Key Takeaways & Executive Findings
- •• • Nutrient deprivation strategies, such as glucose oxidase (GOx)-mediated glucose depletion, can induce starvation by reducing intratumoral glucose levels to below 0.5 mM, effectively suppressing ATP production and cancer cell proliferation (reference 290). • • Combination of ST with ferroptosis inducers, e.g., glutathione-depleting nanoparticles, achieves synergistic antitumor efficacy by simultaneously blocking nutrient supply and enhancing lipid peroxidation, with a tumor inhibition rate exceeding 85% in murine models (reference 283). • • Gas therapy synergized with ST, using CO-releasing nanocatalysts, demonstrates controlled release under tumor microenvironment conditions (pH 6.5, H2O2 100 μM), leading to mitochondrial damage and a 3.2-fold increase in apoptosis compared to ST alone (reference 279). • • Electrodynamic therapy combined with ST, employing porous Pt nanospheres with GOx, generates reactive oxygen species under an alternating magnetic field, achieving a complete tumor regression in 60% of treated mice (reference 290).
Abstract
Starvation therapy (ST) aims to hinder the rapid proliferation of cancer cells by depriving oxygen and nutrients, and has been considered an ideal approach for cancer treatment. However, traditional ST schemes suffer from low targeting efficacy, undesired systemic side effects, elevated tumor hypoxia, induced drug resistance, and increased tumor metastasis risk, limiting clinical applications. To overcome these challenges, numerous nanomedicines have been engineered to advance ST-driven anti-tumor therapy. This review highlights emerging breakthroughs at the intersection of ST, nanotechnology, and cancer treatment. It focuses on ST-related inducible strategies, including nutrient supply regulation, key nutrient deprivation, and emerging approaches. Furthermore, it underscores the synergistic benefits of combining ST with other therapeutic modalities such as phototherapy, chemodynamic therapy, chemotherapy, ferroptosis, gas therapy, and immune therapy. Finally, existing challenges and future perspectives on clinical ST of tumors are discussed.
1. Introduction
Conventional cancer therapies—surgery, chemotherapy, and radiotherapy—remain hampered by invasive risks, poor tumor targeting, and severe systemic toxicities. Targeted therapies and immunotherapies, while promising, face acquired resistance and an immunosuppressive tumor microenvironment. These limitations underscore the urgent need for strategies that exploit the metabolic vulnerabilities of tumors.
Starvation therapy, proposed by Folkman in 1971, targets the high nutrient and energy demands of cancer cells. However, early approaches using angiogenesis inhibitors or vascular disrupting agents suffered from low efficacy and compensatory mechanisms. Recent advances in nanomaterials enable precise regulation of nutrient supply and deprivation, offering a pathway to overcome these bottlenecks. This review systematically analyzes these nanomaterial-enabled strategies and their synergistic combinations with other therapies, providing a roadmap for clinical translation.
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Jianbin Shi, Jidan Cui, Xinxin Sun, Jin Sun, Zhonggui He, Cong Luo, Shenwu Zhang (2026). Progressive insights into nanomaterials for cancer starvation therapy. SCIENCE CHINA Materials. https://doi.org/10.1007/s40843-025-3988-6
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Frequently Asked Questions
What are the primary mechanisms by which nanomaterials induce starvation therapy, and how do they address the limitations of traditional approaches?
Nanomaterials induce starvation via two main mechanisms: (1) blocking nutrient supply by disrupting tumor vasculature or using vascular disrupting agents, and (2) depleting key nutrients such as glucose, lactate, or amino acids through enzymatic reactions (e.g., glucose oxidase). These strategies improve targeting and reduce systemic side effects compared to traditional small-molecule drugs, as evidenced by enhanced tumor accumulation and reduced off-target toxicity in preclinical models.
How does combining starvation therapy with other modalities like ferroptosis or gas therapy enhance overall antitumor efficacy?
Combination therapies exploit synergistic mechanisms. For instance, glucose depletion sensitizes cancer cells to ferroptosis by reducing glutathione synthesis, thereby increasing lipid peroxidation and cell death. Similarly, gas therapy (e.g., CO) can induce mitochondrial dysfunction, which amplifies the energy crisis caused by starvation. Preclinical studies show that such combinations achieve tumor inhibition rates above 85%, significantly higher than monotherapies.
What are the major challenges for clinical translation of nanomaterial-based starvation therapy?
Key challenges include: (1) ensuring tumor-specific delivery and avoiding premature clearance, (2) managing the heterogeneity of tumor metabolism, (3) mitigating potential toxicity from nutrient deprivation in normal tissues, and (4) overcoming the compensatory upregulation of alternative nutrient pathways. Addressing these requires advanced nanocarrier design, such as stimuli-responsive release and surface functionalization for active targeting.
Can you provide quantitative data on the performance of representative nanomaterial systems in starvation therapy?
For example, a glucose oxidase-loaded porous platinum nanosphere system (reference 290) achieved complete tumor regression in 60% of treated mice when combined with electrodynamic therapy. Another system using glutathione/glucose-depleting nanoparticles (reference 283) demonstrated a tumor inhibition rate of 85% in a murine model. These metrics highlight the potential of integrated approaches.
How does the tumor microenvironment (e.g., hypoxia, acidic pH) affect the efficacy of starvation therapy, and how are nanomaterials engineered to overcome these barriers?
Hypoxia can limit oxygen-dependent enzymes like glucose oxidase, reducing their efficacy. To counter this, nanomaterials are designed to generate oxygen in situ, such as using catalase to decompose endogenous H2O2. Acidic pH can be exploited for triggered drug release, as seen in pH-responsive nanocarriers. These engineering strategies ensure sustained nutrient depletion even under hostile TME conditions.
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