The ability of IL-12 to affect both innate and adaptive immunity positions this cytokine as a promising candidate to overcome the immunosuppressive microenvironment within tumours. Despite its potent activity in experimental models, the clinical use of IL 12 has been thwarted by its reported toxicity in human trials. Intranasal administration of an IL-12-coding lentivirus efficiently transduced alveolar macrophages in tumour-bearing mice, restricting IL-12 expression to the lung parenchyma and promoting rejection of established lung metastases. IL-12 stimulated IFNγ production by innate lymphoid cells (ILC), inducing the activation of interstitial macrophages, whose presence was essential for tumour eradication. These data demonstrates the potent anti tumour activity of local lentiviral IL-12 therapy against metastatic disease in the lung and the critical role played by the innate crosstalk established between ILCs and tissue resident phagocytes within the lung microenvironment.