Retinoid X receptors (RXRs) are essential modulators of human physiology and attractive targets for treating cancer (Altucci, Leibowitz, Ogilvie, de Lera, & Gronemeyer, 2007; Schierle & Merk, 2019). By binding to other nuclear receptors (NRs), RXRs help to regulate multiple processes including development, metabolism, and homeostasis (Evans & Mangelsdorf, 2014; Sharma et al., 2022). RXRs exist in three subtypes: RXRα (also called NR2B1, nuclear receptor subfamily 2, group B, member 1), RXRβ (NR2B2) and RXRγ (NR2B3), encoded by the RXRA, RXRB, and RXRG genes (Germain et al., 2006). Each subtype is widely expressed and is thought to have analogous cellular functions. However, the relative expression patterns of the subtypes vary in different cell types (Ahuja, Szanto, Nagy, & Davies, 2003; Germain et al., 2006). One classic example is RXRγ, which is highly expressed in thyrotropes and thyrotrope-derived cells. Deficiency of the RXRγ subtype is associated with higher serum thyroid-stimulating hormone (TSH) and thyroxine levels in mice (Brown et al., 2000; Haugen, Brown, Wood, Gordon, & Ridgway, 1997).

RXRs are the heterodimerization partner of multiple NRs, including the peroxisome proliferator-activated receptors (PPAR, NR1C1-3), liver X receptors (LXR, NR1H2,3), farnesoid X receptors (FXR, NR1H4,5), retinoic acid receptors (RAR, NR1B1-3), vitamin D receptor (VDR, NR1l1) and thyroid hormone receptors (TR, NR1A1,2) (Mangelsdorf & Evans, 1995). RXR partners can be categorized as permissive (PPARs, LXR, and FXR) or non-permissive (RAR, VDR, and TR) (Vivat-Hannah et al., 2002; Altucci et al., 2007; Evans & Mangelsdorf, 2014; Thompson et al., 2001; Brtko & Dvorak, 2020). Agonists of either partner receptor can activate the permissive heterodimers. Furthermore, agonist binding to both RXR and a partner can result in cumulative or synergistic effects. Nonpermissive partners, in contrast, are typically activated only by ligands specific to the partner receptor but not to RXR (Evans & Mangelsdorf, 2014; Forman et al., 1995). Increasing the concentration of a RXR ligand may skew activity from one dimer to another, inducing entirely different regulatory mechanisms in various tissues (Davies et al., 2001; De Luca, 1991). In addition to their primary function as heterodimer partners, RXRs can act as homodimers and even homotetramers to control gene expression (Lefebvre, Benomar, & Staels, 2010). Once a heterodimer or homodimer binds to target DNA, it activates transcription, resulting in a vast and varied range of biological effects. This versatility permits RXRs to regulate multiple biological processes relevant to cancer, including cell proliferation, differentiation, survival, and immune cell function (Dawson & Xia, 2012; Germain et al., 2006; Menéndez-Gutiérrez et al., 2023; Nagy, Szanto, Szatmari, & Széles, 2012; Oliveira, Teixeira, & Sato, 2018; Rőszer, Menéndez-Gutiérrez, Cedenilla, & Ricote, 2013; Saito-Hakoda et al., 2015; Szanto et al., 2004).

