# Targeting RNA-Binding proteins Roquin-1 and Regnase-1 could enhance CAR-iPSC-derived macrophage immunotherapy for solid tumors: a perspective and challenges

## TL;DR

This paper explores how targeting RNA-binding proteins Roquin-1 and Regnase-1 could improve CAR-iPSC-derived macrophage immunotherapy for solid tumors.

## Contribution

The novel approach involves using CRISPR-Cas9 to knock out Roquin-1 and Regnase-1, enhancing macrophage anti-tumor activity.

## Key findings

- Knocking out Roquin-1 and Regnase-1 shifts macrophages from an M2-like to an M1 state.
- This shift boosts pro-inflammatory signaling and phagocytic and cytotoxic capabilities in the tumor microenvironment.

## Abstract

Solid tumours present major treatment obstacles because of their immunosuppressive microenvironment and poor response to traditional chimeric antigen receptor (CAR)-based immunotherapies. Recent advances in cellular engineering have introduced CAR-macrophages derived from induced pluripotent stem cells (CAR-iMacs) as a promising approach to get around these obstacles. CAR-iMacs are designed to attack tumours, but their phenotypic plasticity can cause them to transform into M2-like macrophages in the tumour environment (TME), where they may instead suppress immune responses and promote tumour progression and metastasis. Roquin-1 and Regnase-1 are RNA-binding proteins that act as negative regulators of inflammatory genes that contribute to the phenotypic plasticity of macrophages. This perspective highlights a novel approach to augmenting anti-tumour responses of CAR-iMacs by simultaneously knocking out Roquin-1 and Regnase-1 via CRISPR-Cas9 gene editing. This approach drives a shift from an immunosuppressive M2-like state to an M1 state, promoting sustained pro-inflammatory signalling, boosting phagocytic and cytotoxic capabilities within the tumour microenvironment. Addressing a serious constraint in conventional adoptive cell therapies, this dual-targeting platform could provide a potent and scalable immunotherapeutic treatment for solid malignancies.