Background: Hepatic inflammation is a common initiator of liver diseases and considered as the primary driver of hepatocellular carcinoma (HCC). However, the precise mechanism of inflammation-induced HCC development and immune evasion remains elusive and requires extensive investigation. This study sought to identify the new target that is involved in inflammation-related liver tumorigenesis. Methods: RNA-sequencing (RNA-seq) analysis was performed to identify the differential gene expression signature in primary human hepatocytes treated with or without inflammatory stimulus. A giant E3 ubiquitin protein ligase, HECT domain and RCC1-like domain 2 (HERC2), was identified in the analysis. Prognostic performance in the TCGA validation dataset was illustrated by Kaplan–Meier plot. The functional role of HERC2 in HCC progression was determined by knocking out and over-expressing HERC2 in various HCC cells. The precise molecular mechanism and signaling pathway networks associated with HERC2 in HCC stemness and immune evasion were determined by quantitative real-time PCR, immunofluorescence, western blot, and transcriptomic profiling analyses. To investigate the role of HERC2 in the etiology of HCC in vivo, we applied the chemical carcinogen diethylnitrosamine (DEN) to hepatocyte-specific HERC2-knockout mice. Additionally, the orthotopic transplantation mouse model of HCC was established to determine the effect of HERC2 during HCC development. Results: We found that increased HERC2 expression was correlated with poor prognosis in HCC patients. HERC2 enhanced the stemness and PD-L1-mediated immune evasion of HCC cells, which is associated with the activation of signal transducer and activator of transcription 3 (STAT3) pathway during the inflammation-cancer transition. Mechanically, HERC2 coupled with the endoplasmic reticulum (ER)-resident protein tyrosine phosphatase 1B (PTP1B) and limited PTP1B translocation from ER to ER-plasma membrane junction, which ameliorated the inhibitory role of PTP1B in Janus kinase 2 (JAK2) phosphorylation. Furthermore, HERC2 knockout in hepatocytes limited hepatic PD-L1 expression and ameliorated HCC progression in DEN-induced mouse liver carcinogenesis. In contrast, HERC2 overexpression promoted tumor development and progression in the orthotopic transplantation HCC model. Conclusion: Our data identified HERC2 functions as a previously unknown modulator of the JAK2/STAT3 pathway, thereby promoting inflammation-induced stemness and immune evasion in HCC.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Although sorafenib is a standard first-line molecule-targeted drug against advanced HCC, the drug resistance development and adverse side effects usually limit its efficacy. This study investigated the effect of fucoidan on the sorafenib sensitivity of sorafenib-resistant human HCC cell line HepG2-SR established by long-time exposure of HepG2 to sorafenib. We demonstrated fucoidan combined with sorafenib synergistically promoted apoptosis and cell cycle arrest whereas inhibited cell migration in HepG2-SR cells. This combination treatment effectively suppressed the cellular epithelial growth factor receptor (EGFR) nuclear distribution and downstream gene transcription. Interestingly, fucoidan bound the cell surface EGFR, dampening EGFR translocation to lipid raft and further nuclear distribution, restoring the sorafenib sensitivity in HepG2-SR cells. Blocking fucoidan-EGFR interaction using EGFR antibody restrained the enhanced anti-tumor effects upon the combined administration. Besides, EGFR knockdown abolished the combination treatment-improved anti-tumor efficacy. This combination also suppressed in vivo xenograft tumor growth in nude mice. Our present study uncovered that fucoidan overcame sorafenib resistance in HCC via its interaction with cell membrane EGFR and further suppression of EGFR redistribution and downstream signaling in sorafenib-resistant cells. Overall, current results suggest that simultaneous treatment of fucoidan and sorafenib might serve as a potential therapeutic strategy against sorafenib-resistant HCC.

Immunological heterogeneity in esophageal squamous cell carcinoma (ESCC) poses a significant challenge to the efficacy and response to immunotherapy. In this study, we used single-cell RNA sequencing to uncover substantial heterogeneity in the tumor microenvironments (TMEs) among patients received PD-1 inhibitor with partial response (PR), stable disease (SD), and that who underwent surgery without prior therapy. Notably, tumors classified as SD demonstrated an immunosuppressive environment, characterized by a higher prevalence of M2-like macrophages and lower frequencies of T and B cells, especially PD1^highCD8⁺ T cells. These PD1^highCD8⁺ T cells were found to frequently engage with macrophages within the TMEs. Focusing on macrophages, we observed elevated expression of the Iron-Sulfur Cluster Assembly Enzyme (ISCU) in macrophages infiltrating SD tumors. ISCU was identified as a promoter of M2 macrophage polarization in a p53-dependent manner. Mechanistically, ISCU sequestrates p53 in the cytoplasm, reducing its nuclear location and relieving transcriptional repression of xCT and Arg1. Consequently, the increased expression of xCT and Arg1 modulates macrophage sensitivity to ferroptosis and the arginine metabolic pathway, thus affecting macrophage differentiation and inflammatory responses. Furthermore, inhibition of ISCU expression was found to repolarize macrophages, enhance CD8⁺ T cell cytotoxicity, and boost the efficacy of anti-PD-1 antibody. Collectively, our findings highlight the complex interplay within ESCC TMEs and suggest that targeting ISCU might be a novel strategy to reprogram the immunosuppressive TME, potentially improving immunotherapy outcomes in ESCC patients.

Cancer-associated fibroblasts (CAF) are pivotal constituents of the tumor microenvironment that significantly influence cancer aggressiveness through the secretion of various factors. A more detailed characterization of the specific secretions exclusive to CAFs that drive tumor progression could identify potential targets to perturb this intracellular cross-talk. In this study, we identified latent TGFβ-binding protein 2 (LTBP2) as a unique protein secreted exclusively by esophageal squamous cell carcinoma (ESCC) CAFs that promotes metastasis and chemoresistance. LTBP2 exerted its oncogenic effects by interacting with integrin α6β4, which serves as a functional receptor, and thereby activating Src signaling in ESCC cells. Notably, targeting LTBP2 with specific antagonistic antibodies markedly increased the susceptibility of ESCC cells to chemotherapeutic agents. These findings highlight the pivotal role of LTBP2 as a crucial mediator of CAF-induced cancer cell aggression and introduce it as a promising target to enhance chemotherapeutic efficacy in ESCC. Significance: CAF-secreted LTBP2 binds integrin α6β4 and activates Src signaling to drive metastasis and chemoresistance in esophageal cancer, highlighting LTBP2 as a key regulator of CAF-mediated tumor progression that can be therapeutically targeted.

During virus infection, PRRs are engaged to detect specific viral components, such as viral RNA or DNA, and regulate the innate immune response in the infected cells or other immune cells. We reported that deficiency of SRA, an important innate PRR, promoted IRF3 activation, type I IFN production, and innate antiviral responses against RNA and DNA viruses in vivo and in vitro .