ST3GAL1 and βII-spectrin pathways control CAR T cell migration to target tumors

Nat Immunol. 2023 Jun;24(6):1007-1019. doi: 10.1038/s41590-023-01498-x. Epub 2023 Apr 17.


Adoptive transfer of genetically engineered chimeric antigen receptor (CAR) T cells is becoming a promising treatment option for hematological malignancies. However, T cell immunotherapies have mostly failed in individuals with solid tumors. Here, with a CRISPR-Cas9 pooled library, we performed an in vivo targeted loss-of-function screen and identified ST3 β-galactoside α-2,3-sialyltransferase 1 (ST3GAL1) as a negative regulator of the cancer-specific migration of CAR T cells. Analysis of glycosylated proteins revealed that CD18 is a major effector of ST3GAL1 in activated CD8+ T cells. ST3GAL1-mediated glycosylation induces the spontaneous nonspecific tissue sequestration of T cells by altering lymphocyte function-associated antigen-1 (LFA-1) endocytic recycling. Engineered CAR T cells with enhanced expression of βII-spectrin, a central LFA-1-associated cytoskeleton molecule, reversed ST3GAL1-mediated nonspecific T cell migration and reduced tumor growth in mice by improving tumor-specific homing of CAR T cells. These findings identify the ST3GAL1-βII-spectrin axis as a major cell-intrinsic program for cancer-targeting CAR T cell migration and as a promising strategy for effective T cell immunotherapy.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes
  • Cell Line, Tumor
  • Cell Movement
  • Female
  • Humans
  • Immunotherapy, Adoptive
  • Lymphocyte Function-Associated Antigen-1
  • Mice
  • Receptors, Chimeric Antigen*
  • Spectrin


  • Lymphocyte Function-Associated Antigen-1
  • Receptors, Chimeric Antigen
  • Spectrin