Abstract: Objective To analyze the prognostic differences of hepatocellular carcinoma (HCC) with different levels of differentiation and to assess the efficacy of immunotherapy on poorly differentiated HCC. Methods The data of SEER database and HCC patients who underwent surgical resection at the First Affiliated Hospital of Xi'an Jiaotong University were collected for the clinical data analysis. The immune microenvironment characteristics of poorly differentiated HCC were analyzed by TCGA-LIHC seq data, and the efficacy of immunotherapy was analyzed in combination with one patients with poorly differentiated HCC. Results The data of 4, 114 patients from SEER database and 590 patients from the First Affiliated Hospital of Xi'an Jiaotong University were collected, and the survival analysis showed that the overall survival of patients with poorly differentiated HCC was worse than that of patients with high-moderately differentiated HCC (P<0.001). WGCNA and pathway enrichment analysis showed that the gene pathways affecting HCC differentiation and prognosis were mainly enriched in the E2F1-related pathway, which also affected immune cell infiltration in tumor tissues. TCGA-LIHC seq data analysis confirmed the enrichment of CD8⁺ T lymphocytes and high PD-1 expression in poorly differentiated HCC. Clinical data analysis showed that one patient with poorly differentiated HCC achieved complete response status after receiving immunotherapy, suggesting that poorly differentiated HCC was a potential beneficiary for immunotherapy. Conclusions The poorly differentiated HCC has a poor prognosis. The characteristics of the immune microenvironment with highly infiltrated PD-1⁺CD8⁺T cells of poorly differentiated HCC implies that immunotherapy may achieve better outcome.

Key words: Hepatocellular carcinoma, Poorly differentiated, Prognosis, Immunotherapy, PD-1 inhibitor