Table 2 Advantages and limitations of current CSC-targeting strategies
From: Cancer stem cells: landscape, challenges and emerging therapeutic innovations
Strategy | Mechanism | Advantages | Limitations |
|---|---|---|---|
Targeting CSC-specific pathways (Wnt, Notch, Hedgehog) | Inhibits CSC self-renewal and differentiation pathways | - Directly targets core CSC maintenance mechanisms - Potential to prevent tumor recurrence | - Pathway inhibitors may affect normal stem cells - High variability in pathway activation across cancers |
Immunotherapy (CAR-T-cell therapy, immune checkpoint inhibitors) | Enhances immune-mediated CSC eradication | - Potential for long-lasting immune memory against CSCs - Combination with other therapies can enhance efficacy | - CSCs exhibit immune evasion mechanisms - Tumor microenvironment suppresses immune activity |
Metabolic targeting (OXPHOS, FAO, glutaminolysis inhibitors) | Disrupts CSC metabolic flexibility to induce cell death | - Targets metabolic vulnerabilities of CSCs - Can be used in combination with standard therapies | - CSCs exhibit metabolic plasticity, leading to escape mechanisms - Potential systemic toxicity due to normal cell metabolism interference |
Epigenetic therapy (DNA methylation and histone modifiers) | Reprograms CSC epigenetic landscape to reduce tumorigenic potential | - Potential to reverse therapy resistance mechanisms - Can be combined with existing targeted therapies | - Epigenetic alterations are highly dynamic and reversible - Off-target effects on normal stem cells |
CSC-specific surface marker targeting (CD44, CD133, EpCAM inhibitors) | Selectively eliminates CSC populations expressing unique markers | - Minimizes damage to non-CSC tumor cells - Can be used in antibody-based therapies | - No universal CSC marker across all cancers - Marker expression can fluctuate under environmental stress |
TME-modulating strategies (CAFs, TAMs, vascular niche disruption) | Disrupts supportive stromal interactions to weaken CSC survival | - Targets CSC dependencies beyond intrinsic factors - Reduces resistance to metabolic and immune therapies | - High interpatient variability in the TME composition - Complex interactions may limit therapy specificity |
Combination therapies (dual-targeting metabolism, CSCs & TME, CSCs & immunotherapy) | Simultaneously, targets multiple CSC vulnerabilities | - Lowers the risk of CSC adaptation and resistance - Potentially more effective in preventing relapse | - Increased risk of toxicity due to multitargeting - Challenges in optimizing dosing and patient stratification |
