New strategy harnesses pre-existing antiviral immunity to boost anti-tumor responses

Because many different types of cancer cells overexpress programmed death-ligand 1 (PD-L1), this cell surface protein is a major target of cancer immunotherapy. Unfortunately, drugs that target it do not trigger especially strong anti-cancer immune responses. New research published in Advanced Science reveals a promising strategy that harnesses pre-existing antiviral immunity to boost anti-tumor responses.

Researchers engineered what they call a PD-L1-binding antigen presenter (PBAP) that functions as a molecular bridge between tumor cells and immune cells. The construct fuses a protein segment that specifically binds to tumor-expressed PD-L1 with a highly immunogenic viral antigen, called varicella-zoster virus glycoprotein E (gE).

Experiments in cells and mouse models demonstrated that PBAP effectively anchors to PD-L1 on tumor surfaces, thereby tagging cancer cells with a viral signature recognized by the immune system. The strategy holds significant potential because most adults carry high amounts of anti-gE antibodies resulting from prior vaccination or natural infection. These pre-existing antibodies recognize PBAP-decorated tumor cells and execute a dual function: they trigger natural killer cells into action while simultaneously binding to the PBAP-gE complexes on tumor surfaces. This redirection transforms virus-specific immune memory into precision anti-cancer weapons.

Importantly, this strategy can extend beyond viral antigens. As an example, the researchers created PBAP-HER2, which redirected HER2-targeting therapies to eliminate HER2-negative, PD-L1-positive tumor cells. This expands applicability to multiple tumor types, addressing unmet needs for hard-to-treat cancers lacking effective targeted therapies.

This strategy represents a lower-cost, safer avenue for tumor immunotherapy. It opens a transformative pathway that repurposes the body's natural antiviral defenses for therapeutic gain, with significant promise for clinical translation."

Fan Zou, PhD, Professor at Shenzhen University of Advanced Technology