ABSTRACT: Despite the proven clinical activity of checkpoint inhibitors (ICIs) in several cancer indications, frequent occurrence of primary and secondary resistance reduces their overall effectiveness. Development of ICI resistance has been attributed mainly to genetic or epigenic alterations that affect the tumor antigen presentation machinery leading to diminished anti-tumor immune responses. There is an urgent need for new approaches which can either re-sensitize resistant tumors to the ICIs or engage alternate immune pathways to inhibit tumors. Intratumoral delivery of nanoparticle encapsulated murine IL12 (mIL12) mRNA induces powerful anti-tumor immune responses in murine tumor models, and the human version of this drug results in objective responses in patients with advanced disease. Here, we tested the efficacy of mIL12 mRNA as a single agent and in combination with anti-PD-L1 antibodies in ICI-sensitive Yummer 1.7 melanoma and MC38 colorectal murine tumors and in ICI resistant, _2-microglobulin (B2M) knockout versions of these models. mIL12 mRNA monotherapy was sufficient to cause complete responses (CRs) in_³_60% of both ICI-sensitive or -resistant Yummer 1.7 melanoma and MC38 colorectal carcinoma tumors. The mIL12 mRNA treatment resulted in potent upregulation of T(H)1 type cytokines and chemokines. A reduction in number of Tregs, increase in numbers and activation state of both cytotoxic T cells (CTLs) as well as tumor-associated macrophages (TAMs) was observed indicating enhanced anti-tumor, cell-based immune responses in the tumor microenvironment. This mIL12-induced concerted immune activation was associated with a robust killing and phagocytosis of tumor cells resulting in durable CRs. These observations suggest that intratumoral IL12mRNA therapy may benefit patients with ICI-resistant cancers.