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Multi-compartment immune and tumor cell reprogramming by IFNa2 overcomes colon cancer immunotherapy resistance

Zainab Tiamiyu, Patrick Czabala, Jennifer Worthy

    Biorxiv : the Preprint Server for Biology
    |July 10, 2026
    PubMed

    Insights

    Lipid nanoparticle-delivered interferon-alpha2 (LNP-mIFNα2) gene therapy suppresses colon cancer lung metastasis by reprogramming the tumor microenvironment. This therapy enhances anti-tumor immunity and sensitizes tumors to immune checkpoint inhibitor (ICI) therapy.

    Area of Science:

    • Immunology
    • Gene Therapy
    • Cancer Research

    Background:

    • Tumor cell PD-L1 inhibits anti-tumor immunity by repressing IFN signaling, despite an IFN-responsive phenotype predicting response to immune checkpoint inhibitor (ICI) therapy in colorectal cancer.
    • Lipid nanoparticle (LNP)-encapsulated IFNα2-encoding nanoplasmid (LNP-mIFNα2) gene therapy shows potential in suppressing tumor progression, but its mechanism and cytokine response trade-offs are unclear.

    Purpose of the Study:

    • To elucidate the mechanism by which LNP-mIFNα2 gene therapy suppresses colon cancer lung metastasis.
    • To investigate the reprogramming of the tumor microenvironment (TME) by LNP-mIFNα2.
    • To determine if LNP-mIFNα2 sensitizes tumors to ICI therapy.

    Main Methods:

    • Utilized syngeneic and humanized mouse models of colon cancer lung metastasis.
    • Administered LNP-mIFNα2 gene therapy.
    • Performed single-cell RNA sequencing to analyze TME reprogramming.
    • Assessed efficacy through tumor suppression and sensitization to ICI therapy.

    Main Results:

    • LNP-mIFNα2 selectively transfected tumor cells, restoring local IFNα2 production and suppressing lung metastasis.
    • Efficacy was dependent on canonical IFNAR1 signaling and enhanced by neutralizing IL6.
    • Single-cell RNA sequencing revealed TME reprogramming: SPP1+ macrophages underwent apoptosis, monocytes became IFN-responsive, Tpex cells expanded, and tumor cells reduced cycling and increased antigen presentation.
    • Tumor cells shifted away from a hypoxia/HIF-1α-driven cuproptosis-resistance program, suggesting sensitization to coproptosis.
    • The reprogrammed TME mirrored T cell and myeloid signatures of pembrolizumab-responsive human tumors.

    Conclusions:

    • LNP-delivered IFNα2 acts as a multi-compartment TME regulator, reprogramming myeloid suppression and reinvigorating exhausted T cells.
    • This therapy restores tumor immunogenicity and sensitizes tumors to ICI therapy.
    • LNP-mIFNα2 presents a promising strategy for enhancing anti-tumor immunity and cancer treatment.

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