Ganglioside therapy in cancer molecular insights and therapeutic opportunities.

Introduction: understanding the ganglioside biosynthesis process

Sialylated glycosphingolipids, known as gangliosides, are widely expressed in the human body, with the highest levels in the brain and nervous system [ 1 ]. They play crucial roles in cell–cell interactions, influence signal transduction via receptor tyrosine kinases in lipid rafts, and protect against autoimmune responses. Gangliosides, characterized by sialic acid incorporation, originate in the endoplasmic reticulum and undergo elongation in the Golgi apparatus [ 2 ]. Glycosphingolipids, the primary glycolipids in cell membranes, are synthesized stepwise, beginning with the galactosylation of ceramide to generate galactosylceramide (GalCer) or glucosylation by UDP-glucose ceramide glucosyltransferase to produce glucosylceramide (GlcCer). Among these, GalCer can undergo sulfation to form sulfatide (GalCer sulfate), a major glycolipid of the central nervous system (CNS) that plays a crucial role in myelin stability, axon-glia interactions, and proper nerve conduction. Glycosylation, the enzymatic process of attaching sugars to proteins and lipids, is catalyzed by diverse glycosyltransferases, thereby linking biosynthetic pathways of glycosphingolipids directly to their structural and functional significance in maintaining CNS integrity [ 3 ].

Lactosylceramide (LacCer), synthesized from GlcCer via B4GALT6, serves as the precursor for complex glycosphingolipids, including gangliosides. Sialylation of LacCer by ST3GAL5 (GM3-synthase) generates GM3, which is further converted to GD3 by ST8SIA1 (GD3-synthase). Addition of N-acetylgalactosamine (GalNAc) by B4GALNT1 produces GM2, GD2, and GT2 gangliosides, with subsequent sialylation largely ceasing after GalNAc incorporation, defining the a-, b-, and c-series gangliosides [ 4 ].

Altered ganglioside biosynthesis, including activation of biosynthetic pathways and upregulation of glycosyltransferase expression, contributes to tumor progression [ 5 ]. ST8SIA1, the enzyme catalyzing GD3 synthesis, is also implicated in maintaining stem-like and aggressive phenotypes in tumors [ 6 – 11 ]. These cancer-associated alterations in glycosylation patterns provide potential diagnostic markers and therapeutic targets, including anti-ganglioside immunotherapies that can modulate the tumor microenvironment (Fig. 1 ) [ 12 ]. Fig. 1 Multifaceted Roles of Gangliosides in Cancer Detection, Progression, and Therapy: Gangliosides serve as key molecular players in various aspects of cancer biology. As tumor biomarkers, their detection via high-resolution mass spectrometry (MS) and liquid chromatography-electrospray ionization mass spectrometry (LC-ESI MS) facilitates early diagnosis and molecular profiling of tumors. In tumor growth, gangliosides contribute to immune evasion, promoting EMT, enhancing cell migration and metastasis. Therapeutically, ganglioside GD2 is a validated target in several cancers

