Overcoming nutritional immunity by engineering iron-scavenging bacteria for cancer therapy

Certain bacteria demonstrate the ability to target and colonize the tumor
microenvironment, a characteristic that positions them as innovative
carriers for delivering various therapeutic agents in cancer therapy.
Nevertheless, our understanding of how bacteria adapt their physiological
condition to the tumor microenvironment remains elusive. In this work, we
employed liquid chromatography-tandem mass spectrometry to examine the
proteome of E. coli colonized in murine tumors. Compared to E. coli
cultivated in the rich medium, we found that E. coli colonized in tumors
notably upregulated the processes related to ferric ions, including
enterobactin biosynthesis and iron homeostasis. This finding indicated
that the tumor is an iron-deficient environment to E. coli. We
also found that the colonization of E. coli in the tumor led to an
increased expression of lipocalin 2 (LCN2), a host protein that can
sequester enterobactin. We therefore engineered E. coli to evade
the nutritional immunity provided by LCN2. By introducing the IroA
cluster, the E. coli synthesizes the glycosylated enterobactin, which
creates steric hindrance to avoid the LCN2 sequestration. The IroA-E. coli
showed enhanced resistance to LCN2 and significantly improved the
anti-tumor activity in mice. Moreover, the mice were cured by the IroA-E.
coli treatment became resistant to the tumor re-challenge, indicating the
establishment of immunological memory. Overall, our study underscores the
crucial role of bacteria's ability to acquire ferric ions within the
tumor microenvironment for effective cancer therapy.