It remains a great challenge to eliminate CSCs and improve the survival of patients, because CSCs are typically quiescent and resistant to conventional radio- and chemotherapy [
32,
33]. It was believed that CSCs largely contribute to formation of clinically undetectable minimal residual disease(MRD) after conventional anti-tumor therapies, and therefore are implicated in disease persistence or relapse. Alterations in cellular bioenergetics impart CSCs in MRD to develop adaptive or acquired resistance to anti-tumor therapy, thus leading to tumor recurrence [
34]. For example, comprehensive transcriptomic and metabolic analyses of oncogene ablation-resistant pancreatic cancer cells possessing CSCs characteristics revealed enhanced mitochondrial respiration but diminished dependence on the Warburg effect, as well as increased autophagy and lysosome activity, suggesting metabolic alterations and active autophagy are critical features of CSCs [
35]. Autophagy primarily acts as a lysosomal dependent metabolic-recycling mechanism which is important for cell survival in stress [
36‐
38]. It has been considered that autophagy may exert a anticarcinogenic role in early stage of cancer development by safeguarding against genomic instability through the clearance the old and dysfunctional mitochondria and protein aggregates [
36,
39]. Furthermore, autophagy may exert tumor suppressive function through destabilizing the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2), which imparts tumor cells with resistance to redox stress [
40]. Nevertheless, active autophagy is recognized as one of the hallmarkers of cancer [
41]. In established cancers, constitutive activation of autophagy contributes to accquired therapeutic resistance. For example, active autophagy protects glioblastoma multiforme (GBM) cells from the unfavorable tumor microenvironment characterized by hyper-oxidative, hypoxic, nutrient-poor conditions [
42]. Further more, compelling evidence suggests that autophagic-lysosomal pathway largely contributes to generation, maintenance and differentiation of CSCs [
43]. Many studies have shown that CSCs frequently have higher basal level of autophagy than that of non-stem cancer cells. Active autophagy help CSCs to rapidly respond to metabolic stress to maintain their energetic balance. For example, the fusion of lipid droplets with autophagosomes, a process named lipophagy, confer a survival advantage on oncogene ablation-resistant pancreatic cancer cells through increase of fatty acid β-oxidation [
35]. A number of studies have shown either chemical or genetical blockade of autophagy impairs self-renewal and tumorigenicity of CSCs [
44‐
46]. Recent studies revealed that some of “conventional” agents used in non-cancerous diseases treatment exert antitumor therapeutic effects by modulating autophagic pathway, suggesting that drug re-positioning targeting autophagy may be a promising therapeutic strategies for human malignancies [
40].
Ferroptosis is recognized as an iron-dependent form of nonapoptotic cell death implicated in various human diseases, including ischemic tissue damage and human malignant diseases [
47]. Recent study unveiled the crucial role of autophagy in ferroptosis. Pharmacological induction of ferroptosis leads to lysosomal degradation of cellular iron storage proteins ferritin and ferritinophagy cargo receptor NCOA4 in an autophagy dependent manner (a process known as ferritinophagy), suggesting the close relationship between ferroptosis and autophagic cell death [
48]. Recently, a synthetic derivative of natural product salinomycin named as ironomycin sequesters lysosomal iron and induces ferroptosis, showing a selective antitumor activity against breast CSCs in vitro and in vivo [
49]. In addition, ferroptosis is triggered by iron-dependent excessive lipid hydroperoxides accumulation due to insufficient antioxidant glutathione (GSH) level, the cystine/glutamate antiporter system x(c)(−) is likely to be involved [
50]. System x(c)(−) is composed of a light chain, xCT, and a heavy chain, 4F2 heavy chain (4F2hc) [
50]. Upregulation of xCT contributes to drug resistance in pancreatic cancers [
51]. Up-regulation of xCT also has been demonstrated in other cancers in including lymphomas [
52], and gliomas [
53,
54]. CD44v has recently been shown to involved in the scavenging of ROS via the stabilization of xCT protein at the cellular membrane, thus activation of CD44v-xCT-GSH axis play a crucial role in redox regulation of CSCs and is likely contribute to the relapse and distant metastasis after repeated radiation therapy [
55]. Remarkably, chemotherapy is able to induce ectopic expression of CD44v, which is evidenced in osteosarcoma and hepatic cancer cells of the Li-Fraumeni patient [
56]. This is probably due to the selective clonal amplification of undetectable number of CD44v8–10-positive CSCs under the pressure of excessive ROS after radiation and chemotherapy.