Gangliosides: exploring therapeutic opportunities in cancer treatment

The aberrant upregulation followed by shedding of select gangliosides in many tumors help them to serve as ideal targets for antibody therapy and diagnostic markers for various cancers (Table 1 ) [ 13 , 14 ]. Several antibodies targeting tumor-associated gangliosides are under investigation in preclinical and clinical studies, such as anti-GD2 in neuroblastoma ( NCT01704716 ) and a GD3 antibody–drug conjugate in melanoma ( NCT03159117 ) [ 4 , 15 , 16 ]. Despite ubiquitous cellular presence, expression patterns of specific ganglioside vary from development to adult tissues, which corresponds to differential glycosyltransferase expression pattern. GD2, a b-series ganglioside with two sialic acid residues, is typically highly expressed during development but is absent in adult tissues outside the nervous system [ 15 , 17 – 19 ]. Whereas its precursor GD3 maintains a stable proportion of 5% throughout development [ 20 ]. Historically targeting GD2 in cancer therapy has been widely studied that we have reviewed below along with involvement of other gangliosides in cancer as potential therapeutic targets (Table 2 ). Table 1 Selective ongoing, completed and terminated clinical trials investigating gangliosides in cancer ClinicalTrials.gov Cancer type Study phase Drugs Enrollment (actual) status NCT02641782 Neuroblastoma 2 antibody ch14.18 (anti-GD2 antibody), GM-CSF, IL-2, retinoic acid 3 Terminated NCT02998983 Neuroblastoma 2 Racotumomab 39 Completed NCT01598454 Neuroblastoma, Ewing's Sarcoma, Wilm's Tumor, Retinoblastoma, Glioma 1 Racotumomab 15 Completed NCT01141491 Metastatic Sarcoma (who are rendered disease free) 2 Trivalent ganglioside vaccine (GM2, GD2 Lactone, and GD3 Lactone) plus adjuvant OPT-821 136 Completed NCT02998983 Neuroblastoma 2 Racotumomab 39 Completed NCT00679289 Metastatic and cutaneous melaloma 2 Anti-Ganglioside GD3 Mouse/Human chimeric antibody KW2871 combined with high dose interferon-α2b 36 Completed NCT00590824 Melanoma 2 hu14.18-IL2 23 Completed NCT00775502 Multiple Myeloma 1 GM2 Ganglioside Monoclonal Antibody BIW-8962 23 Terminated NCT00597272 Melanoma N.A GD2L, GD3L, QS-DG or OPT-821 34 Completed NCT04222790 Early Breast Cancer 2 monosialic gangliosides (GM1), albumin paclitaxel 159 Completed NCT02468739 Breast Cancer 3 Ganglioside-monosialic acid (GM1), adjuvant chemotherapy 206 Completed NCT05802342 Breast cancer 2, 3 GM1, albumin- paclitaxel 150 Not yet recruiting NCT05751668 Anatomic Stage IV Breast Cancer AJCC v8, Chemotherapy-Induced Peripheral Neuropathy, Metastatic Breast Carcinoma 2 Monosialoanglioside GM1, Paclitaxel 98 Recruiting NCT01240447 Advanced Non-small Cell Lung Cancer 2 Racotumomab 7 Completed NCT06515587 PDAC N.A Diagnostic Test : Lewis genotype test and CA19-9 ganglioside test 40 Recruiting Racotumomab (anti-idiotype antibody capable of inducing anti-N-glycolyl GM3 antibodies) hu14.18-IL2 (monoclonal antibody fused with IL2 that binds with tumor cells expressing GD2 antigen) Status of select clinical trials: The Phase II trial of Racotumomab in high-risk neuroblastoma ( NCT02998983 ) demonstrated strong immune responses with favorable safety and a two-year progression-free survival benefit in patients achieving complete or very good partial remission. Similarly, the Phase III racotumomab-alum vaccine study in advanced NSCLC ( NCT01240447 ) reported significant improvements in both overall and progression-free survival, along with robust anti-NeuGcGM3 immune responses. In contrast, the trivalent ganglioside vaccine trial in sarcoma ( NCT01141491 ) elicited strong serologic responses but failed to improve survival outcomes, and the combination of ecromeximab with interferon-α2b in metastatic melanoma ( NCT00679289 ) showed limited clinical benefit with low response rates. The hu14.18-IL2 immunocytokine trial in resectable advanced melanoma ( NCT00590824 ) yielded manageable toxicities and a subset survival benefit associated with higher tumor-infiltrating lymphocytes, while the anti-GM2 antibody BIW-8962 in multiple myeloma ( NCT00775502 ) was well tolerated but demonstrated no meaningful clinical responses. Beyond oncology, GM1 was assessed in breast cancer patients for prevention of chemotherapy-induced neuropathy: while the Phase III study ( NCT02468739 ) reported significant reductions in incidence and severity of neuropathy, a subsequent Phase II trial ( NCT04222790 ) found no added benefit over placebo in neurotoxicity scores and suggested a negative impact on quality of life. With respect to terminated studies, NCT02641782 was withdrawn without a publicly stated reason, while NCT00775502 was explicitly terminated due to lack of efficacy, as no objective responses were observed. Table 2 Summary of selected ganglioside expression patterns across different cancer types, their functional roles in tumor biology, and therapeutic strategies targeting these pathways Cancer type Ganglioside expression Functional role Therapeutic strategies Neuroblastoma GD2: Overexpressed in tumor tissues; high expression correlates with poor prognosis B3GALT4: Downregulated in neuroblastoma ST8SIA1: Downregulated in mesenchymal-like neuroblastoma Promotes tumor cell proliferation, migration; restricted expression in normal tissues; targetable surface antigen Converts GD2 to complex gangliosides; promotes recruitment of CD8 + T cells via CXCL9/10 Catalyzes GD3 synthesis upstream of GD2; affects ganglioside lineage and GD2 expression Monoclonal antibodies (Dinutuximab, Dinutuximab-beta, Naxitamab), CAR-T cells (GD2-CART01), vaccine strategies Potential tumor suppressor; overexpression enhances anti-tumor immunity Catalyzes GD3 synthesis upstream of GD2 Small Cell Lung Cancer (SCLC) GD2: up to 39% Enhances proliferation, supports CSC traits GD2 CAR-T, anti-GM2 IL-7/CCL19 CAR-T, Dinutuximab + Irinotecan, Anti-fucosyl-GM1 + Nivolumab Lung Adenocarcinoma (LUAD) GD2: up to 72% Not explicitly reported GD2 CAR-T Squamous NSCLC GD2: up to 56% Not explicitly reported GD2 CAR-T Pancreatic Ductal Adenocarcinoma (PDAC) Aberrant glycosylation & hypersialylation Promotes immune evasion (Siglec interactions), metastasis, tumor growth GSLs as biomarkers Breast Cancer GD2: 45% in TNBC CSC traits, EMT, tumor progression; poor prognosis Dinutuximab, anti-GD2 CAR-T, ST8SIA1 inhibition Prostate Cancer GD2: expressed in a subset of metastatic cells; overexpressed in Enzalutamide-resistant cells CSC traits, EMT, drug resistance ST8SIA1 knockout, GD2-targeted therapies Bladder Cancer (BLCA) GD2: Elevated in high-grade BLCA CSC phenotype, mesenchymal traits Potential GD2-targeted therapies Glioblastoma Elevated GM2, GD2, GM1, GD1a Modulate T/B cell function, induce T cell apoptosis, suppress immune responses GD2 CAR-T (H3K27M-mutated DIPG/DMG) Melanoma GD3: aberrantly expressed Promotes cell proliferation, migration, G2/M phase progression 7,8-DHF (GD3 inhibitor) Ovarian Cancer GM1b: aberrantly expressed Promote tumor growth, metastasis GCS & sialyltransferase inhibitors, Dicalcin peptide

