Rui Zhang

Tumors display marked similarities with embryos, exploiting embryonic developmental programs. Beyond the embryo, the placenta also shares features with malignant tumors, such as invasion, immune evasion, and rapid nutrient exchange, highlighting the need for mechanistic investigations of tumor development through the lens of placental biology. In this study, by screening placental-specific genes with aberrant expression in hepatocellular carcinoma (HCC), we found that the paternally expressed gene 10 (PEG10, a retrovirus-like gene) was overexpressed in HCC and associated with poor patient prognosis. Liver-specific deletion of Peg10 significantly impeded hepatocarcinogenesis and tumor progression in a hydrodynamic tail vein injection–induced HCC mouse model. PEG10 drove tumor cells to co-opt the metabolic phenotype of trophoblast cells by upregulating key glucose metabolic regulators glucose transporter 1 (GLUT1) and hexokinase 2 (HK2). Mechanistically, as an RNA-binding protein, PEG10 inhibited the Staufen 1 (STAU1)–mediated mRNA decay (SMD) pathway, stabilizing GLUT1 and HK2 mRNA to enhance glucose uptake and aerobic glycolysis. Furthermore, retinoic acid pharmacologically suppressed PEG10 expression, effectively abrogating the adaptive metabolic advantage and acting synergistically with sorafenib to restrict tumor growth. Collectively, this study reveals how HCC aberrantly reactivates the placental gene PEG10 to orchestrate oncogenic glucose uptake and metabolism, identifying it as a compelling therapeutic target for metabolic intervention in cancer. Significance: Aberrant reactivation of the placental gene PEG10 drives tumor glucose uptake and metabolic reprogramming in hepatocellular carcinoma by inhibiting Staufen1-mediated mRNA decay, which may open avenues for targeting onco-fetal pathways in cancer.

Cholangiocarcinoma (CCA) is a fibroblast-rich tumor. Lymph node metastasis (LNM) is the main prognostic risk factor for CCA. We determined that stanniocalcin 1 (STC1) is highly expressed in cancer-associated fibroblasts (CAFs) with LNM in CCA. However, the roles of CAFs and STC1 in CCA progression and LNM remain unelucidated. Here, we demonstrated that primary CCA tissues with LNM (LN⁺CCA) were enriched with more CAFs and lymphatic vessels than those with LN⁻CCA. LN⁺ CAFs strongly promoted CCA cell migration, invasion, TrEM, and LNM both in vitro and in vivo. LN⁺CAFs exhibited significantly higher STC1 expression than LN⁻CAFs. The in vitro and in vivo results demonstrated that STC1 is mainly responsible for the role of LN⁺CAFs in promoting CCA malignant behavior. Mechanistic studies demonstrated that STC1 activates integrin αVβ3 and its downstream FAK–YAP pathway. Additionally, we found that targeting STC1 and integrin αVβ3 rescued the pro-tumor effects of CAF on CCA in vitro and in vivo. Therefore, CAF-derived STC1 predicts LNM and is a potential therapeutic target in CCA.

Immune checkpoint inhibitors (ICIs) are widely used for treating hepatocellular carcinoma (HCC), yet their efficacy remains limited, with suboptimal response rates. The predictive power of the current biomarker, programmed death ligand‐1 (PD‐L1), is limited by detection variability and glycosylation, underscoring the need for complementary biomarkers to enhance predictive accuracy. In this study, mass spectrometry was employed to identify proteomic alterations in HCC tissues from responders and nonresponders to anti‐programmed cell death‐1 (PD‐1) therapy. Survival analysis established the role of Yin Yang 1 (YY1) in determining ICI efficacy. Coculture models of hepatoma and CD8 ⁺ T cells revealed the immunosuppressive function of YY1. Transcriptome sequencing identified polypeptide N‐acetylgalactosaminyltransferase 16 (GALNT16) as a transcriptional target of YY1, and subsequent Western blot and coimmunoprecipitation assays demonstrated that GALNT16 augments PD‐L1 expression. Furthermore, in vivo mouse models demonstrated that YY1 knockdown potentiated the efficacy of anti‐PD‐1 therapy, an effect that was partially reversed by GALNT16 overexpression. Specifically, YY1 upregulates GALNT16, which in turn promotes PD‐L1 glycosylation and stability, leading to diminished CD8 ⁺ T cell activity. Thus, GALNT16 knockdown rescued the compromised CD8 ⁺ T cell cytotoxicity induced by YY1. Collectively, these results elucidate the YY1/GALNT16/PD‐L1 axis as a pivotal mechanism underlying HCC resistance to ICI therapy. This highlights the therapeutic potential of targeting PD‐L1 glycosylation pathways.

