Enteroviral epitope mimicry enables NK cell-mediated targeting of ASPH in hepatocellular carcinoma

Hung, M. H.; Li, Q.; Wang, L.; Forgues, M.; Lee, A. S.; Jenkins, L. M.; Maity, T. K.; Buffington, J.; Chaisaingmongkol, J.; Rabibhadana, S.; Ruchirawat, M.; Ho, M.; Wang, X. W.

doi:10.64898/2026.04.07.717032

bioRxiv · 10.64898/2026.04.07.717032

Enteroviral epitope mimicry enables NK cell-mediated targeting of ASPH in hepatocellular carcinoma

Hung, M. H.·Li, Q.·Wang, L.·Forgues, M.·Lee, A. S.·Jenkins, L. M.·Maity, T. K.·Buffington, J.·Chaisaingmongkol, J.·Rabibhadana, S.·Ruchirawat, M.·Ho, M.·Wang, X. W.

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Abstract

Cancer development is shaped by host-microbe interactions, including viral infections. While several viruses are established oncogenic drivers, their potential protective roles in cancer remain unclear. Here we identify a dominant antibody response to CE1, a consensus epitope of enterovirus and rhinovirus, that is associated with reduced hepatocellular carcinoma (HCC) incidence and mortality. Anti-CE1 antibodies selectively recognize HCC cells and mediate anti-tumor activity through NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC). Mechanistically, anti-CE1 antibodies cross-react with aspartate {beta}-hydroxylase (ASPH), with CE1-ASPH sequence homology underpinning tumor recognition and cytotoxicity. Clinically, ASPH is aberrantly upregulated in HCC and correlates with inferred NK cell-associated ADCC activity and improved survival in CE1-seropositive patients. Collectively, these findings reveal a mechanism by which antiviral humoral immunity confers cancer protection through molecular mimicry and highlight anti-CE1 immunity as a potential therapeutic strategy in HCC.

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Hung, M. H., Li, Q., Wang, L., Forgues, M., Lee, A. S., Jenkins, L. M., Maity, T. K., Buffington, J., Chaisaingmongkol, J., Rabibhadana, S., Ruchirawat, M., Ho, M., Wang, X. W.. 2026-04-10. Enteroviral epitope mimicry enables NK cell-mediated targeting of ASPH in hepatocellular carcinoma. https://doi.org/10.64898/2026.04.07.717032

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