The membrane-associated ubiquitin ligase MARCHF8 degrades MHC-I in HPV-positive head and neck cancer for immune evasion
Recommended Citation
Khalil MI, Wang J, Vu L, Yang C, Yin C, Chadha S, Nabors H, Vocelle D, May DG, Chrisopulos RJ, Welbon CC, Zhou L, Roux KJ, Spanos WC, Bernard MP, Mi QS, Pyeon D. The membrane-associated ubiquitin ligase MARCHF8 degrades MHC-I in HPV-positive head and neck cancer for immune evasion. Proc Natl Acad Sci U S A. 2026;123(11):e2525730123.
Document Type
Article
Publication Date
3-17-2026
Publication Title
Proceedings of the National Academy of Sciences of the United States of America
Keywords
Humans, Animals, Ubiquitin-Protein Ligases, Mice, Histocompatibility Antigens Class I, Head and Neck Neoplasms, Killer Cells, Natural, CD8-Positive T-Lymphocytes, Papillomavirus Infections, Tumor Microenvironment, Cell Line, Tumor, Immune Evasion, Membrane Proteins, Papillomaviridae, Tumor Escape
Abstract
The loss of major histocompatibility complex class I (MHC-I) molecules has been proposed as a mechanism for cancer immune evasion. Nevertheless, the mechanism is poorly understood. We report here that membrane-associated RING-CH-type finger 8 (MARCHF8), upregulated by human papillomavirus (HPV), ubiquitinates and degrades MHC-I in HPV-positive head and neck cancer (HPV+ HNC). Inhibiting MARCHF8 restores MHC-I levels on HPV+ HNC cells, suppresses tumor growth, and increases the infiltration of natural killer (NK) and T cells in the tumor microenvironment. Furthermore, Marchf8 knockout markedly increases cross talk between cytotoxic NK cells and CD8(+) T cells with macrophages and enhances the tumor-killing activity of CD8(+) T cells. Interestingly, Marchf8 knockout, in combination with anti-PD-1 treatment, further enhances tumor suppression and increases NK and T cell infiltration in mice bearing immune checkpoint inhibitor-refractory tumors. Our findings suggest that MARCHF8 could be a promising target for immunotherapy for HPV+ HNC patients.
Medical Subject Headings
Humans; Animals; Ubiquitin-Protein Ligases; Mice; Histocompatibility Antigens Class I; Head and Neck Neoplasms; Killer Cells, Natural; CD8-Positive T-Lymphocytes; Papillomavirus Infections; Tumor Microenvironment; Cell Line, Tumor; Immune Evasion; Membrane Proteins; Papillomaviridae; Tumor Escape
PubMed ID
41802050
Volume
123
Issue
11
First Page
2525730123
Last Page
2525730123
