Immune microenvironment driven immunotherapy resistance in 11q13-amplified hepatocellular carcinoma

Background: Immune checkpoint inhibitors (ICIs) have provided new therapeutic opportunities for patients with liver hepatocellular carcinoma (LIHC); however, only a subset of patients achieve meaningful benefit. Previous studies have suggested that co-amplification of the chromosome 11q13 region-which includes CCND1, FGF3, FGF4, and FGF19-is associated with poor immunotherapy response and unfavorable prognosis. Nonetheless, whether the immune microenvironment contributes to ICI resistance in 11q13-amplified LIHC remains unclear. This study aimed to elucidate the genomic and immunologic correlates of 11q13 amplification in LIHC. Methods: Tumor samples from 890 LIHC patients were analyzed using a 733-gene next-generation sequencing (NGS) panel to characterize genomic alterations, including DNA damage repair (DDR) pathway genes, tumor mutation burden (TMB), and intratumor heterogeneity (ITH). Multiplex immunofluorescence (mIF) was performed to evaluate the immune microenvironment, focusing on stromal and intratumoral immune cell populations. Comparative analyses were conducted between patients with and without 11q13 amplification to determine differences in genomic alterations and immune cell infiltration patterns. Results: Among the 890 LIHC patients, 8.9% (79/890) harbored chromosome 11q13 amplification. Genomic profiling revealed no significant differences in DDR pathway mutations, TMB, or ITH between 11q13-amplified and non-amplified patients, suggesting that 11q13-associated immunotherapy resistance is unlikely to stem from genomic instability. In contrast, immune microenvironment analysis revealed substantial alterations associated with 11q13 amplification: patients with amplification demonstrated increased stromal CD8⁺ T-cell positivity (P=0.04), as well as significantly elevated intratumoral infiltration of CD68⁺CD163⁺ M2-TAMs (higher density, P=0.03; higher positivity, P=0.03) and increased positivity of CD68⁺HLA-DR⁺ M1-TAMs (P=0.03). These findings indicate that 11q13-amplified tumors may harbor a more complex immunosuppressive and inflammatory microenvironment, potentially contributing to ICI resistance. Conclusion: Chromosome 11q13 amplification in LIHC is not associated with distinct genomic instability features but is strongly correlated with alterations in the tumor immune microenvironment, including increased CD8⁺ T-cell presence and enrichment of both M1 and M2 tumor-associated macrophages. These results suggest that immune microenvironment dysregulation, rather than genomic variation, may underlie immunotherapy resistance in 11q13-amplified LIHC, underscoring the need for tailored immunotherapeutic strategies for this molecularly defined subgroup.