Glucose-Conjugated Anti-Cancer Therapies: Targeting Tumor
Metabolism and Sialylation to Enhance Immune Clearance
Ian Y.H. Chua
1, 2, 3, 4
7 February 2025
Abstract
The metabolic reprogramming of cancer cells, characterized by increased glucose
uptake and overexpression of glucose transporters (GLUTs), presents a promising target
for cancer therapy. Exploiting this phenomenon, researchers have developed glucose-
conjugated anticancer agents designed to enter malignant cells while minimizing toxicity
to normal tissues selectively. This review explores the development and eicacy of
glucose-based drug delivery systems, including glucose-conjugated
chemotherapeutics, glycolysis inhibitors, and glucose-coated nanoparticles.
Furthermore, recent advances in targeting cancer cell sialylation to unmask tumors for
immune clearance are discussed, including the use of glucose-conjugated sialylation
inhibitors and antibody-sialidase conjugates. While preclinical and clinical trials have
demonstrated varying degrees of success, challenges such as drug resistance and
metabolic adaptability remain. Future directions include the optimization of glucose-
based drug delivery, combination therapies, and the integration of metabolic inhibitors
with immunotherapies. Understanding these mechanisms provides a foundation for
designing more eective and selective cancer treatments.
1. Introduction
Cancer cells exhibit increased glucose consumption, a phenomenon known as the
Warburg eect, where glycolysis is favored even in the presence of oxygen. This
metabolic alteration is associated with upregulated GLUT expression, providing a unique
opportunity for selective drug targeting. In addition, many tumors evade immune
surveillance by upregulating sialic acid residues on their surfaces, creating a protective
glycocalyx. Strategies targeting both glucose metabolism and sialylation have emerged
as promising approaches in cancer therapy. This review provides a comprehensive
analysis of glucose-conjugated anticancer therapies, clinical trial outcomes, and future
directions in targeting metabolic vulnerabilities and immune evasion mechanisms.
2. Glucose-Conjugated Anticancer Agents
2.1. Glucose-Conjugated Chemotherapeutics
Glucose-conjugated drugs exploit the high GLUT expression in cancer cells for selective
drug delivery.
• Glufosfamide: A conjugate of glucose and isophosphoramide mustard, designed
to utilize glucose transport mechanisms for enhanced tumor targeting. While
Phase I and II trials demonstrated some eicacy in pancreatic cancer, subsequent
trials did not show signicant improvement over standard therapies (Mazur et al.,
2011).
• Camptothecin Derivatives: Studies have shown that glucose-linked
camptothecin derivatives enhance selective tumor targeting, increasing drug
solubility and minimizing systemic toxicity (Molejon et al., 2020).
2.2. Glycolysis Inhibitors
• 2-Deoxy-D-Glucose (2-DG): A glucose analog that competes with glucose for
uptake, inhibiting glycolysis and ATP production. Despite promising preclinical
results, its clinical eicacy remains limited due to metabolic compensation
mechanisms (Wick et al., 1957).
• 3-Bromopyruvate (3-BP): An inhibitor of glycolysis targeting hexokinase-2 (HK2),
eectively disrupting cancer metabolism (Ko et al., 2004).
2.3. Glucose-Coated Nanoparticles
• Glucose-functionalized nanoparticles improve drug delivery by enhancing tumor
uptake and reducing o-target toxicity. Studies show improved eicacy when
combined with chemotherapeutics such as doxorubicin (Martin et al., 2022).
3. Targeting Sialylation to Enhance Immune Clearance
3.1. Role of Sialylation in Cancer
Sialylation contributes to immune evasion by masking tumor antigens and inhibiting
immune cell activation through Siglec receptors. Reducing sialylation can restore
immune recognition and enhance tumor clearance.
3.2. Glucose-Conjugated Sialylation Inhibitors
• Peracetylated 3Fax-Neu5Ac (PFN) Prodrug: A glucose-conjugated sialylation
inhibitor activated by tumor-specic metabolites, selectively reducing sialic acid
expression and increasing immune susceptibility (Kasahara et al., 2024).
3.3. Antibody-Sialidase Conjugates
• HER2-Sialidase Fusion Proteins: Antibody–sialidase conjugates selectively
desialylate cancer cells, enhancing natural killer (NK) cell-mediated cytotoxicity.
Studies show improved immune clearance and synergy with existing
immunotherapies (Xiao et al., 2016).
4. Challenges and Future Directions
4.1. Drug Resistance and Tumor Adaptability
• Cancer cells exhibit metabolic plasticity, shifting to alternative fuel sources (e.g.,
lipids, amino acids) when glycolysis is inhibited.
• Combination strategies incorporating glucose-conjugated drugs with metabolic
inhibitors (e.g., metformin) may improve therapeutic eicacy.
4.2. Optimizing Drug Delivery
• Advancements in nanoparticle-based delivery systems can improve targeted drug
accumulation and reduce systemic toxicity.
4.3. Integrating Immunotherapy
• Combining glucose-targeting therapies with immune checkpoint inhibitors (e.g.,
anti-PD-1/PD-L1) could enhance anti-tumor immune responses.
• Personalized therapy approaches based on tumor GLUT and sialylation proles
may optimize patient selection.
5. Conclusion
The use of glucose as a Trojan horse for drug delivery represents a promising strategy for
cancer therapy. By exploiting the Warburg eect and targeting sialylation, researchers
have developed innovative therapeutic approaches aimed at enhancing drug selectivity
and immune clearance. While clinical outcomes have been mixed, ongoing
advancements in metabolic and immune-targeting strategies hold promise for future
therapeutic breakthroughs. Further research should focus on optimizing combination
strategies, rening targeted delivery mechanisms, and improving patient stratication to
maximize treatment eicacy.
Acknowledgments
This paper was developed with the assistance of ChatGPT 4.0, which provided insights and renements in the
articulation of philosophical and scientic concepts.
1
Founder/CEO, ACE-Learning Systems Pte Ltd.
2
M.Eng. Candidate, Texas Tech University, Lubbock, TX.
3
M.S. (Anatomical Sciences Education) Candidate, University of Florida College of Medicine, Gainesville, FL.
4
M.S. (Medical Physiology) Candidate, Case Western Reserve University School of Medicine, Cleveland, OH.
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