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July 06, 2025, 09:23

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Hepatocellular carcinoma (HCC) remains a major global health burden, ranking as the sixth most common cancer and the third leading cause of cancer-related mortality worldwide. Despite advances in surveillance, early diagnosis, and the emergence of molecular-targeted and immunotherapeutic agents, the prognosis for many patients with HCC remains poor. This is particularly true in advanced-stage disease, where therapeutic resistance and immune escape mechanisms hinder durable responses. As our understanding of HCC pathogenesis deepens, the tumor microenvironment (TME) has emerged as a critical determinant of disease progression and therapeutic outcome. Among the key regulators in this microenvironment are galectins (Gals)—a family of glycan-binding proteins with various immunomodulatory and tumor-regulatory functions. Gal-1, Gal-3, Gal-4, and Gal-9 have attracted significant attention for their diverse roles in HCC. These proteins guide important cellular processes vital for tumor development, including inflammation, immune evasion, angiogenesis, epithelial–mesenchymal transition (EMT), proliferation, and metastasis. What sets galectins apart is their functional duality—their effects depend on their cellular location, expression levels, and the tumor microenvironment (TME). This complexity highlights their potential as both biomarkers and therapeutic targets in HCC. They coordinate processes like inflammation, angiogenesis, EMT, tumor growth, and spread. Importantly, galectins display dynamic, context-dependent behavior, capable of exerting both tumor-promoting and tumor-inhibiting effects depending on their expression, cellular localization, and the surrounding microenvironment. Recent studies, including the comprehensive review by Gajovic and colleagues (WJG 2025; 31:107260), highlight the diverse functions of Galectins in liver cancer. For instance, Gal-1 and Gal-3 are consistently associated with aggressive tumor features such as vascular invasion, immunosuppression, and poor prognosis. Conversely, Gal-4 and Gal-9 appear as favorable prognostic indicators in specific HCC subtypes, possibly due to their roles in immune activation and metastasis suppression. This duality not only reflects the complexity of Galectin biology but also encourages the development of improved biomarkers and personalized therapeutic strategies. The current therapeutic landscape of HCC—although expanded by immune checkpoint inhibitors and molecularly targeted agents—remains inadequate for many patients, especially those with advanced disease. In this context, Galectin-targeted therapies show considerable promise. Gal-3 inhibitors and Gal-3C fusion proteins, for example, are actively being studied for their ability to reverse immune suppression, disrupt tumor–stromal interactions, and improve the effectiveness of existing treatments. Meanwhile, profiling Galectin expression may help predict treatment responses and guide personalized therapy strategies. Elevated levels of Gal-1 and Gal-3 in serum or tumor tissue have consistently been associated with aggressive clinical features, such as vascular invasion, immune evasion, and poor overall survival. Conversely, Gal-4 and Gal-9 expression have been linked to favorable prognostic indicators in some patient groups, highlighting the biological diversity of HCC and the complex roles that galectins play in disease progression. The therapeutic implications are equally compelling. Galectin-targeted agents—such as Gal-3 inhibitors and Gal-3C fusion proteins—are being studied for their ability to modify the TME, boost anti-tumor immunity, and overcome resistance to current therapies. At the same time, integrating galectin profiling into clinical practice could improve risk assessment, enhance prognostic models, and support more personalized treatment approaches. However, these promising advancements must be accompanied by rigorous clinical validation. The dual and sometimes conflicting roles of galectins in cancer emphasize the importance of context—what may be beneficial in one cellular environment could be detrimental in another. Large-scale, well-controlled clinical trials and mechanistic research are critical for fully understanding the therapeutic potential of galectin modulation in HCC. Galectins are an area of study within the field of HCC biology and therapeutics that has not been extensively researched. In addressing treatment resistance and disease heterogeneity, galectins have potential for the development of biomarkers and targeted therapies. Including galectins in future HCC management strategies may contribute to more effective and personalized treatment methods.

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