Immune checkpoint blockade (ICB) on macrophages can improve their anti-tumor immune activity, yet it is hampered by on-target
off-tumor toxicity and the lack of direct visualization of macrophages response. This work develops a kind of engineered oncolytic bacteria
(pEDp@MM) for repolarization-gated ICB and real-time monitoring of macrophage. Enzyme-activated DNA prodrug (Dp) containing ICB drug is
anchored on macrophage membranes-encapsulated catalase-expressing Escherichia coli (pE.coli). After targeting tumor-associated macrophages
(TAMs), pEDp@MM induce oxygen production for photoacoustic imaging-guided self-localization and repolarize TAMs toward M1 phenotype
with pE.coli, triggering nuclear-t... More
Immune checkpoint blockade (ICB) on macrophages can improve their anti-tumor immune activity, yet it is hampered by on-target
off-tumor toxicity and the lack of direct visualization of macrophages response. This work develops a kind of engineered oncolytic bacteria
(pEDp@MM) for repolarization-gated ICB and real-time monitoring of macrophage. Enzyme-activated DNA prodrug (Dp) containing ICB drug is
anchored on macrophage membranes-encapsulated catalase-expressing Escherichia coli (pE.coli). After targeting tumor-associated macrophages
(TAMs), pEDp@MM induce oxygen production for photoacoustic imaging-guided self-localization and repolarize TAMs toward M1 phenotype
with pE.coli, triggering nuclear-to-cytoplasmic translocation of apurinic/apyrimidinic endonuclease 1 (APE1) and elevation of IL-6 mRNA within
macrophages. The translocated APE1 triggers the releases of ICB drug from Dp for on-demand immunotherapy, while the IL-6 mRNA initiates the
fluorescence recovery of cleaved Dp for visualization of macrophage phenotype change and drug release. In vivo studies demonstrate the phenotype
dependent ICB induces effective immune activation with real-time macrophage imaging, offering a promising approach for on-demand
immunotherapy and precision diagnostics.
