Autophagy, a conserved cellular degradation process, exhibits dual roles in cancer—suppressing
tumorigenesis early while promoting progression in established tumors. Cancer stem cells (CSCs),
key drivers of therapy resistance and metastasis, leverage autophagy for survival, yet the therapeutic
potential of autophagy inhibition remains contested. This meta-analysis evaluates autophagy’s contextdependent
role in CSCs and the efficacy of its inhibition across malignancies. Following PRISMA
guidelines, 45 experiments from 26 preclinical and clinical studies were analyzed. Autophagy inhibition
significantly reduced CSC populations (pooled SMD = -1.89; 95% CI: -2.75 to -1.03; p < 0.001), with
heterogeneity (I² = 72%) reflecting cancer-type variability. Subgroup analyses revealed pronounced
effects in leukemia (SMD = -1.85) and breast cancer (SMD = -3.02), while glioblastoma showed
moderate reductions (SMD = -1.01). Clinically, combining chloroquine with temozolomide improved
glioblastoma survival (HR = 0.36; p = 0.001). Autophagy supports CSC resilience through metabolic
adaptation, stemness maintenance, and therapy resistance, yet its tumor-suppressive roles in normal
cells necessitate precision. Findings underscore autophagy inhibition as a promising strategy to target
CSCs, particularly in advanced disease, but highlight the imperative for context-driven approaches,
biomarker-guided patient stratification, and combinatorial regimens to optimize therapeutic outcomes.
This duality positions autophagy as both friend and foe in CSCs.
