Table 3 Current advances in CSC-targeted therapeutics: approaches, key technologies, and potential benefits

Next-generation metabolic inhibitors

Targeting multiple metabolic pathways

Dual inhibition of glycolysis and OXPHOS

2-DG + oligomycin/metformin⁴⁸⁶

- Limiting CSC survival and adaptability

- Preventing metabolic plasticity-driven resistance^311,490

Metformin + JQ-1/LY294002^287,487

Glycolysis inhibitor + FAO inhibitors

CPT1A inhibitors^362,488

Glycolysis inhibitor + Glutaminase inhibitor

CB-839⁴⁸⁹

Bioengineering and synthetic biology

Targeting CSCs with engineered cells, circuits, and viruses^485,495

Multitarget CAR-T cells⁴⁹²

CD44, CD133, EpCAM, LGR5 (targeting multi-CSC markers)

- Increased CSC target therapeutic specificity and efficacy

- Overcoming limitations of conventional therapies

Armored CAR-T cells⁴⁹³

IL-12, IFN-γ (secreting pro-inflammatory cytokines)

TCR-engineered T cells⁴⁹⁴

Targeting intracellular CSC antigens presented by MHC complex

AND-gated synthetic gene circuits

Therapeutic activation occurs only when multiple CSC-specific markers are present

Self-regulating feedback loops

Improving T-cell persistence and preventing exhaustion

Oncolytic viruses (OV)

Selectively replicating within CSCs to induce tumor cell lysis and anti-tumor immune response^497,498,499

Bioinformatics-driven personalized therapies

Integrating multi omics data and computational modeling

Integrating multiomics data (genomics, transcriptomics, proteomics, metabolomics, lipidomics)^500,501

Identifying CSC-specific vulnerabilities and optimizing personalized therapeutic strategies

- Optimizing personalized therapeutic strategies

- Accelerating the discovery of novel targets and therapies

RNA-seq-based deep learning models^502,511

Classifying CSC populations and aiding in the selection of targeted therapies

Computational models

Predicting CSC plasticity and designing adaptive therapeutic strategies

AI-driven drug discovery platforms^504,505

Screening CSC-targeted drugs (using in silico molecular docking)

Bioinformatics^506,507,512

Developing patient-specific CSC vaccines