A. Neuroblastoma Before 2009, therapy for high-risk neuroblastoma primarily consisted of surgery, localized radiotherapy, and progressively aggressive chemotherapy regimens, often followed by high-dose chemotherapy with autologous hematopoietic stem cell rescue transplantation. Despite these efforts, the 5-year relapse free survival in patients is less than 40% [ 21 ]. GD2 was observed to be overexpressed in tumor tissues, with its high expression being associated with poor prognosis in neuroblastoma [ 22 ]. Additionally, B3GALT4 , the enzyme that converts GD2 to more complex gangliosides, was found to be downregulated in neuroblastoma tissues, and low expression of B3GALT4 was indicative of poor prognosis in neuroblastoma patients [ 23 ]. Notably, B3GALT4 overexpression was observed to enhance the recruitment of CD8 + T lymphocytes via the chemokines CXCL9 and CXCL10 [ 23 ], suggesting activation of anti-tumor immunity. Owing to GD2’s restricted expression to malignant tissues and mesenchymal stromal cell, coupled with its role in cell proliferation and migration, GD2 has become an attractive target for antibody-based immunotherapies [ 24 ]. A breakthrough came with the identification of murine neuroblastoma-reactive monoclonal antibodies (mAbs) 14.18 and 3F8, recognizing disialoganglioside GD2 [ 25 ]. These mAbs exhibited significant efficacy in preclinical studies, primarily through antibody-dependent cell-mediated cytotoxicity (ADCC) mediated by Fc receptor-bearing cells, such as natural killer cells and macrophages. Subsequent phase III trials, notably the Children’s Oncology Group (COG) ANBL0032 study ( NCT00026312 ), demonstrated improved event-free survival and overall survival in patients receiving Dinutuximab, a chimeric version of mAb 14.18. The addition of interleukin-2 (IL2) and granulocyte–macrophage colony-stimulating factor (GM-CSF) further enhanced therapeutic benefit, ultimately leading to its FDA approval [ 26 ]. Dinutuximab-beta, a similar antibody to Dinutuximab but derived from different cell line, is approved in Europe [ 27 ]. Additionally, Naxitamab, a humanized version of mAb 3F8, received FDA approval for treating neuroblastoma with relapsed or refractory disease confined to bone or bone marrow [ 28 ]. These approvals highlight the therapeutic potential of utilizing GD2-targeted therapies in combating various cancers. Key challenges include relapse despite upfront anti-GD2 therapy, often driven by antigen modulation or immune escape, as well as decreased GD2 expression at relapse reflecting antigen remodeling. In addition, anti-GD2 mAb administration causes substantial neuropathic pain that limits dosing and requires intensive pain management, while recent studies further reveal heterogeneity in GD2 expression in neuroblastoma [ 29 – 32 ]. GD2 heterogeneity in neuroblastoma is driven by lineage-specific transcriptional states, with mesenchymal tumors showing reduced GD2 due to ST8SIA1 downregulation. A study revealed that tumor cell lineage plasticity drives resistance to anti-GD2 therapy in neuroblastoma and that inhibition of histone methytransferase-EZH2 can restore GD2 expression by reversing epigenetic suppression [ 32 ]. Emerging evidence suggests that GD2 density may predict response to anti-GD2 therapies [ 30 , 33 – 35 ], yet the mechanisms by which neuroblastoma cells downregulate GD2 to evade immune detection remain largely undefined.

Another phase 2 randomized clinical trial demonstrates the potential of oral β-glucan as an adjuvant during vaccine priming to enhance anti-GD2 IgG1 antibody response in patients with high-risk neuroblastoma, without causing additional toxicity. The findings underscore the significance of exploring adjuvant strategies to improve vaccine efficacy in high-risk neuroblastoma, highlighting potential for improved therapeutic strategies [ 36 ]. The role of gangliosides with innate immune cells like NK cells and macrophages in contributing to antitumor activity within neuroblastoma tumors has also been explored, with evidence showing that β-glucan can further prime these cells through Dectin-1 or CR3 activation to enhance their cytotoxic and phagocytic functions. Phase I study ( NCT00492167 ) combining yeast-derived β-glucan with the anti-GD2 monoclonal antibody 3F8 in patients with relapsed or refractory high-risk neuroblastoma. The regimen was well tolerated, with no maximum tolerated dose reached, and demonstrated tumor responses, with 2-year progression-free survival of 28% and overall survival of 61%, indicating that β-glucan can enhance anti-GD2 efficacy [ 37 ]. Clinical trials combining anti-CD47 and anti-GD2 antibodies have shown synergistic effects in overcoming Rituximab resistance in non-Hodgkin lymphoma, now under evaluation for relapsed neuroblastoma [ 33 ].

CAR-T cell therapy targeting GD2 holds promise in neuroblastoma treatment by exploiting T cell cytolytic capacity. Despite preclinical and clinical successes, challenges persist, including limited expansion and persistence in the tumor microenvironment. Engineering approaches to enhance CAR-T cell functionality must mitigate toxicity risks, such as cytokine release syndrome controlled by IL-6 blockade and off-tumor recognition reduced by suicide gene safety switches [ 38 , 39 ]. Early clinical evaluation of GD2-directed CAR T cells (GD2-CART01) in children with high-risk, relapsed or refractory neuroblastoma demonstrated promising feasibility, safety, and antitumor activity. In the initial phase 1/2 report ( NCT03373097 ) including 27 patients, GD2-CART01 was successfully manufactured in all cases, with cytokine release syndrome occurring in most patients but generally mild and manageable; one case required activation of the inducible caspase-9 suicide gene. No dose-limiting toxicities were observed, and the recommended phase 2 dose was established as 10 × 10⁶ CAR-positive T cells/kg. At this dose level, the overall response rate (ORR) was 63%, including nine complete and eight partial responses, with GD2-CART01 detectable in peripheral blood for up to 30 months. Importantly, the 3-year overall survival (OS) and event-free survival (EFS) rates were 60% and 36%, respectively [ 40 ]. More recently, the final analysis with extended follow-up (median 4.2 years) and an expanded cohort of 54 children, including patients treated under hospital exemption, confirmed and strengthened these findings. In this larger dataset, the ORR among evaluable patients was 66%, with complete remissions sustained in 40% of patients at 6 months, and GD2-CART01 persistence ≥ 12 months in 64% of cases. The 5-year OS for the trial cohort was 42.7%, but outcomes were substantially superior in the “target population” of patients treated at the recommended dose with low disease burden, who achieved an ORR of 77%, a 5-year OS of 68%, and a 5-year EFS of 53% ( NCT03373097 ) [ 41 ]. Both analyses highlight that GD2-CART01 induces durable remissions in neuroblastoma, with the best outcomes achieved in patients treated earlier in their disease course and with lower disease burden at infusion. These findings suggest that GD2-CART01 therapy holds promise as a potentially effective and well-tolerated immunotherapy for patients with high-risk neuroblastoma. Next-generation CAR-T cells incorporating additional modules may aim to improve specificity and prevent off-tumor toxicities, potentially through strategies like Boolean logic gating [ 42 ].

