# ZC3H12A: A Critical Mediator of Inflammation, Tumor Immunotherapy, and Metabolic–Immune Crosstalk—Implications for Disease Treatment

## TL;DR

ZC3H12A is an RNA-binding protein that regulates inflammation, immune balance, and cancer treatment, offering new therapeutic potential for various diseases.

## Contribution

This review highlights ZC3H12A's multifunctional roles in immune regulation, tumor therapy, and metabolic-immune crosstalk, suggesting new treatment opportunities.

## Key findings

- ZC3H12A degrades inflammatory mRNAs like IL-6 and IL-1β and regulates immune cells.
- ZC3H12A knockout improves T-cell persistence and anti-tumor efficacy in immunotherapy.
- ZC3H12A influences metabolic-immune interactions and inflammation-related diseases.

## Abstract

ZC3H12A is a key RNA-binding protein and ribonuclease that plays a central role in negatively regulating inflammation and maintaining immune homeostasis. It does this by degrading the mRNA of multiple inflammatory mediators (such as IL-6 and IL-1β), as well as through its deubiquitinating enzyme activity. Not only does it limit excessive immune activation by regulating innate and adaptive immune cells (e.g., macrophages and T cells), but it also exerts bidirectional effects in tumors, acting as an anti-tumor factor to inhibit angiogenesis and oncogenic signal pathways, while promoting tumor progression under specific conditions. In recent years, ZC3H12A has emerged as a critical target for tumor immunotherapy, particularly CAR-T cell therapy. Its knockout significantly enhances T-cell persistence and anti-tumor efficacy, demonstrating broad translational potential. Furthermore, ZC3H12A plays a crucial role in systemic metabolic–immune crosstalk and infectious diseases. This review systematically summarizes the multifunctional roles of ZC3H12A in immune regulation, tumor therapy, metabolic disorders and inflammation-related diseases, with the aim of providing new insights into its potential application in the treatment of human diseases.