No abstract

The rapid development and remarkable success of checkpoint inhibitors have provided significant breakthroughs in cancer treatment, including hepatocellular carcinoma (HCC). However, only 15-20% of HCC patients can benefit from checkpoint inhibitors. Cancer stem cells (CSCs) are responsible for recurrence, metastasis, and local and systemic therapy resistance in HCC. Accumulating evidence has suggested that HCC CSCs can create an immunosuppressive microenvironment through certain intrinsic and extrinsic mechanisms, resulting in immune evasion. Intrinsic evasion mechanisms mainly include activation of immune-related CSC signaling pathways, low-level expression of antigen presenting molecules, and high-level expression of immunosuppressive molecules. External evasion mechanisms are mainly related to HBV/HCV infection, alcoholic/nonalcoholic steatohepatitis, hypoxia stimulation, abnormal angiogenesis, and crosstalk between CSCs and immune cells. A better understanding of the complex mechanisms of CSCs involved in immune evasion will contribute to therapies for HCC. Here we will outline the detailed mechanisms of immune evasion for CSCs, and provide an overview of the current immunotherapies targeting CSCs in HCC.

No abstract

Intrahepatic cholangiocarcinoma (ICC) is a relatively rare but highly aggressive tumor type that responds poorly to chemotherapy and immunotherapy. Comprehensive molecular characterization of ICC is essential for the development of novel therapeutics. Here, we constructed two independent cohorts from two clinic centers. A comprehensive multiomics analysis of ICC via proteomic, whole-exome sequencing (WES), and single-cell RNA sequencing (scRNA-seq) was performed. Novel ICC tumor subtypes were derived in the training cohort (n = 110) using proteomic signatures and their associated activated pathways, which were further validated in a validation cohort (n = 41). Three molecular subtypes, chromatin remodeling, metabolism, and chronic inflammation, with distinct prognoses in ICC were identified. The chronic inflammation subtype was associated with a poor prognosis. Our random forest algorithm revealed that mutation of lysine methyltransferase 2D (KMT2D) frequently occurred in the metabolism subtype and was associated with lower inflammatory activity. scRNA-seq further identified an APOE+C1QB+ macrophage subtype, which showed the capacity to reshape the chronic inflammation subtype and contribute to a poor prognosis in ICC. Altogether, with single-cell transcriptome-assisted multiomics analysis, we identified novel molecular subtypes of ICC and validated APOE+C1QB+ tumor-associated macrophages as potential immunotherapy targets against ICC.

The combination of ferroptosis inducers and immune checkpoint blockade can enhance antitumor effects. However, the efficacy in tumors with low immunogenicity requires further investigation. In this work, a water‐in‐oil Pickering emulsion gel is developed to deliver (1S, 3R)‐RSL‐3 (RSL‐3), a ferroptosis inducer dissolved in iodized oil, and programmed death‐1 (PD‐1) antibody, the most commonly used immune checkpoint inhibitor dissolved in water, with optimal characteristics (RSL‐3 + PD‐1@gel). Tumor lipase degrades the continuous oil phase, which results in the slow release of RSL‐3 and PD‐1 antibody and a notable antitumor effect against low‐immunogenic hepatocellular carcinoma and pancreatic cancer. Intriguingly, the RSL‐3 + PD‐1@gel induces ferroptosis of tumor cells, resulting in antitumor immune response via accumulation of helper T lymphocyte cells and cytotoxic T cells. Additionally, the single‐cell sequence profiling analysis during tumor treatment reveals the induction of ferroptosis in tumor cells together with strong antitumor immune response in ascites.