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MECHANISM EXPLAINED

HOW ONCOLYTIC
VIRUSES WORK

The second phase is what makes the first phase matter. Direct viral cell killing triggers immunogenic cell death โ€” and the immune cascade that follows is the point.

Reviewed by: CancerFax Medical Team, Oncology & Haematology SpecialistsLast reviewed: April 16, 202612 min read

The Two-Phase Mechanism

Neither phase is sufficient alone. The combination is what the clinical data reflects.

  1. 1

    Viral Entry

    The virus enters any cell it can reach. Entry is not selective โ€” the selectivity comes from what happens next.

  2. 2

    Interferon Defence Check

    Normal cells activate type I interferon signalling, preventing replication or inducing controlled death. Cancer cells with disabled pathways cannot mount this defence.

  3. 3

    Selective Replication

    The virus replicates using cancer cell machinery. Thousands of viral copies accumulate inside the cell.

  4. 4

    Cell Lysis

    The cell ruptures, releasing viral copies and tumour antigens. Neighbouring cancer cells are infected and the cycle repeats.

  5. 5

    Immunogenic Cell Death

    Calreticulin, HMGB1, and ATP are released โ€” danger signals that activate innate immune sensors. This is not the clean, contained death of apoptosis; it's inflammatory and flags the immune system.

  6. 6

    Dendritic Cell Processing

    Dendritic cells process tumour antigens from lysed cells and present them to T cells. T cells are activated against tumour-specific antigens.

  7. 7

    Systemic T-Cell Response

    Trained T cells circulate from the injection site. At distant sites expressing the same antigens, they attack โ€” producing responses at uninjected tumours.

Key Mechanistic Concepts

Five concepts with direct clinical implications for patients evaluating oncolytic virus therapy.

  • Immunogenic vs Non-Immunogenic Cell Death

    Apoptosis doesn't trigger immune activation. Viral lysis does. The combination of calreticulin exposure, HMGB1 release, and ATP release is the biological trigger. This is why viral lysis generates immune response that most chemotherapy doesn't.

  • Cold-to-Hot Tumour Conversion

    Cold tumours have no T-cell infiltration. Viral infection creates acute inflammation, recruits immune cells, transforms the microenvironment. Checkpoint inhibitors can then work on those T cells that are now present.

  • Transgene Payloads

    Next-generation constructs carry IL-12, IL-15, anti-PD-1 fragments, and bispecific T-cell engagers โ€” all expressed within the tumour microenvironment, avoiding systemic toxicity.

  • Viral Spread Kinetics

    Replication and spread depend on tumour architecture, vascularity, and the immune response the virus simultaneously triggers. Pre-existing neutralising antibodies can limit spread.

Frequently Asked Questions

Mechanism Questions

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