# Targeting the UPR with Small Molecules: Emerging Strategies for Immune Regulation

## TL;DR

This review explores how small molecules can target the unfolded protein response to regulate immune responses in diseases like cancer and inflammation.

## Contribution

The paper introduces emerging strategies focusing on stress granules and protein–protein interactions in UPR for immune modulation.

## Key findings

- Small molecules can modulate immune responses by targeting UPR sensors like IRE1α, PERK, and ATF6.
- Stress granules and LCD-mediated interactions in UPR offer new opportunities for immune regulation.
- UPR modulation shows potential for applications in immunotherapy and inflammatory diseases.

## Abstract

The unfolded protein response (UPR) is a highly conserved adaptive mechanism that restores endoplasmic reticulum (ER) homeostasis under stress. Beyond its canonical roles in proteostasis, the UPR has emerged as a central regulator of immune responses across diverse contexts, including infection, inflammation, cancer, and autoimmunity. IRE1α, PERK, and ATF6 are three principal UPR sensors that coordinate complex signaling networks to regulate antigen presentation, cytokine production, and immune cell differentiation. This review highlights the molecular mechanisms by which small molecules target the UPR to modulate immune responses. In addition, we highlight stress granules (SGs) and the prevalence of protein–protein interactions mediated by intrinsically low-complexity domains (LCDs) in the UPR as potential new avenues for immune modulation. Finally, we discuss future directions for leveraging UPR modulation in immunotherapy, infectious disease, and chronic inflammatory disorders.