Dysregulated mRNA translation is increasingly recognized as a critical driver of tumor progression and immune modulation. Building on our previous work implicating RNA helicase EIF4A in the translational control of oncogenes such as MYC and KRAS, we investigated whether targeted disruption of EIF4A and oncogene KRAS and MYC could reprogram the translational landscape to favor immune activation. We demonstrate that pharmacologic blockade of EIF4A upregulates non-canonical mRNA translation encoding immunogenic proteins, resulting in the generation of neo-antigens. Next, mRNA translation of proteins involved in HLA Class I antigen processing and presentation machinery, including B2M, HLA-A/B/C, is upregulated through an EIF4A-independent and EIF4G2-dependent mechanism. Our integrative approach—combining RNA-seq, Ribosome Footprinting, mRNA Translation Start Site (RTSS) mapping, and MHC-I immunopeptidomics—revealed that EIF4A inhibition leads to the emergence of novel immune epitopes and promotes their presentation via HLA-A/B/C. This reprogramming enhances cytotoxic CD8 T-cell infiltration and anti-tumor immunity in PDAC models, effectively converting immunologically “cold” tumors into “hot” ones. EIF4A inhibition further sensitizes murine KPC tumors of the pancreas to anti-PDL1 immunotherapy. Our findings establish therapy-induced mRNA translation as a previously underappreciated source of tumor neoepitopes and a key regulator of immune responsiveness in cancer.

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