B. Lung cancer Studies investigating small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC) or lung adenocarcinoma (LUAD) cell lines and tissue biopsies analyzed by flow cytometry and immunohistochemistry reveals GD2 expression up to 39% in SCLC, 72% in LUAD and 56% in squamous histology [ 43 ]. Notably, higher GD2 expression in SCLC cell lines contribute to enhanced cell proliferation [ 44 ]. CAR-T therapy targeting GD2 expressing lung tumor cells in xenograft model demonstrated antigen-dependent cytotoxicity, suggesting that GD2 is a promising antigen target for CAR-T cell therapy in lung cancer [ 43 ]. Interestingly, pretreatment of GD2-low/negative lung cancer cell lines with the epigenetic drug Tazemetostat upregulated GD2 expression, suggesting a novel strategy to enhance susceptibility to CAR-T cells targeting in tumors with low GD2 expression [ 43 ]. In another study, the possibility of GM2 as a solid tumor target for CAR-T cell therapy was explored using anti-GM2, interleukin (IL)-7 and chemokine (C–C motif) ligand 19 (CCL19)-expressing human CAR-T system in a mouse model with human small-cell lung cancer. Treatment with anti-GM2 IL-7/CCL19-producing CAR-T cells resulted in complete tumor regression, abundant T cell infiltration into solid tumor tissue, and long-term memory responses, without detectable adverse events. Additionally, the Herpes simplex virus-thymidine kinase (HSV-TK) suicide gene was incorporated to limit cytokine-release syndrome and neurotoxicity [ 45 ]. Two clinical studies have evaluated disialoganglioside (GD2)-targeting strategies in relapsed/refractory small cell lung cancer (SCLC), with contrasting outcomes. In the first study, BMS-986012, an anti-GD2 antibody, showed limited efficacy as monotherapy with an objective response rate (ORR) of only 4% and a median overall survival (OS) of 5.4 months. However, when combined with nivolumab, outcomes improved substantially, with an ORR of 38%, a durable median response of 26.4 months, progression-free survival (PFS) at 24 weeks of 39.3%, and a median OS of 18.7 months, all with a manageable safety profile (pruritus being the most common adverse event) ( NCT04702880 ) [ 46 ]. By contrast, a larger phase III trial assessing dinutuximab plus irinotecan compared with irinotecan or topotecan alone did not demonstrate a survival benefit. Median OS was similar across treatment arms (6.9 vs 7.0 vs 7.4 months), with no significant differences in PFS (3.5 vs 3.0 vs 3.4 months) or ORR (17.1% vs 18.9% vs 20.2%). Clinical benefit rates were comparable, and toxicities such as neutropenia, anemia, and diarrhea were consistent with known chemotherapy-related adverse events ( NCT03098030 ) [ 47 ]. These findings suggest that GD2-directed therapy alone or in combination with chemotherapy may not confer added benefit, whereas integration with immune checkpoint blockade, as in the BMS-986012 plus nivolumab study, appears more promising and warrants further investigation in SCLC.

C. Pancreatic ductal adenocarcinoma Recent evidence using liquid chromatography electrospray ionization tandem mass spectrometry analysis from 12 paired pancreatic ductal adenocarcinoma (PDAC) tissues and normal counterparts revealed significant differences [ 48 ], suggesting aberrant glycosylation and sialylation are an integral part of malignant transformation and tumor progression. In fact, aberrant glycosylation and hypersialylation have shown to drive pancreatic ductal adenocarcinoma progression by promoting immune evasion through Siglec interactions, enhancing metastatic spread, and sustaining tumor growth signaling [ 39 , 49 , 50 ]. These findings highlight the potential of GSL as biomarkers for early detection of PDAC and other cancers, offering a promising avenue for improving diagnostic strategies.

D. Breast cancer GD2 expression has been detected by immunohistochemical analysis in 45–59% of breast cancer patients, highlighting its association with the breast cancer [ 7 , 51 ]. Investigation of GD2 expression in 76 patients with triple-negative breast cancer (TNBC) and its association with clinicopathological factors, recurrence-free survival (RFS), and overall survival (OS) revealed GD2 expression in 45% of TNBC patients, with significantly worse 5-year RFS rates and a trend towards inferior OS in GD2-positive TNBCs compared to GD2-negative TNBCs [ 7 ]. This study highlights the potential clinical significance of GD2 expression in predicting TNBC patient outcomes as an independent unfavorable prognostic factor.

Battula et al ., demonstrated that GD2 positive breast cancer cell lines exhibit characteristics features of cancer stem cells with CD44hiCD24lo expression and enhanced tumorigenic potential with mammosphere forming ability [ 52 ]. Intuitively, anti−GD2 antibody Dinutuximab showed inhibition of triple−negative breast tumor growth by targeting GD2−positive breast cancer stem−like cells [ 53 ], demonstrating therapeutic efficacy of anti−GD2 therapy in breast cancer. Further, preclinical studies with anti-GD2 CAR-T cells suggest effective elimination of GD2-positive cells with minimal toxicity [ 54 ], reflecting potential therapeutic efficacy in GD2-targeted immunotherapies for TNBC.

Despite evidence of higher GD2 expression in TNBC, the reason why only a subset of cells with stem-like characteristics express GD2 remains unclear. Intuitively, ST8SIA1, the enzyme in the ganglioside biosynthesis pathway, is overexpressed in TNBC and basal-like breast cancers and its inhibition prevents EMT and cancer stem cell (CSC) properties, suggesting GD2 expression may be regulated by ST8SIA1 levels [ 55 ]. In fact, knockout of ST8SIA1 was found to inhibit GD2 expression in TNBC cells, leading to reduced tumorigenesis and migration [ 55 ], supporting the idea that ganglioside expressions are regulated by the expression of ganglioside synthase enzymes. These results collectively support the role of ST8SIA1 in regulating GD2 expression and driving EMT, cancer stem cell properties, and tumor progression in TNBC. Taken together, targeting GD2 expression via regulation of ST8SIA1 presents an intriguing avenue for combating metastatic breast cancer [ 56 , 57 ].

