Metabolic modulation of tumours with engineered bacteria for immunotherapy

Nature. 2021 Oct;598(7882):662-666. doi: 10.1038/s41586-021-04003-2. Epub 2021 Oct 6.


The availability of L-arginine in tumours is a key determinant of an efficient anti-tumour T cell response1-4. Consequently, increases of typically low L-arginine concentrations within the tumour may greatly potentiate the anti-tumour responses of immune checkpoint inhibitors, such as programmed death-ligand 1 (PD-L1)-blocking antibodies5. However, currently no means are available to locally increase intratumoural L-arginine levels. Here we used a synthetic biology approach to develop an engineered probiotic Escherichia coli Nissle 1917 strain that colonizes tumours and continuously converts ammonia, a metabolic waste product that accumulates in tumours6, to L-arginine. Colonization of tumours with these bacteria increased intratumoural L-arginine concentrations, increased the number of tumour-infiltrating T cells and had marked synergistic effects with PD-L1 blocking antibodies in the clearance of tumours. The anti-tumour effect of these bacteria was mediated by L-arginine and was dependent on T cells. These results show that engineered microbial therapies enable metabolic modulation of the tumour microenvironment leading to enhanced efficacy of immunotherapies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • Arginine / metabolism
  • B7-H1 Antigen / antagonists & inhibitors
  • Cell Line, Tumor
  • Escherichia coli
  • Female
  • Immunotherapy / methods*
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Metabolic Engineering*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microorganisms, Genetically-Modified*
  • Neoplasms, Experimental / metabolism
  • Neoplasms, Experimental / microbiology
  • Neoplasms, Experimental / therapy*
  • Probiotics
  • Proteome
  • Synthetic Biology
  • T-Lymphocytes / immunology
  • Tumor Microenvironment / immunology


  • B7-H1 Antigen
  • Proteome
  • Arginine