Galectin-9 - ligand axis: an emerging therapeutic target for multiple myeloma

Abstract

Galectin-9 (Gal-9) is a tandem-repeat galectin with diverse roles in immune homeostasis, inflammation, malignancy, and autoimmune diseases. In cancer, Gal-9 displays variable expression patterns across different tumor types. Its interactions with multiple binding partners, both intracellularly and extracellularly, influence key cellular processes, including immune cell modulation and tumor microenvironment dynamics. Notably, Gal-9 binding to cell-specific glycoconjugate ligands has been implicated in both promoting and suppressing tumor progression. Here, we provide insights into Gal-9 and its involvement in immune homeostasis and cancer biology with an emphasis on multiple myeloma (MM) pathophysiology, highlighting its complex and context-dependent dual functions as a pro- and anti-tumorigenic molecule and its potential implications for therapy in MM patients.

Keywords: galectin-9; galectins; multiple myeloma; therapy; tumor microenvironment.

Figure 1

Galectin classification. Galectin members are categorized into three main groups: proto-type, chimera-type, and tandem repeat based on the number, structures, and orientation of carbohydrate recognition domains (CRDs). They specifically recognize and bind to β-galactoside on glycoconjugates (proteins, lipids, or other molecules) through these CRDs. Proto-type Gal-1, -2, -5, -7, -10, -11, -13, -14, and -15, are characterized by a single CRD which can form homodimers; chimera-type Gal-3, is composed of one CRD and an amino-terminal polypeptide tail rich in proline, glycine, and tyrosine residues for oligomer formation; and tandem-repeat Gal-4, -6, -8, -9, and -12, consist of two distinct CRDs connected by a peptide linker of variable length, ranging from 5 to over 50 amino acids.

Figure 2

Gal-9 isoforms. Gal-9 is a tandem-repeat galectin with a molecular weight of 34 to 39 kDa. It consists of two distinct CRDs linked by a peptide of variable lengths. Humans have three natural isoforms of this lectin, which differ in the length of this interdomain peptide. These isoforms are termed i) long form Gal-9 (58 amino acids), ii) medium form Gal-9 (26 amino acids), and short form Gal-9 (14 amino acids).

Figure 3

The dual role of Gal-9 in MM and potential therapeutic strategies. The left panel depicts the pro-tumorigenic effect of Gal-9, showing its binding to Tim-3 on CD4+ T cells, which leads to disrupted T cell subset balance by inhibiting Th1 and enhancing the immune response of Th2 and Th17 cells. The right panel illustrates the anti-tumorigenic effect of Gal-9, demonstrating its binding to myeloma cells and subsequent activation of apoptotic pathways through caspases and JNK/p38 MAPK signaling. Thick black arrows indicate activation and bar-ended red lines represent inhibition. Potential therapeutic strategies are shown within green frames.