E. Prostate cancer In metastatic prostate cancer (PC), recent evidence demonstrates over expression of GD2 in a subset of cells that correlates with Enzalutamide drug resistance [ 58 ]. Higher GD2 expression in PC cells is associated with CSC and EMT properties. Notably, CRISPR-Cas9 knockout of ST8SIA1 impaired oncogenic traits, reduced CSC populations and EMT marker expression, and suppressed growth of bone-implanted xenograft tumors in castration-resistant PC models, highlighting GD2 as a promising candidate for targeted therapy in advanced PC. [ 58 , 59 ].

F. Bladder cancers Tissues and cell lines of high-grade bladder cancer (BLCA), an aggressive and treatment-resistant cancer associated with poor prognosis, show elevated levels of GD2 compared to low-grade by high-resolution mass spectrometry. Notably, BLCA cell lines with high GD2 expression like UMUC3 and J82 demonstrates CSC property (CD44 hi CD24 lo ) and mesenchymal phenotype [ 60 ], similar to that observed in breast and prostate cancers. Together, these findings suggest a pan-cancer role for GD2 in CSC-mediated tumorigenesis.

G. Glioblastoma The presence and positioning of sialic acids on gangliosides play a crucial role in modulating T cell functionality. While GM3 and GD3 inhibit IL-2, GM2 and GD2 stimulate T cell proliferation by enhancing IL-2 response [ 61 ]. Conversely, GD1b, GM2, and GD3 can inhibit T cell proliferation by interfering with IL-4 signaling, with GM2 also induces apoptosis in human T cells [ 62 , 63 ]. Glioblastoma cell lines expressing CD70 and elevated levels of GM2 and GD1a are particularly prone to promoting T cell apoptosis [ 64 ]. Gangliosides GM3 and GM1 inhibit CD4 expression in murine and human T lymphocytes, while GD1a and GM3 induce IL-10 secretion, suppressing T cell production [ 65 – 67 ]. Some gangliosides, like GD1b, enhance IL-2 and IFNγ production while reducing IL-4 and IL-5, and GD3 suppresses Th17 activity in cutaneous T cell lymphoma [ 68 ]. Additionally, gangliosides modulate immunoglobulin secretion in B cells, with GM2 inhibiting IgM, IgA, and IgG production, and GD1b and GT1b suppressing IgM, IgG, and IgA production by reducing IL-6 and IL-10 release from CD4 + T cells and monocytes, respectively [ 69 , 70 ]. A recent study presents promising results from a phase I clinical trial utilizing GD2-directed CAR-T cells in patients with H3K27M-mutated DIPG or spinal cord DMG, demonstrating clinical benefit and radiographic improvement in three out of four patients [ 71 ]. Importantly, the observed toxicity was largely manageable and reversible with intensive supportive care, and no evidence of on-target, off-tumor toxicity was observed, highlighting the safety and efficacy potential of this therapeutic approach for these aggressive pediatric brain tumors. Transcriptomic analyses reveal heterogeneity in response among patients and administration routes, providing valuable insights for further optimization and personalized treatment strategies.

H. Melanoma In a study, specific anti-proliferative, anti-migratory, and G2/M phase cell-cycle arrest in response to 7,8-DHF treatment were observed on melanoma cancer cell lines with reduced the expression levels of ganglioside GD3 and its synthase, which are closely implicated in carcinogenesis, suggesting its potential as an anti-cancer drug candidate for malignant melanoma [ 72 ].

I. Ovarian cancer Small molecule inhibitors targeting ganglioside biosynthesis and metabolism have been investigated as potential anti-cancer agents. Inhibitors of enzymes involved in ganglioside biosynthesis pathways, such as glucosylceramide synthase (GCS) and sialyltransferases, have demonstrated anti-tumor activity in preclinical models [ 73 , 74 ]. These inhibitors disrupt ganglioside synthesis, leading to decreased ganglioside expression on the cancer cell surface and inhibition of tumor growth and metastasis. Dicalcin, a Ca 2+ binding protein, demonstrated the ability to suppress migration of ovarian cancer cells in vitro without affecting cell viability or proliferation. Intraperitoneal injection of a partial peptide of Dicalcin prolonged survival and reduced liver microcolonies in cancer-bearing mice by inhibiting the GM1b-Erk1/2 axis, suggesting Dicalcin as a promising novel suppressor of ovarian cancer invasion and metastasis [ 75 ].

Gangliosides’ role in shaping plasticity in cancer

Cancer plasticity reflects the ability of tumor cells to dynamically shift between phenotypic states, contributing to heterogeneity and disease progression. While this property arises from the inherent adaptability of cancer cells, recent evidence highlights that therapeutic selection pressures can further drive transitions into distinct lineages, fostering resistance and relapse [ 76 ]. This dual origin of plasticity underscores its central role in shaping tumor evolution and therapeutic outcomes. Gangliosides have been implicated in modulating cancer cell plasticity in various cancer types through multiple mechanisms including dedifferentiation to stem cell like properties and EMT, the later a process by which epithelial cells lose polarity and adhesion properties and acquire mesenchymal features that enhance motility and invasiveness.

Role in CSC maintenance : Gangliosides, have been increasingly recognized for their involvement in cancer biology, particularly in the context of cancer stem cells (CSCs). CSCs are a subpopulation of cancer cells with self-renewal capacity that drives tumor progression and therapeutic resistance. A significant proportion of CD44 hi CD24 low cells in breast cancer, which are known as breast cancer stem-like cell (BCSCs), co-expressed GD2 on their cell membrane [ 52 , 53 ]. Gangliosides have been implicated in CSC maintenance, promoting their self-renewal and tumorigenic potential. Specific ganglioside species, such as GD3 and GD2, are enriched in CSCs of various cancer types, including breast, glioblastoma, and melanoma [ 52 , 77 ]. Knockdown of B4GALNT1 and ST8SIA1 , the GTs responsible for synthesizing GD2 and GD3, respectively, led to a reversion of CSC to non-CSC phenotype, as evidenced by decreased mammosphere formation efficiency, cell motility and inhibit tumor growth in vivo [ 52 , 55 , 78 ]. Metabolic stress showed induction of GD2-positive BCSC phenotype in triple-negative breast cancer (TNBC), suggesting a link between metabolic stress induced regulation of BCSC by gangliosides [ 79 ]. Glutathione biosynthesis was found to be upregulated in GD2-high cells and inhibition of glutamine uptake using the small-molecule inhibitor V9302 significantly reduced GD2 cells and BCSC characteristics in TNBC cells, with mechanistic studies revealing inhibition of the mTOR pathway and induction of ferroptosis by V9302.

