Interleukin 12 (IL-12) is a potent weapon for cancer immunotherapy. However, its systemic delivery as a recombinant protein showed unacceptable toxicity in early clinical trials. Ongoing clinical trials are evaluating the intra-tumoral injection of IL-12-encoding mRNA or DNA to prevent such side effects. In this study, we sought to improve this strategy by further favoring IL-12 tethering to the tumor microenvironment. Therefore, we generated in vitro transcribed mRNAs encoding murine single-chain IL-12 fused to diabodies targeting CSF1R and/or PD-L1, molecules expressed in the tumor microenvironment, particularly on myeloid cells. The binding capacity of chimeric constructs and the bioactivity of IL-12 were demonstrated in vitro. Intra-tumoral administration of naked IL-12-encoding mRNA induced significant expression of the protein of interest that peaked at 6 h and slowly declined over time up to 72 h. Interestingly, even doses as low as 0.5 µg of the IL-12-encoding mRNA achieved potent anti-tumor effects in subcutaneously injected tumors derived from B16-OVA and MC38 cell lines. Treatment delivery was associated with measurable increases of IL-12p70 and IFN-γ levels systemically. Fusion of IL-12 to the diabodies targeting PD-L1 and/or CSF1R exerted comparable efficacy against bilateral tumor models, when compared to untethered IL-12. However, tethering IL-12 to the tumor infiltrating myeloid cells resulted in nearly undetectable IL-12 and IFN-γ levels systemically. Moreover, the anti-tumor efficacy was associated with favorable modulation of the tumor immune microenvironment. In conclusion, tethering IL-12 to myeloid cell populations in the mRNA-transfected tumors attains similar anti-tumor efficacy whilst reducing potentially dangerous systemic bioavailability of IL-12.