colorectal-cancer

mRNA-delivered fusion protein combines immune activation and direct cell killing for a new approach to cancer gene therapy

mRNA-based cancer therapeutics are an emerging area, building on the success of mRNA vaccines. This study engineered a novel fusion protein combining interferon-gamma (IFN-γ) — which activates immune responses — with the intracellular domain of Fas, a protein that triggers apoptotic cell death when activated. The fusion was expressed as an mRNA-delivered membrane protein.

In cancer cell lines, the fusion protein reduced viability within 24 hours — approximately 50% cell death in colorectal cancer cells and 75% in melanoma cells. The mechanism involves both direct apoptosis induction through Fas signaling and immune activation through IFN-γ, creating a dual-action effect that exceeded either component alone.

This represents a potentially versatile platform for mRNA-based cancer gene therapy that harnesses two complementary killing mechanisms simultaneously.

Key Findings

IFN-γ–FasICD fusion protein is robustly expressed on cell surface after mRNA transfection
~50% cell death in MC38 (colorectal) cells and ~75% in B16OVA (melanoma) cells within 24 hours
Cytotoxicity exceeds FasICD-alone control, confirming additive/synergistic effect of IFN-γ component
Mechanism involves both Fas-driven apoptosis and IFN-γ signaling
mRNA delivery enables transient, controllable expression

Implications

This fusion protein concept could be incorporated into mRNA cancer vaccines or direct tumor injection strategies to combine local immune stimulation with direct cytotoxicity. The modularity of the approach (swapping out the cytokine or apoptosis domain) also suggests it could be adapted to other combinations.

Caveats

Preprint — not peer reviewed. Based on abstract only. Cell line data only — in vivo validation not described. Achieving selective delivery to tumor cells versus normal cells is a critical unsolved challenge for mRNA cancer gene therapy. Immune context of full-scale in vivo testing will be more complex.

Source: bioRxiv — 2026-04-08

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