Role in EMT: Cancer cells exhibit remarkable plasticity, often transitioning between epithelial and mesenchymal states, a phenomenon known as EMT. This process, implicated in various aspects of cancer progression including metastasis and drug resistance [ 80 ]. Recent research highlights the significance of cells in intermediate EMT states, which display heightened plasticity and are linked to therapy resistance and poor prognosis across multiple cancer types [ 81 , 82 ]. While transitioning back to an epithelial state, known as mesenchymal-to-epithelial transition (MET), is believed to be rare, recent studies shed light on distinct cellular mechanisms governing EMT and MET. Interestingly, specific gene expression signatures classify cancer types into different EMT categories, underscoring the complexity of this process. Additionally, alterations in glycosphingolipids have been observed during EMT, suggesting their involvement in maintaining cellular characteristics. Of particular interest is the glycosyltransferase ST8SIA1 , identified as a key player in the glycosphingolipid pathway and a predictor of poor prognosis in cancers displaying mesenchymal characteristics. Deletion of ST8SIA1 has been hypothesized to induce MET, with emerging evidence suggesting its role in both EMT initiation and maintenance [ 83 ]. Mechanistically, ST8SIA1 's involvement in glioma progression has been associated with reduced phosphorylation of AktS473 [ 84 ]. Insights into the role of ST8SIA1 inducing EMT has also been reported in breast cancer cell lines as suppression of ST8SIA1 reduces mesenchymal cell markers and phenotypes [ 57 ]. Additionally, our previous work demonstrated that B4GALNT1 knocked out murine kidney cancer cells display more epithelial characteristics with significant reduction in EMT markers, resistance to anoikis which is a programmed anchorage dependent cell death, and elevated anchorage dependence suggesting a crucial role of GM2 and B4GALNT1 in EMT [ 11 ]. Further, studies have shown that aberrant expression of glycosyltransferases involved in N- and O-glycan synthesis can impact TGF-β signaling and contribute to TGF-β-induced EMT [ 85 , 86 ]. In a recent study, significant decrease in glycosphingolipid levels during TGF-β-induced EMT were observed in NMuMG and A549 cells, used as in vitro EMT models. Intriguingly, lower expression of ST3GAL5 was noted in lung cancer tissues compared to adjacent normal tissues, correlating with a favorable prognosis in lung cancer patients [ 87 ]. Enhanced TGF-β signaling and EMT were also noted both in vitro and in vivo upon glycosphingolipid expression inhibition via inactivation of UDP-glucose ceramide glucosyltransferase (UGCG), an enzyme involved with sphingolipid metabolism that is overexpressed in several cancers and associated with multidrug resistance [ 87 , 88 ]. The findings underscore the intricate interplay between glycosphingolipids and TGF-β signaling in EMT regulation, suggesting therapeutic potential in targeting GSL synthesis pathways, particularly through UGCG inhibition or ST3GAL5 modulation, for disrupting TGF-β-induced EMT and potentially improving cancer prognosis.

Controlling ganglioside expression: insights from genetics and epigenetics

The biosynthesis of GD2, a pivotal ganglioside in neuroblastoma and other cancers, primarily hinges upon the coordinated activity of glycosyltransferases, notably ST8SIA1 , B4GALNT1 , and B3GALT4 , which are regulated at multiple levels including epigenetic, transcriptional, and post-transcriptional mechanisms (Fig. 2 ). Interestingly, the transcriptional regulation of these key enzymes lacks conventional promoter elements and exhibits GC-rich boxes, resembling constitutively active genes. This underscores the significance of epigenetic modifications in shaping ganglioside expression patterns, particularly during physiological development and in cancer contexts. In cancers with low GD2 expression, such as Ewing sarcoma and certain neuroblastomas, targeting epigenetic modifications that silence gene expression has shown to augment GD2 levels [ 20 ]. Interestingly, co-culture of neuroblastoma cells, particularly those in the mesenchymal state with lower baseline GD2 expression, has been shown to upregulate GD2 and enhance the efficacy of anti-GD2 antibodies, supporting combination strategies to overcome lineage-driven resistance [ 89 ]. Consistently, pharmacologic inhibition of the histone methyltransferase EZH2 in mesenchymal neuroblastoma cells led to ST8SIA1 re-expression, restoration of surface GD2, and renewed sensitivity to anti-GD2 antibody therapy, confirming the role of epigenetic suppression in regulating GD2 [ 32 ]. Fig. 2 Genetic and epigenetic regulation of ganglioside synthase genes. This figure illustrates the complex mechanisms that regulate ganglioside synthase gene expression at both the genetic and epigenetic levels. Epigenetic modifications including DNA methylation, which typically suppresses gene expression, and histone acetylation or deacetylation, which respectively open or compact chromatin play a central role in controlling the accessibility of the gene to transcriptional machinery. Promoter motifs, such as SP1 binding sites and GC-rich sequences, act as cis-regulatory elements that serve as docking sites for transcription factors and other regulatory proteins, directly influencing the initiation and rate of transcription. The integration of these epigenetic modifications and promoter-driven signals determines whether ganglioside synthase genes are actively transcribed or silenced in a given cellular context. By modulating these regulatory layers, cells can precisely control ganglioside levels, which are critical for processes such as cell signaling, adhesion, and interaction with the immune system. This schematic emphasizes how alterations in these mechanisms through mutations, epigenetic changes, or dysregulated transcription factor activity can impact ganglioside expression in both normal physiology and pathological conditions such as cancer

B4GALNT1 and B3GALT4 exhibit complex regulation involving multiple promoters and associated transcription factor binding sites. Tissue or cell specificity in promoter usage underscores the control of ganglioside expression. In the analysis of B4GALNT1 gene, multiple transcription initiation sites and 5’-uncoding exons have been identified, shedding light on the regulatory mechanisms for these ganglioside synthase genes by us and other groups [ 6 , 90 , 91 ]. B4GALNT1 harbors an SP1 site in its promoter which is negatively regulated [ 6 ]. Clear promoter activity has been also observed in the regions containing SP1-recognition motifs in the promoter analysis of the ST8SIA1 , along with suppression activity at the upstream unique GT/CG repeat sequences [ 90 ], indicating a complex regulatory landscape characterized by frequently occurring GC sequences and the absence of TATA boxes in the promoter regions of glycosyltransferase genes.

