TY - JOUR
T1 - The ISGylation tapestry in cancer
T2 - weaving phenotypic plasticity through multidimensional regulatory looms
AU - Wu, Ruicheng
AU - Shao, Fanglin
AU - Koh, Siang Boon
AU - Okoli, Uzoamaka Adaobi
AU - Li, Dengxiong
AU - Wang, Jie
AU - Tuo, Zhouting
AU - Zhang, Rong
AU - Wusiman, Dilinaer
AU - Cheema, Umber
AU - Kong, Depei
AU - Feng, Dechao
N1 - Publisher Copyright:
© The Author(s) 2025.
PY - 2025/11/5
Y1 - 2025/11/5
N2 - Post-translational modification is an important mechanism for regulating protein function and cell signaling networks. Among these modifications, ISGylation is a ubiquitin-like modification regulated by ISG15. In this review, we explore the role of ISGylation in a variety of related phenotypes in the tumor context, including apoptosis regulation, autophagy regulation, immune escape, metabolic reprogramming, cancer stem cell maintenance, and DNA damage repair. ISGylation plays a dual role in apoptosis, promoting either pro-survival or pro-death pathways depending on contexts. It also regulates autophagy by promoting tumor adaptation or by regulating immune responses. Moreover, ISGylation contributes to the immune escape mechanism by regulating the stability of PD-L1 and immune cell infiltration. In addition, ISGylation is involved in metabolic reprogramming, supporting tumor growth and therapeutic resistance by regulating key metabolic pathways. It also plays a key role in maintaining the properties of cancer stem cells by stabilizing essential metabolic and signaling proteins. In sum, this review examines the functions and mechanisms of ISG15 and ISGylation in various tumor-associated phenotypes, enhancing our understanding of their role in tumorigenesis and disease progression. Graphical abstract:
AB - Post-translational modification is an important mechanism for regulating protein function and cell signaling networks. Among these modifications, ISGylation is a ubiquitin-like modification regulated by ISG15. In this review, we explore the role of ISGylation in a variety of related phenotypes in the tumor context, including apoptosis regulation, autophagy regulation, immune escape, metabolic reprogramming, cancer stem cell maintenance, and DNA damage repair. ISGylation plays a dual role in apoptosis, promoting either pro-survival or pro-death pathways depending on contexts. It also regulates autophagy by promoting tumor adaptation or by regulating immune responses. Moreover, ISGylation contributes to the immune escape mechanism by regulating the stability of PD-L1 and immune cell infiltration. In addition, ISGylation is involved in metabolic reprogramming, supporting tumor growth and therapeutic resistance by regulating key metabolic pathways. It also plays a key role in maintaining the properties of cancer stem cells by stabilizing essential metabolic and signaling proteins. In sum, this review examines the functions and mechanisms of ISG15 and ISGylation in various tumor-associated phenotypes, enhancing our understanding of their role in tumorigenesis and disease progression. Graphical abstract:
KW - ISGylation
KW - Drug resistance
KW - Tumor microenvironment
KW - Post-translational modification
KW - Immune evasion
U2 - 10.1186/s11658-025-00815-6
DO - 10.1186/s11658-025-00815-6
M3 - Review article (Academic Journal)
C2 - 41193953
SN - 1425-8153
VL - 30
JO - Cellular and Molecular Biology Letters
JF - Cellular and Molecular Biology Letters
IS - 1
M1 - 132
ER -