Like other nuclear hormone receptors, RXRs have a variable N-terminal domain (NTD) followed by a central highly conserved DNA binding domain (DBD), which is linked to the C-terminal ligand binding domain (LBD) via a flexible hinge region (Fig. 1A) (Penvose, Keenan, Bray, Ramlall, & Siggers, 2019). The RXR subtypes, despite being encoded by three distinct genes, have a significant degree of sequence similarity and structural homology (de Lera, Bourguet, Altucci, & Gronemeyer, 2007). The DNA binding domains of RXRs are crucial for the specificity of heterodimer binding to specific DNA sequences in the promoter regions of target genes (Giguère & Evans, 2022; Petkovich & Chambon, 2022; Predki, Zamble, Sarkar, & Giguère, 1994). The ligand-binding domains of RXRs bind lipophilic signaling molecules, such as RAs, in the hydrophobic pockets (Aranda & Pascual, 2001; Evans & Mangelsdorf, 2014). Ligand binding causes conformational changes that favor the interaction between RXR and its heterodimeric partner and the binding efficiency to DNA. It also sets off a chain of events, such as co-regulator exchange or binding, that results in positive or negative gene transcription and other biological activities (Fig. 1B) (Germain et al., 2006; Sever & Glass, 2013; Egea et al., 2002; Evans & Mangelsdorf, 2014). In the absence of an agonist, the activation function (AF2) domain in the LBD promotes interaction with the corepressor complex, which inhibits transcription (Fig. 1C). In the presence of a ligand, conformational changes occur in the AF2 domain that weaken corepressor interactions and encourage the binding of coactivators, which activate the transcription of target genes (Dawson & Xia, 2012; Germain et al., 2006).

9-cis-Retinoic acid (9-cis-RA) was initially identified as an endogenous ligand for RXR (Heyman et al., 1992; Mangelsdorf et al., 1992). However, multiple groups were unable to detect endogenous 9-cis-RA in tissues under physiological conditions (Blomhoff & Blomhoff, 2006; Calléja et al., 2006; Gundersen, 2006; Gundersen, Bastani, & Blomhoff, 2007; Kane, Chen, Sparks, & Napoli, 2005; Kane, Folias, Wang, & Napoli, 2008; Schmidt, Brouwer, & Nau, 2003; Wolf, 2006). Therefore, 9-cis-RA may be present in sufficient amounts to bind and activate RXRs only after pharmacological or dietary supplementation (Arnhold, Tzimas, Wittfoht, Plonait, & Nau, 1996; Krężel, Rühl, & de Lera, 2019; Ulven, Gundersen, Sakhi, Glover, & Blomhoff, 2001). Subsequently, several fatty acids such as docosahexaenoic acid (DHA), oleic acid, phytanic acid (de Urquiza et al., 2000; Kitareewan et al., 1996; Lemotte, Keidel, & Apfel, 1996), and other ligands (Brtko & Dvorak, 2020) were identified as potential RXR ligands. However, none of these compounds have been proven to be the putative endogenous ligand of RXR (Calléja et al., 2006; Krężel et al., 2019; Wolf, 2006). Despite this challenge, a variety of potent synthetic RXR ligands (known as “rexinoids”) have been synthesized, which have shown promising activity in multiple preclinical models of disease including cancer (Martino & Welch, 2019; Moerland et al., 2020; Reich, Leal, Ellsworth, & Liby, 2023; Uray, Dmitrovsky, & Brown, 2016; Zhang et al., 2019) and even for prevention in clinical trials (Moyer & Brown, 2023). However, most of these studies reported efficacy or studied changes only in the cancer cells following treatment with a RXR agonist.

One of the most intriguing and underexplored areas of investigation in the RXR field is the effects of RXR agonists on immune cells within the tumor microenvironment (Leal et al., 2019; Leal et al., 2021), which have emerged as significant druggable targets in cancer (Lu et al., 2023). A remarkable shift in cancer therapy from solely targeting cancer cells to focusing on modulating the immune response with immunotherapy has profoundly improved patient survival in certain cancers (Sanmamed & Chen, 2018; Zhang & Zhang, 2020). Because of the complexities of RXR receptor dimerization, signaling crosstalk, and regulation by co-repressors and co-activators in different cell types (De Bosscher, Desmet, Clarisse, Estébanez-Perpiña, & Brunsveld, 2020), understanding the biology of RXR in immunology is critical for developing new and specific RXR agonists as novel anti-cancer therapies. In this review, we provide an overview of the immunomodulatory effects of RXR agonists in cancer and suggest promising new areas of investigation.