# The membrane-associated ubiquitin ligase MARCHF8 degrades MHC-I in HPV-positive head and neck cancer for immune evasion

## TL;DR

This study shows that MARCHF8, a protein boosted by HPV, helps cancer cells avoid the immune system by reducing MHC-I, and blocking it could improve immunotherapy for HPV-related head and neck cancers.

## Contribution

The study identifies MARCHF8 as a novel driver of immune evasion in HPV-positive head and neck cancers by degrading MHC-I molecules.

## Key findings

- MARCHF8 ubiquitinates and degrades MHC-I molecules in HPV-positive head and neck cancer cells.
- Inhibiting MARCHF8 restores MHC-I levels, suppresses tumor growth, and increases immune cell infiltration.
- Combining MARCHF8 knockout with anti-PD-1 treatment enhances tumor suppression in ICI-refractory tumors.

## Abstract

Immune checkpoint inhibitors (ICIs) have transformed cancer therapy, yet many human papillomavirus (HPV)-positive head and neck cancers remain resistant due to the downregulation of antigen presentation mechanisms. We identify the ubiquitin ligase MARCHF8 as a primary driver of this evasion that degrades major histocompatibility complex class I (MHC-I) molecules. We demonstrate that Marchf8 knockout restores antigen presentation, enhances cytotoxic CD8+ T cell function, and remodels the tumor microenvironment toward an immunostimulatory state. Importantly, MARCHF8 knockout sensitizes ICI-refractory tumors, highlighting MARCHF8 as a compelling therapeutic target to overcome immunotherapy resistance in HPV-associated head and neck cancers.

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.