Evasion of immune surveillance is an accepted hallmark of tumor progression. The production of immune suppressive mediators by tumor cells is one of the major mechanisms of tumor immune escape. Galectin-1 (Gal-1), a pivotal immunosuppressive molecule, is expressed by many types of cancer. Tumor-secreted Gal-1 can bind to glycosylated receptors on immune cells and trigger the suppression of immune cell function in the tumor microenvironment, contributing to the immune evasion of tumors. The aim of this review is to summarize the current literature on the expression and function of Gal-1 in the human tumor microenvironment, as well as therapeutics targeting Gal-1.

The Ras signaling pathway is commonly dysregulated in human malignant peripheral nerve sheath tumors (MPNSTs). It is well known that galectin-1 (Gal-1) is essential to stabilize membrane Ras and thereby induce the activation of Ras. However, the role of Gal-1 in MPNST progression remains unknown. The aim of this study was to examine whether Gal-1 knockdown could have an effect on the Ras signaling pathway. Cell viability, apoptosis assay, and colony formation were performed to examine the effects of inhibition of Gal-1 in MPNST cells. We used a human MPNST xenograft model to assess growth and metastasis inhibitory effects of Gal-1 inhibitor LLS2. Gal-1 was upregulated in MPNST patients and was highly expressed in MPNST cells. Knockdown of Gal-1 by small interfering (si)RNA in Gal-1 expressing MPNST cells significantly reduces cell proliferation through the suppression of C-X-C chemokine receptor type 4 (CXCR4) and the rat sarcoma viral oncogene homolog (RAS)/extracellular signal-regulated kinase (ERK) pathway, which are important oncogenic signaling in MPNST development. Moreover, Gal-1 knockdown induces apoptosis and inhibits colony formation. LLS2, a novel Gal-1 allosteric small molecule inhibitor, is cytotoxic against MPNST cells and was able to induce apoptosis and suppress colony formation in MPNST cells. LLS2 treatment and Gal-1 knockdown exhibited similar effects on the suppression of CXCR4 and RAS/ERK pathways. More importantly, inhibition of Gal-1 expression or function by treatment with either siRNA or LLS2 resulted in significant tumor responses in an MPNST xenograft model. Our results identified an oncogenic role of Gal-1 in MPNST and that its inhibitor, LLS2, is a potential therapeutic agent, applied topically or systemically, against MPNST.

Our study aimed to elucidate the role of Galectin-1 (Gal-1) role in the immunosuppressive tumor microenvironment (TME) of prostate cancer (PCa). Our previous findings demonstrated a correlation between elevated Gal-1 expression and advanced PCa stages. In this study, we also observed that Gal-1 is expressed around the tumor stroma and its expression level is associated with PCa progression. We identified that Gal-1 could be secreted by PCa cells, and secreted Gal-1 has the potential to induce T cell apoptosis. Gal-1 knockdown or inhibition of Gal-1 function by LLS30 suppresses T cell apoptosis resulting in increased intratumoral T cell infiltration. Importantly, LLS30 treatment significantly improved the antitumor efficacy of anti-PD-1 in vivo. Mechanistically, LLS30 binds to the carbohydrate recognition domain (CRD) of Gal-1, disrupting its binding to CD45 leading to the suppression of T cell apoptosis. In addition, RNA-seq analysis revealed a novel mechanism of action for LLS30, linking its tumor-intrinsic oncogenic effects to anti-tumor immunity. These findings suggested that tumor-derived Gal-1 contributes to the immunosuppressive TME in PCa by inducing apoptosis in effector T cells. Targeting Gal-1 with LLS30 may offer a strategy to enhance anti-tumor immunity and improve immunotherapy.

A large number of peptides with anticancer activities have been reported. Many of them were isolated from natural sources. A significant portion was developed from combinatorial library methods. Many of these peptides have direct anti-proliferative or pro-apoptotic activities on cancer cells; others may affect the tumor microenvironment directly or kill the tumor cells via hormonal or immunological modulations of the host. To affect intracellular targets, the therapeutic peptides must be able to get inside the tumor cells. Peptides have been developed to target cell surface receptors. Some of these peptides may affect the tumor cells directly. Some of them have been used as vehicles to deliver potent cytotoxic drugs or nanomedicines to the tumor cells. Research on cancer immunotherapy is bearing fruit over these past few years. There is a great interest to develop effective cancer vaccines and checkpoint blockade peptides. Several cancer therapeutic peptides have already been approved for clinical use and many more are undergoing preclinical and clinical development. It is expected that peptides will become increasingly important as oncologic drugs in the future. This chapter covers the discovery, optimization and application of anticancer peptides, as well as their current status of clinical use and development.

Background/Objective: Prostate cancer (PCa) remains a prevalent and deadly disease, particularly in its advanced stages. Despite various available treatments, resistance to drugs like enzalutamide continues to present significant challenges. This study aimed to investigate the role of Galectin-1 (Gal-1) in enzalutamide-resistant PCa and assess its potential as a therapeutic target to overcome resistance. Methods: The study utilized specific siRNA-mediated knockdown of Gal-1 in enzalutamide-resistant PCa cells to evaluate its effects on cell proliferation and response to enzalutamide treatment. An orthotopic mouse model was employed to examine the in vivo impact of Gal-1 knockdown. Pharmacological targeting of Gal-1 was conducted using LLS30, and its effects were assessed both in vitro and in vivo. RNA sequencing (RNA-seq) analysis was performed to explore the molecular mechanisms underlying the observed effects. Results: The findings demonstrated significant upregulation of Gal-1 in enzalutamide-resistant PCa cells. Gal-1 knockdown inhibited cell proliferation and resensitized resistant cells to enzalutamide treatment in the orthotopic mouse model. Elevated levels of androgen receptor full-length and AR-V7 are key mechanisms under-lying resistance to enzalutamide in PCa. Gal-1 knockdown suppressed AR and AR-V7 expression and their transcriptional activity. Treatment with LLS30 significantly suppressed the growth of enzalutamide-resistant PCa cells and exhibited synergistic effects when combined with enzalutamide. Notably, this combination therapy significantly inhibited the growth of enzalutamide-resistant xenografts in vivo. RNA-seq analysis revealed that LLS30 modulates AR and AR-V7 signaling through the inhibition of associated target genes. Conclusion: These findings highlight Gal-1 as a promising therapeutic target for overcoming enzalutamide resistance in PCa. Targeting the Gal-1/AR/AR-V7 axis with LLS30 presents a novel strategy to enhance enzalutamide efficacy and address drug resistance in advanced PCa.