Due to their constant exposure to inhaled antigens, lungs represent a particularly immunosuppressive environment that limits excessive immune responses; however, cancer cells can exploit this unique environment for their growth. We previously described the ability of aerosolized CpG-ODN combined with Poly(I:C) (TLR9 and TLR3 agonists, respectively) to promote anti-tumor immunity in a B16 melanoma lung metastasis model. Here, we explored the possibility of improving the therapeutic efficacy of TLR9/TLR3 agonist combinations by including in the inhalant either an antibody directed to both Ly6G and Ly6C markers to locally deplete myeloid-derived suppressive cells (MDSC) or IFNα to directly activate the NK and macrophage innate immune cells in the lung. Addition of nebulized anti-MDSC antibody RB6-8C5 to aerosolized CpG-ODN/Poly(I:C) resulted in reduced mRNA levels of immunsuppressive molecules (IL10, Arg-1 and Nos2), increased activation of resident NK cells and improved treatment outcome, with a significant reduction in established B16 melanoma lung metastases compared to treatment with CpG-ODN/Poly(I:C) alone. Likewise, addition of aerosolized IFNα led to increased mRNA levels of proinflammatory cytokines (IL15 and IFNγ) in the lung and recruitment of highly activated NK cells, with no evident signs of toxicity and with a significantly improved anti-tumor effect as compared with aerosolized CpG-ODN/Poly(I:C). Combining both IFNα and RB6-8C5 with CpG-ODN/Poly(I:C) did not produce an additive effect compared to IFNα + CpG-ODN/Poly(I:C) or RB6-8C5 + CpG-ODN/Poly(I:C). Our results indicate that the pulmonary route is a feasible and non-invasive strategy to deliver immunodulatory molecules, including antibodies and cytokines, that reprogram the lung tumor microenvironment to foster immune destruction of tumors.