Table 2.

Crucial anticancer mechanisms associated with copper deficiency and their detailed descriptions.

Mechanism	Detailed Description	Reference
Suppress Compensatory Glycolysis	Copper deficiency under hypoxia can inhibit compensatory glycolysis in HCC cells, thus reducing tumor characteristics.	(172)
Maintain Tumor Cells Dormancy	Long-term copper deficiency can keep tumor cells dormant, suppressing tumor recurrence.	(98, 173)
Target MEK1/2	By targeting copper-dependent kinase activity of MEK1/2, Braf-driven melanoma can be inhibited.	(174)
Improve Pre-Metastatic Niche	Copper deficiency, related to decreased VEGFR2 and LOXL2, suggests potential effects on the pre-metastatic tumor environment.	(175)
Synergize with MAPK Pathway Inhibitors	Copper deficiency can inhibit autophagy-related proteins ULK1/2, reducing protective autophagy induced by KRAS and BRAF mutations during MAPK pathway inhibition.	(176, 177)
Enhance Cisplatin Efficacy	Copper chelation reduces copper’s competitive binding with CTR1, enhancing cisplatin’s binding, transport, and efficacy.	(178)
Promote PDL1 Degradation	Copper chelation can promote ubiquitin-mediated degradation of PDL1 in tumor cells, potentially synergizing with anti-tumor immunotherapy.	(119)
Metabolic Reprogramming	Copper deficiency in mitochondria-dominant tumor cells can shift metabolism from oxidative to glycolytic, reducing energy production.	(179, 180)
Increase Radiosensitivity	Regulating intracellular copper ion homeostasis and reducing their levels can enhance the radiosensitivity of HCC.	(60, 181–183)