Fig. 2. Engineering the bacteria-immune interface.

As single agents, bacteria are immunogenic and can remodel the TME through engagement of TLR-4 and TLR-5, which are stimulated by bacterial LPS and flagella, respectively. Their presence can also lead to an influx of innate immune cells such as neutrophils, natural killer (NK) cells, and monocytes into the tumor and change the phenotype of resident macrophages. As immune cells infiltrate into the tumor, bacteria are phagocytosed, presenting an opportunity to deliver immune cell–specific cargo intracellularly. For example, E. coli have been engineered to deliver STING agonists to intratumoral APCs, thereby inducing an IFN-I response (36). S. typhimurium have also been encoded to express neoantigens on their outer membrane so that once inside the tumor, they can be cleaved, taken up, and presented by surrounding dendritic cells (41). Bacteria can also engage the adaptive immune system through the production of immunomodulators such as cytokines and chemokines to recruit TILs into the tumor space. In addition to directly producing immunomodulatory cargo, they have also been engineered to convert tumor metabolic waste products such as ammonia into metabolites such as L-arginine, which has been correlated with increased frequency of TILs, thereby remodeling the TME (42).