Photomicrographic image of a tumor invasive margin from a syngeneic tumor model (MC38) stained with multiplex immunofluorescence to identify macrophages (F4/80⁺; Red) in the tumor microenvironment. Polarization state of these macrophages was determined using inducible nitric oxide synthase (iNOS; Green), a marker for M1 polarization, and arginase I (Arg1; Cyan) a marker for M2 polarization. In the tumor margins, 152-fold increase in M1 macrophages were observed with exoIL-12 treatment. These studies provide evidence that exoIL-12 was significantly more potent than rIL12 and enabled systemic anti-tumor immunity by facilitating prolonged local pharmacology and undetectable systemic exposure. The improved therapeutic index achieved in pre-clinical models support further clinical investigation of this powerful cytokine. Read the full article on p. 523.