# The ISGylation tapestry in cancer: weaving phenotypic plasticity through multidimensional regulatory looms

## TL;DR

This review explores how ISGylation, a protein modification, influences cancer development through various mechanisms like immune escape and metabolism.

## Contribution

The paper provides a comprehensive overview of ISGylation's dual roles in tumor-related processes, highlighting its regulatory complexity.

## Key findings

- ISGylation can promote either pro-survival or pro-death pathways in apoptosis depending on the context.
- ISGylation contributes to immune escape by regulating PD-L1 stability and immune cell infiltration.
- ISGylation supports tumor growth and resistance by regulating metabolic pathways and cancer stem cell maintenance.

## Abstract

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.

The online version contains supplementary material available at 10.1186/s11658-025-00815-6.