Hepatocellular carcinoma (HCC) exhibits a striking male predominance, particularly in Hepatitis B Virus (HBV) endemic regions. While lifestyle factors and estrogen protection are traditional explanations, they fail to fully account for this disparity. This review elucidates the molecular mechanisms driving this gender gap, focusing on the interplay between the Androgen Receptor (AR), viral replication, and the suppression of NKG2D-mediated immune surveillance. We synthesized experimental and clinical findings linking AR signaling, the viral protein HBx, and the regulation of NKG2D ligands (MICA/MICB). Current evidence identifies a positive feedback loop where AR enhances HBV replication, while HBx amplifies AR activity. Crucially, this axis systematically dismantles innate immunity: AR signaling represses MICA/B transcription via miRNA networks and upregulates ADAM metalloproteases, leading to ligand shedding and the release of soluble MICA (sMICA), effectively blinding Natural Killer (NK) cells. We propose that historical failures of anti-androgen monotherapy likely stemmed from ignoring this immune modulation. Consequently, targeting the AR-NKG2D axis represents a promising strategy to sensitize tumors to immunotherapy, suggesting that future therapeutic approaches should combine AR modulation with immune checkpoint inhibitors or shedding-blockade.
Takahashi et al. (Sun,) studied this question.