# Ubiquitin-centered post-translational modification crosstalk orchestrates tumor immunity and immunotherapy response

## TL;DR

This review explores how ubiquitination and its interactions with other protein modifications shape tumor immunity and influence immunotherapy outcomes.

## Contribution

The paper systematically summarizes the crosstalk between ubiquitination and other PTMs in regulating tumor immunity and immunotherapy response.

## Key findings

- Ubiquitination dynamically regulates immune responses through a balance of ubiquitin ligases and deubiquitinases.
- Crosstalk between ubiquitination and other PTMs forms a multilayered network that controls immune regulators and therapeutic responsiveness.
- Targeting the ubiquitin system offers opportunities for developing precision immunotherapies with combination strategies.

## Abstract

Remarkable progress has been made in cancer immunotherapy in recent years; however, it still faces challenges such as limited response rates, resistance, and immune-related adverse events. Ubiquitination, a key post-translational modification (PTM) of proteins, is indispensable for regulating various tumor immunity-related processes. Through the dynamic balance between ubiquitin ligases and deubiquitinases, this PTM fine-tunes the strength and duration of immune responses, influencing tumor recognition and immune evasion. Accumulating evidence reveals that ubiquitination does not act alone but cooperates and competes with other PTMs—such as phosphorylation, acetylation, SUMOylation, neddylation, and glycosylation—to form a multilayered regulatory network that determines the immune landscape and therapeutic responsiveness. This review systematically summarizes the molecular mechanisms by which ubiquitination-related enzymes modulate the tumor immune microenvironment and immune evasion. Moreover, we highlight emerging insights into the crosstalk between ubiquitination and other PTMs, which collectively govern the stability and signaling of immune regulators. Finally, we discuss the translational potential of targeting the ubiquitin system, emphasizing opportunities and challenges in developing selective ubiquitin modulators and designing rational combination immunotherapies. Decoding this integrated PTM network will not only deepen mechanistic understanding of tumor immunity but also open new avenues for precision immunotherapy.