# Redirecting engineered immune cells using G protein-coupled receptors in cancer therapy

## TL;DR

This paper reviews how engineering G protein-coupled receptors in immune cells can improve their ability to reach and fight solid tumors, potentially enhancing cancer immunotherapy.

## Contribution

The paper introduces synthetic GPCR strategies, such as chemogenetics and optogenetics, to precisely control immune cell migration in cancer therapy.

## Key findings

- Engineering chemokine receptors improves immune cell migration and antitumor efficacy in preclinical models.
- Synthetic GPCRs enable stimulus-controlled immune cell trafficking, enhancing therapy precision.
- GPCR engineering can also remodel the tumor microenvironment and improve metabolic fitness of immune cells.

## Abstract

Chimeric antigen receptor (CAR) cellular therapy, particularly CAR-T cells, has revolutionized the treatment of hematologic malignancies. However, these therapies show limited efficacy against solid tumors, in part due to the inefficient trafficking of effector cells to the tumor. This review explores the potential of engineering natural and synthetic G protein-coupled receptors (GPCRs) to overcome this migratory hurdle. Chemokine receptors have been the most used GPCR family in this setting. Engineering effector immune cells to express chemokine receptors that match tumor-derived chemokines has been shown to increase their chemotaxis and to improve antitumor efficacy in preclinical models. In addition to improved migration, chemokine receptor engineering can also have additional benefits, such as remodeling of the tumor microenvironment and metabolic rewiring of engineered cells. However, the effectiveness of this approach is limited by the tumor-specific and heterogeneous chemokine milieu. Emerging strategies make use of synthetic GPCRs and could overcome some of these limitations using chemogenetic and optogenetic approaches. Here, mutated GPCRs binding only to specific and orthogonal ligands or light-sensitive channels are used for cell modulation and trafficking. Equipping cells with these synthetic GPCRs allows for precise and stimulus-controlled immune cell migration. Together, natural and synthetic GPCR engineering form promising approaches to enhance immune cell trafficking, persistence, and efficacy.

•GPCRs are key regulators of immune cell migration and form interesting targets for engineering in cancer immunotherapy.•GPCR engineering via chemokine receptors enhances effector cell migration and infiltration in preclinical solid tumor models.•Chemokine receptor engineering can enhance metabolic fitness and induce TME remodeling.•Synthetic GPCR engineering in opto- and chemogenetics enables precise ligand- or light-controlled immune cell migration.•Natural and synthetic GPCR engineering are promising approaches to enhance CAR cellular therapy efficacy in solid tumors.

GPCRs are key regulators of immune cell migration and form interesting targets for engineering in cancer immunotherapy.

GPCR engineering via chemokine receptors enhances effector cell migration and infiltration in preclinical solid tumor models.

Chemokine receptor engineering can enhance metabolic fitness and induce TME remodeling.

Synthetic GPCR engineering in opto- and chemogenetics enables precise ligand- or light-controlled immune cell migration.

Natural and synthetic GPCR engineering are promising approaches to enhance CAR cellular therapy efficacy in solid tumors.