Combination of KRAS ASO and RIG-I agonist in extracellular vesicles transforms the tumor microenvironment towards effective treatment of KRAS-dependent cancers

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Rationale: Mutations in the KRAS gene drive many cancers, yet targeting KRAS mutants remains a challenge.Here, we address this hurdle by utilizing a nucleic acid-based therapeutic strategy delivered via extracellular vesicles (EVs) to simultaneously inhibit KRAS mutants and activate the RIG-I pathway, aiming to enhance anti-tumor immunity.Methods: Antisense oligonucleotides against KRAS mutants (KRAS ASOs) and RIG-I agonist immunomodulatory RNA (immRNA) were loaded into EVs and administered to KRAS-mutant cancer models.The therapeutic effects were assessed in colorectal and non-small cell lung cancer (NSCLC) tumor models, as well as patient-derived pancreatic cancer organoids.Immune responses were evaluated by analyzing tumor microenvironment's changes, dendritic cell activation, and T cell memory formation.The treatment efficacy was evaluated based on the tumor development and overall survival.Results: The KRAS-ASO and immRNA combination treatment induced immunogenic tumor cell death and upregulated interferons in KRAS-dependent cancers.In a colorectal tumor model, the therapy shifted the tumor microenvironment to an immunogenic state, activated dendritic cells in sentinel lymph nodes, and promoted memory T cell formation.In an aggressive NSCLC model, the treatment resulted in a strong anti-tumor activity and extended survival without any adverse effects.Validation in patient-derived pancreatic cancer organoids confirmed the clinical translation potential of this approach.Conclusions: EV-mediated delivery of ASOs and immRNA effectively inhibits KRAS mutants and activates RIG-I, leading to a robust anti-tumor immune response.This strategy holds promise for effectively treating KRAS-driven cancers and improving clinical outcomes.

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