriptional and chromatin accessibility patterns. Notably, 27-hydroxycholesterol (27HC) suppressed interferon/STAT1 programs in macrophages and induced a MYC/E2F associated immunosuppressive state, whereas dendritic cells exhibited suppression of interferon stimulated genes and MYC/E2F program.T cell proliferation can be suppressed by 27HC treated macrophages. Preliminary functional assays suggested that this effect could be reversed by inhibiting E2F pathway (CDK4/6 blockade) or by targeting NF-κB, STAT3, or HDAC2 signaling in macrophages. These findings delineate cell-specific mechanisms of LXR selective modulation and suggest that targeting LXR may fine-tune E2F, NF-κB, STAT3, and HDAC2 dependent signaling that impacting macrophage-T cell crosstalk and thereby enhance T cell antitumor function.