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

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.

• Publication year

  2026

• Venue

  Immuno-Oncology Technology

• Publication date

  2026-01-01

• Fields of study

  Medicine, Engineering

• Identifiers
  DOI 10.1016/j.iotech.2026.101582PMID 41674705PMCID 12887374
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar

• No claims are published for this paper.

• No concepts are published for this paper.

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