The role of galectins in modulating the tumor microenvironment and driving metastasis in skin cancers.

Galectins, a family of β-galactoside-binding lectins, are key regulators of tumor progression, immune evasion, and therapy resistance in skin cancers. Among them, Galectin-1, Galectin-3, and Galectin-9 have been most extensively investigated for their multifaceted roles in shaping the tumor microenvironment. These proteins influence cancer cell proliferation, apoptosis, angiogenesis, and immune cell responses through both intracellular and extracellular mechanisms. Galectin-1 and Galectin-3 modulate immune checkpoint pathways and cancer-associated fibroblast activation, whereas Galectin-9 interacts with TIM-3 to induce T-cell exhaustion. Other family members, including Galectin-7 and Galectin-8, display context-dependent functions that may either promote or inhibit tumor development. Recent preclinical and early clinical trials targeting galectins, such as the Gal-3 inhibitors belapectin and GB1211, highlight their translational potential as adjuncts to immunotherapy. This review summarizes current knowledge on galectin expression and function in melanoma and non-melanoma skin cancers, emphasizing their contribution to immune escape and therapeutic resistance, as well as challenges and perspectives for galectin-targeted interventions.