Cholesterol and oxysterol sulfates are important regulators of lipid metabolism, inflammation, cell apoptosis, and cell survival. Among the sulfate-based lipids, cholesterol sulfate (CS) is the most studied lipid both quantitatively and functionally. Despite the importance, very few studies have analysed and linked the actions of oxysterol sulfates to their physiological and pathophysiological roles. Overexpression of sulfotransferases confirmed the formation of a range of oxysterol sulfates and their antagonistic effects on liver X receptors (LXRs) prompting further investigations how are the changes to oxysterol/oxysterol sulfate homeostasis can contribute to LXR activity in the physiological milieu. Here, we aim to bring together for novel roles of oxysterol sulfates, the available techniques and the challenges associated with their analysis. Understanding the oxysterol/oxysterol sulfate levels and their pathophysiological mechanisms could lead to new therapeutic targets for metabolic diseases.

Nuclear receptors, liver X receptor-α (LXRα; NR1H3) and liver X receptor-β (LXRβ; NR1H2), are considered master regulators of lipid homeostasis. During the last couple of decades, their pivotal roles in several physiological and pathological processes ranging from energy supply, immunity, cardiovascular, neurodegenerative disorders and cancer have been highlighted. In this review, the main results achieved during more recent years about our understanding of the LXR involvement in cancer has been mainly obtained using small-molecule chemical probes. Remarkably, all these probes, albeit having different structure and biological properties, have a well demonstrated anti-tumoral activity arising from LXR modulation, indicating a high potential of LXR targeting for the treatment of cancer. K E Y W O R D Scancer, chemical probes, liver X receptor, small-molecules | INTRODUCTIONThanks to their molecular characteristics, nuclear receptors have proven to be a source of very favourable druggable targets. Within the superfamily most of the members classified as classical hormone receptors have become valuable therapeutic targets, even long before their discovery. As an example, the first clinical use of cortisone dates back to 1949 (Hench, Kendall, & Slocumb, 1949), whereas the human glucocorticoid receptor (NR3C1), the first one among nuclear receptors to be cloned, was identified more than 30 years later (Hollemberg et al., 1985). This event paved the way for a decade of an intensive research in the nuclear receptor field leading to the identification of many other members of this now superfamily. However, differently from the classic endocrine nuclear receptors, these newcomers lacked endogenous ligands and therefore were referred to as orphan nuclear receptors (Mazaira et al., 2018). The de-orphanization of these orphan nuclear receptor was due to the successful discovery of their endogenous ligand(s), which allows the receptor to be regarded as "adopted."Undoubtedly, the knowledge of the natural ligand is the first step towards elucidating the physiological functions of the target protein and its potential implications in certain pathological conditions. However, without the creation of high-quality small-molecule probes, our current understanding of adopted nuclear receptors could not be what it is. Moreover, the availability of chemical probes has had a major impact on enabling and improving the drug discovery process in this area. In this context, the liver X receptors (LXRs) is a case in point.Liver X receptor-α (LXRα) and liver X receptor-β (LXRβ), which by the IUPHAR nomenclature are respectively NR1H3 and NR1H2, were discovered between 1994 and 1995 and classified as orphan receptors by different research groups

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The bulk solvent-free synthesis of cyclopropanes via a ball-milling-enabled Simmons–Smith reaction is herein described.

Lipid and cholesterol metabolism play a crucial role in tumor cell behavior and in shaping the tumor microenvironment. In particular, enzymatic and non-enzymatic cholesterol metabolism, and derived metabolites control dendritic cell (DC) functions, ultimately impacting tumor antigen presentation within and outside the tumor mass, dampening tumor immunity and immunotherapeutic attempts. The mechanisms accounting for such events remain largely to be defined. Here we perturbed (oxy)sterol metabolism genetically and pharmacologically and analyzed the tumor lipidome landscape in relation to the tumor-infiltrating immune cells. We report that perturbing the lipidome of tumor microenvironment by the expression of sulfotransferase 2B1b crucial in cholesterol and oxysterol sulfate synthesis, favored intratumoral representation of monocyte-derived antigen-presenting cells, including monocyte-DCs. We also found that treating mice with a newly developed antagonist of the oxysterol receptors Liver X Receptors (LXRs), promoted intratumoral monocyte-DC differentiation, delayed tumor growth and synergized with anti-PD-1 immunotherapy and adoptive T cell therapy. Of note, looking at LXR/cholesterol gene signature in melanoma patients treated with anti-PD-1-based immunotherapy predicted diverse clinical outcomes. Indeed, patients whose tumors were poorly infiltrated by monocytes/macrophages expressing LXR target genes showed improved survival over the course of therapy. Thus, our data support a role for (oxy)sterol metabolism in shaping monocyte-to-DC differentiation, and in tumor antigen presentation critical for responsiveness to immunotherapy. The identification of a new LXR antagonist opens new treatment avenues for cancer patients.