Alternative splicing regulates <i>FGGY-</i>derived neoantigen presentation and promotes immune evasion in metabolic-associated hepatocellular carcinoma

The elucidation of actionable, tumor-specific neoantigens remains a challenge in cancer immunotherapy. We identify <i>FGGY</i>-204, an alternatively spliced isoform of <i>FGGY</i>, as a source of tumor-specific neoantigen presentation. <i>FGGY</i>-204 expression is elevated in HCC and encodes a cryptic peptide that is derived from the primate-specific exon 12. This neoantigen candidate peptide is repressed in the normal liver parenchyma by a multifaceted regulatory program, where the <i>FGGY</i> exon 12 locus is epigenetically silenced by abrogated active chromatin marks and DNA methylation. Exon 12 inclusion is directly suppressed by HNRNPA1, whose silencing promotes <i>FGGY</i>-204 biogenesis, revealing a repressive mechanism with potential in therapy. Critically, <i>FGGY</i>-204 expression defines immune-cold HCC tumors, inversely correlated with CD8⁺ T cell tumor infiltration and antigen presentation. Its immune association dynamically shifts in response to immunotherapy. <i>FGGY</i>-204 presents a neopeptide, a potential immunotherapeutic target, revealing its precise molecular mechanism of control as an entry point to modulate tumor immunogenicity.