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Engineering NK and T cells with metabolite-sensing receptors to target solid tumors

Young-Min Kim1, Min K Tsai1,2, Chang Sun1

  • 1Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.

Nature Immunology
|March 24, 2026
PubMed

Insights

Scientists engineered natural killer (NK) and T cells to infiltrate solid tumors by equipping them with metabolite-sensing receptors. This approach enhances tumor targeting and eradication, offering new therapeutic strategies for cancer treatment.

Area of Science:

  • Immunology
  • Cell Biology
  • Biochemistry

Background:

  • Effective cancer immunotherapy requires immune cells like natural killer (NK) and T cells to infiltrate solid tumors.
  • Current strategies face challenges in directing these cells to tumor sites.

Purpose of the Study:

  • To identify and utilize metabolite-sensing receptors to program NK and T cell migration towards solid tumors.
  • To enhance tumor infiltration and therapeutic efficacy of immune cells.

Main Methods:

  • Conducted in vivo and in vitro CRISPR activation screens using NK-92 cells to identify key receptors.
  • Expressed identified receptors (GPR183, GPR84, GPR34, GPR18) in NK and T cells.
  • Assessed cell migration, transcriptomic changes, and tumor control in preclinical models.

Main Results:

  • GPR183, GPR84, GPR34, and GPR18 were identified as critical for NK cell infiltration and chemotaxis.
  • Engineered NK and T cells expressing these receptors demonstrated enhanced migration to cancer cell-derived factors.
  • Expression of GPR183 in NK, CAR-NK, CAR T, and mouse T cells significantly improved tumor infiltration, control, and eradication.

Conclusions:

  • Metabolite-sensing receptors can be reprogrammed to guide immune cells to solid tumors.
  • This approach offers a novel method for biochemically guided, spatially targeted cell therapies.
  • Rewiring metabolite sensing presents new avenues for cancer therapeutic interventions.

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