Reportedly ST8SIA1 is a marker for glioblastoma stem cells and breast cancer stem cells [ 52 , 77 ], and its expression is regulated by promoter methylation [ 92 ]. DNA methylation of the promoter region of ST8SIA1 is suggested to play crucial roles in regulating gene expression, thereby enhancing malignant phenotypes [ 84 ], modulating tumor microenvironments [ 93 ], and influencing cancer stem cell properties in gliomas [ 77 ]. Further, work from our group and others have demonstrated that increased B4GALNT1 mRNA expression is contributed by higher histone acetylation particularly H3K9 and H3K14 acetylation at B4GALNT1 promoter in various cancer cell lines and renal cell carcinoma patients similar to that observed in brain during development [ 6 , 94 ]. Taken together, epigenetic regulation of GD2 biosynthetic enzymes such as ST8SIA1 and B4GALNT1 offers opportunities to enhance GD2 expression in otherwise low-expressing tumors, thereby improving responsiveness to anti-GD2 immunotherapies.

Challenges and future directions

Regulation of ganglioside synthase genes: Despite promising data, several biological and clinical challenges remain. While targeting transcriptional control of ganglioside synthesis holds promise as a therapeutic strategy for cancer, several challenges must be addressed to realize its full potential in clinical practice. First, the transcriptional control of ganglioside synthesis involves a complex network of regulatory mechanisms and factors, including transcription factors, epigenetic modifications, and signaling pathways which often overlap with regulation of other key genes. Understanding the intricacies of these regulatory processes presents a significant challenge for developing targeted therapies. Second, modulating transcriptional control of ganglioside synthesis may have indirect effects on cellular physiology beyond ganglioside expression such as immune modulation, cell adhesion, and apoptosis resistance. Antigen escape: Ganglioside-targeted therapies hold immense promise for cancer treatment, yet several challenges must be addressed to maximize their clinical efficacy (Fig. 3 ). One major hurdle is achieving selective targeting of cancer cell-expressed gangliosides while sparing normal cells, thus minimizing off-target effects. Strategies aimed at enhancing the specificity of ganglioside-targeted therapies are imperative to mitigate potential adverse effects on healthy tissues. Gangliosides are often overlooked due to their lipid nature, which complicates detection in FFPE tissues. This challenge is further compounded because lipid extraction occurs during the processing of formalin-fixed, paraffin-embedded (FFPE) samples. Additionally, predicting a GD2-positive phenotype using genomic and transcriptome data remains largely unexplored, as it requires understanding the combinatorial interactions of multiple genes involved in ganglioside synthesis. A recent study demonstrated that two-gene signature ( ST8SIA1 and B4GALNT1 ) may aid in identifying GD2-positive medulloblastoma and the ganglioside profile could potentially reflect differentiation status in neuroblastoma and help define medulloblastoma subtypes [ 95 ], however such studies in other cancer types warrants further investigation through prospective clinical studies. Moreover, the development of resistance to ganglioside-targeted therapies poses a significant clinical challenge. Cancer cells can employ various mechanisms to evade the effects of these therapies, including upregulation of alternative survival pathways and alterations in ganglioside expression profiles. Understanding these resistance mechanisms is crucial for devising effective therapeutic strategies to overcome treatment resistance and improve patient outcomes. Delivery challenge: Advances in drug delivery are opening new avenues to improve the safety and efficacy of ganglioside-directed agents. GD2-coated nanoparticle-based formulations have enabled tumor-specific delivery and controlled release in neuroblastoma and glioblastoma models [ 96 , 97 ]. Bispecific antibodies engaging both GD2 and immune checkpoint molecules such as B7-H3, or tumor-associated antigens such as GPC2 demonstrated enhanced cytotoxicity while limiting antigen escape [ 98 , 99 ]. Antibody–drug conjugates directed against GD2 demonstrated potent cytotoxic and provided a strategy to overcome resistance mechanisms [ 100 , 101 ]. Collectively, these platforms hold promise for broadening the therapeutic window and expanding the clinical application of GD2-targeted therapies (Table 3 ). Interestingly, ganglioside-directed therapies represent a unique class within cancer immunotherapy, differing fundamentally from established protein-targeted approaches such as PD-1, HER2, or CD20. Whereas immune checkpoint inhibitors like anti-PD-1 enhance antitumor immunity by reversing T-cell exhaustion, and HER2 or CD20 antibodies target lineage-specific surface proteins with well-characterized biology, gangliosides such as GD2 are glycosphingolipid antigens enriched on tumors of neuroectodermal origin. Importantly, GD2-targeted strategies may complement checkpoint blockade by augmenting effector cell activity, or be combined with lineage-restricted antigens (e.g., HER2, GPC2) to mitigate antigen escape, thereby broadening the therapeutic repertoire available in oncology. Their membrane localization and restricted expression on normal tissues make them attractive for monoclonal antibodies, antibody–drug conjugates, and cell-based therapies. However, their relatively low immunogenicity and heterogeneous expression patterns pose distinct challenges. Efficient delivery of ganglioside-targeted therapies to tumor sites remains a critical obstacle, especially considering biological barriers such as the blood–brain barrier. Optimization of drug delivery systems and pharmacokinetic profiles is essential to ensure adequate drug concentrations at tumor sites while minimizing systemic toxicity. Innovative targeting strategies, such as antibody–drug conjugates, nanoparticles, and gene editing technologies like CRISPR-Cas9 or base editing, offer promising avenues to enhance the specificity and efficacy of ganglioside-targeted therapies. Combining ganglioside-targeted therapies with conventional treatments, immunotherapies, and targeted agents may synergistically overcome resistance mechanisms and improve treatment outcomes. Notably, several gangliosides rely on specific signaling pathways including but not limited to MAPK signaling, the crosstalk of which determines ganglioside mediated tumorigenic phenotype suggesting combinatorial strategies employing anti-ganglioside monoclonal antibody along with MAPK