We recently uncovered a key mechanism by which HPV-positive tumors hide from the immune system. We found that the virus upregulates a host protein, MARCHF8, a ubiquitin ligase that targets the major histocompatibility complex class I (MHCI) for destruction. This degradation occurs through a specialized cellular recycling process called selective autophagy. By destroying MHC-I—the primary molecule that presents tumor antigens to CD8 + T cells—the cancer effectively becomes invisible to these cells. We have demonstrated that blocking this MARCHF8-autophagy axis restores cell-surface MHC-I levels, reactivates robust T-cell responses, and sensitizes resistant tumors to checkpoint inhibitor therapies.
