# Ursodeoxycholic acid reduces antitumor immunosuppression by inducing CHIP-mediated TGF-β degradation

## TL;DR

This study shows that ursodeoxycholic acid (UDCA) can reduce tumor immunosuppression by degrading TGF-β, enhancing anti-tumor immunity in mice and potentially improving cancer treatment.

## Contribution

UDCA is shown to act as a TGF-β inhibitor by inducing its degradation via the CHIP protein, offering a new strategy to enhance antitumor immunity.

## Key findings

- UDCA enhances antitumor immunity by degrading TGF-β and inhibiting Treg cell activity in tumor-bearing mice.
- UDCA synergizes with anti-PD-1 therapy to improve antitumor immunity and immune memory in mice.
- Combining UDCA with anti-PD-1 or anti-PD-L1 therapy shows better clinical efficacy in tumor patients.

## Abstract

TGF-β is essential for inducing systemic tumor immunosuppression; thus, blocking TGF-β can greatly enhance antitumor immunity. However, there are still no effective TGF-β inhibitors in clinical use. Here, we show that the clinically approved compound ursodeoxycholic acid (UDCA), by degrading TGF-β, enhances antitumor immunity through restraining Treg cell differentiation and activation in tumor-bearing mice. Furthermore, UDCA synergizes with anti-PD-1 to enhance antitumor immunity and tumor-specific immune memory in tumor-bearing mice. UDCA phosphorylates TGF-β at T282 site via TGR5-cAMP-PKA axis, causing increased binding of TGF-β to carboxyl terminus of Hsc70-interacting protein (CHIP). Then, CHIP ubiquitinates TGF-β at the K315 site, initiating p62-dependent autophagic sorting and subsequent degradation of TGF-β. Notably, results of retrospective analysis shows that combination therapy with anti-PD-1 or anti-PD-L1 and UDCA has better efficacy in tumor patients than anti-PD-1 or anti-PD-L1 alone. Thus, our results show a mechanism for TGF-β regulation and implicate UDCA as a potential TGF-β inhibitor to enhance antitumor immunity.

TGF-β can function to increase Treg cell function and reduce anti-tumour immunity. Here the authors show that UDCA is a potential mediator that can reduce TGF-β activity and promote anti-tumour immune responses in mice and can be additive to other checkpoint inhibitors.