inhibitors might provide effective outcome [ 102 ]. Rational design of combination regimens based on mechanistic insights is crucial for maximizing therapeutic efficacy. Regulatory or manufacturing challenges for GD2-targeted agents: The development and clinical deployment of GD2-targeted agents face several regulatory and manufacturing challenges. Large-scale production of monoclonal antibodies and CAR-T cells requires rigorous quality control, standardized potency assays, and reproducible manufacturing platforms, all of which are resource-intensive and time-consuming. Regulatory oversight is particularly stringent due to the risk of on-target/off-tumor neurotoxicity, as GD2 is expressed on peripheral nerves. In clinical settings, this manifests most commonly as neuropathic pain, which is typically managed through opioid-based analgesia, gabapentinoids, and optimized infusion protocols. Additional immune-related adverse events such as cytokine release syndrome (CRS) and neurotoxicity in CAR-T therapy necessitate careful dosing strategies, early monitoring, and the use of tocilizumab or corticosteroids when indicated. Risk stratification approaches, including step-up dosing regimens, have also been incorporated to mitigate acute toxicities. To further enhance safety, innovative measures such as the incorporation of suicide gene switches (e.g., inducible caspase-9 systems) into CAR-T constructs provide a controllable mechanism to ablate engineered cells in the event of severe or refractory toxicity. Dual-antigen targeting and armored CAR-T platforms are also being explored to reduce off-tumor effects and improve tumor selectivity. Overcoming these hurdles will therefore depend not only on optimizing bioprocessing pipelines and harmonizing regulatory guidelines but also on integrating robust toxicity management strategies, precision dosing, and next-generation safety switches to enhance both accessibility and therapeutic efficacy. Predictive biomarkers: Identifying predictive biomarkers of response to ganglioside-targeted therapies particularly by modern lipidomic approaches, specifically those involving orbitraps facility can facilitate patient selection and enable personalized treatment approaches [ 103 ]. Biomarker discovery efforts should focus on molecular signatures associated with ganglioside expression and therapy response, thereby enabling more precise and effective treatment strategies. Furthermore, advanced preclinical models, including patient-derived xenografts, organoids, and genetically engineered mouse models, offer valuable tools to investigate the efficacy and mechanisms of ganglioside-targeted therapies in diverse cancer types. Insights gained from these models can inform clinical trial design and improve the translation of ganglioside therapy from bench to bedside. Fig. 3 Mechanisms of Resistance to GD2-Targeted Immunotherapy and Re-sensitization Strategies in Cancer: This figure depicts how tumor cells develop resistance to GD2-targeted immunotherapies and highlights strategies to overcome this resistance. GD2, a cell-surface ganglioside highly expressed in certain tumor cells, serves as a key immunotherapeutic target for monoclonal antibodies and CAR-T-cell therapies. While tumor cells with high GD2 expression are generally sensitive to these treatments, resistance can occur through mechanisms such as decrease in ganglioside-GD2 expression, antigen remodeling, where the epitope is altered, and intratumoral heterogeneity, where subpopulations of cells exhibit variable GD2 levels, allowing some cells to evade therapy. Re-sensitization strategies aim to restore GD2 expression and enhance therapeutic efficacy. These include epigenetic modulation, which alters chromatin structure through histone modifications or DNA hypomethylation to reactivate silenced GD2 genes, and combination therapies, in which CAR-T cells are paired with epigenetic modulators to increase antigen availability and improve cytotoxic targeting. Collectively, these mechanisms and interventions provide a framework for overcoming resistance and improving the clinical potential of GD2-directed immunotherapies in cancer Table 3 Comparative perspective of different platforms targeting gangliosides Platform Strengths Weaknesses / limitations Regulatory status / notes Monoclonal Antibodies (mAbs) Well-characterized, relatively straightforward manufacturing, established dosing regimens, high target specificity On-target/off-tumor toxicity (e.g., neuropathic pain), infusion-related reactions, limited tumor penetration in some cases Several approved in neuroblastoma; clinical trials ongoing in SCLC (e.g., BMS-986012) CAR-T Cells Highly potent, customizable, can target multiple antigens, long-term persistence Cytokine release syndrome (CRS), neurotoxicity, complex manufacturing, high cost, stringent regulatory oversight Approved for hematologic malignancies; early-phase trials in solid tumors including GD2-positive cancers Antibody–Drug Conjugates (ADCs) Targeted delivery of cytotoxic payloads, can overcome resistance mechanisms, improved efficacy in resistant tumors Off-target toxicity, linker instability, heterogeneous payload distribution, complex production Several ADCs approved for other indications; GD2-targeted ADCs in early-phase trials Vaccines Safe, minimally toxic, can induce long-term immune memory Modest clinical efficacy, often require adjuvants or combination strategies, slower onset of action Mostly investigational; clinical trials ongoing in neuroblastoma and other GD2-positive cancers

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Acknowledgements

The authors sincerely acknowledge Dr. Kaushik Biswas, Professor and Head, Division of Molecular Medicine at Bose Institute, India for his valuable insights and continued support during the preparation of this review.

Author contributions

A.B. conceived the study and drafted the main manuscript. S.B. and A.B. prepared the figures. S.R.M. and A.D. contributed to manuscript writing and critical editing. All authors reviewed and approved the final version of the manuscript.

Funding

This work was partially supported by Gennova Biopharmaceuticals Ltd, Pune, Maharashtra, India, through corporate social responsibility (CSR) funding.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable. This is a review based on published literature, with no experimental work performed.

Consent for publication

Not applicable.

Competing interests

Avisek Banerjee declares they are a Guest Editor for Discover Oncology and confirms that they were not involved in the handling or decision-making of their own submission.

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