Long non-coding RNAs (lncRNAs), which were implicated in many pathophysiological processes including cancer, were frequently dysregulated in hepatocellular carcinoma (HCC). Studies have demonstrated that ferroptosis and immunity can regulate the biological behaviors of tumors. Therefore, biomarkers that combined ferroptosis, immunity, and lncRNA can be a promising candidate bioindicator in clinical therapy of cancers. Many bioinformatics methods, including Pearson correlation analysis, univariate Cox proportional hazard regression analysis, least absolute shrinkage and selection operator (LASSO) analysis, and multivariate Cox proportional hazard regression analysis were applied to develop a prognostic risk signature of immune- and ferroptosis-related lncRNA (IFLSig). Finally, eight immune- and ferroptosis-related lncRNAs (IFLncRNA) were identified to develop and IFLSig of HCC patients. We found the prognosis of patients with high IFLSig will be worse, while the prognosis of patients with low IFLSig will be better. The results provide an efficient method of uniting critical clinical information with immunological characteristics, enabling estimation of the overall survival (OS). Such an integrative prognostic model with high predictive power would have a notable impact and utility in prognosis prediction and individualized treatment strategies.

Malignant ascites (MA) is a common symptom of peritoneal metastasis in liver cancer. Cancer immunotherapy can modulate immune cells to induce antitumor immune efficiency. Reprogramming tumor immune microenvironment (TIME) is a momentous strategy to overcome immunosuppression and achieve immune functional normalization. Inspired by the inherent apoptotic bodies and vesicles, we proposed and systematically studied engineered apoptosis-bioinspired nanoparticles (EBN) for cancer immunotherapy of MA. Using both in vitro and in vivo experimental validations, we elucidated that EBN could be efficiently engulfed by the tumor-associated macrophages (TAMs) and manipulate their polarization. Moreover, a boosted immune cascade response as a result of heightening cytotoxic T-lymphocytes (CTLs) activity was investigated. Based on these results, EBN was confirmed to have strong immune cascade activation capability. Remarkably, the injection of EBN further reduced ascites volume and reformed immune cell subtypes, compared to the injection of either PBS or free TMP195 alone. In short, this novel nanodrug delivery system (NDDS) represents a prospective immunotherapeutic approach for clinical therapeutics of hepatoma ascites and other malignant effusion.

Liver cancer is an extraordinarily heterogeneous malignant disease. The tumor microenvironment (TME) and tumor-associated macrophages (TAMs) are the major drivers of liver cancer initiation and progression. It is critical to have a better understanding of the complicated interactions between liver cancer and the immune system for the development of cancer immunotherapy. Based on the gene expression profiles of tumor immune infiltration cells (TIICs), upregulated genes in TAMs and downregulated genes in other types of immune cells were identified as macrophage-specific genes (MSG). In this study, we combined MSG, immune subtypes, and clinical information on liver cancer to develop a tumor immune infiltration macrophage signature (TIMSig). A four-gene signature (S100A9, SLC22A15, TRIM54, and PPARGC1A) was identified as the TAM-related prognostic genes for liver cancer, independent of multiple clinicopathological parameters. Survival analyses showed that patients with low TIMSig had a superior survival rate than those with high TIMSig. Additionally, clinical immunotherapy response and TIMSig was observed as highly relevant. In addition, TIMSig could predict the response to chemotherapy. Collectively, the TIMSig could be a potential tool for risk-stratification, clinical decision making, treatment planning, and oncology immunotherapeutic drug development.