Harnessing the cGAS‐STING DNA sensing pathway in dendritic cells (DCs) to enhance anti‐tumor immunity in immunosuppressive pancreatic tumors remains a significant challenge. While manganese (Mn ²⁺ ) enhances cGAS sensitivity to DNA, the precise mechanisms and potential of Mn‐DNA complexes in this process are unclear. Here, this work introduces a strategy to encapsulate Mn‐DNA complexes into DC‐derived immunogenic extracellular vesicle (EV _DC @Mn‐DNA) to trigger robust anti‐tumor immunity. This work shows that Mn ²⁺ induces tumor cell‐DNA transition to Z‐DNA, strengthening cGAS binding and promoting its phase condensation for optimal activation in DCs. Using this newly developed Raft‐Ultra method, this work engineers immunogenic EVs derived from tumor cell lysate‐pulsed DCs, loaded with Mn‐DNA complexes (EV _DC @Mn‐DNA). These EVs efficiently deliver Mn‐DNA complexes to DCs, activating the cGAS‐STING pathway both in vitro and in vivo. In animal models, EV _DC @Mn‐DNA administration enhances vascular function, as evidenced by increased blood flow and perfusion, improved anti‐PD‐L1 delivery, reduced hypoxia, and elevated endothelial cell‐ICAM1 expression, which facilitates T cell adhesion. This approach expands the intratumoral population of activated DCs and T cells and promotes the formation of larger tertiary lymphoid structures, ultimately suppressing orthotopic pancreatic tumor growth. Overall, this EV _DC @Mn‐DNA strategy reprograms intratumoral DCs, restores vascular‐immune homeostasis, and potentiates anti‐tumor immunity in pancreatic cancer.

Cancer is a significant challenge to society and public health in the 21st century. According to GLOBOCAN 2020, there were 19.3 million new cancer cases with approximately 10.0 million deaths in 2020 globally. By 2040, 28 million new cases and 16.2 million deaths are estimated. With the escalating challenges of cancer and limitations of conventional therapies like surgery, chemotherapy, and radiotherapy, the development of novel therapies such as immunotherapy and targeted therapy is required. Immunotherapy, especially immune checkpoint inhibitors (ICIs), has become a significant advancement in cancer treatment, combating tumors by activating the immune system. This review offers a thorough overview of ICIs, including their classification, mechanisms of action, and adverse events. It also examines the application of ICIs across various cancer types especially on advanced or unresectable malignancies, such as head and neck squamous cell carcinoma, esophageal cancer, non‐small cell lung cancer, breast cancer, hepatocellular carcinoma, and bladder cancer, highlighting their therapeutic potential and the challenges they face. By providing a comprehensive analysis, this review aims to construct a reference system for clinicians to better understand and utilize ICIs in treating cancer.

Gallbladder carcinoma (GBC) is an extremely aggressive tumor of the biliary tract with a bleak prognosis, and the evidence supporting the benefit of available systemic therapy for advanced GBC is scarce. Herein, this study intended to investigate the real-world outcome of chemotherapy combined with programmed death-1 (PD-1) inhibitor for the management of unresectable or recurrent GBC. From January 2018 to December 2023, consecutive patients who were treated with systematic treatment, including chemotherapy or the combination of chemotherapy plus PD-1 inhibitor, for unresectable or recurrent GBC were retrospectively identified. Clinical data regarding baseline characteristics, therapeutic response, adverse events (AEs), and oncological outcomes were collected. The eligible patients were allocated to combination therapy arm (n = 46) and mono-chemotherapy arm (n = 19). After propensity score matching (PSM), 16 patients were allocated in each arm. The overall survival (OS) and progression-free survival (PFS) of combination therapy were marginally superior to mono-chemotherapy both before and after PSM. The combination therapy exhibited advantage over mono-chemotherapy in regards to partial response (PR) (before PSM: P = 0.009; after PSM: P = 0.037) and objective response rate (ORR) (before PSM: P = 0.006; after PSM: P = 0.015). In combined therapy cohort, 1 patient achieve a complete response, and 13 patients were assessed as appropriate for surgical excision, among which 1 patient refused further surgical intervention. In patients with unresectable or recurrent GBC, the combination of chemotherapy and PD-1 inhibitor as first-line therapy exhibited prolonged OS and PFS, and increased PR and ORR over those receiving chemotherapy alone, with an acceptable toxicity profile. The combination therapy may be a potential conversion therapy in unresectable GBC patients.

Patients with cholangiocarcinoma (CCA) with lymph node metastasis (LNM) have the worst prognosis, even after complete resection; however, the underlying mechanism remains unclear. Here, we established CAF-derived PDGF-BB as a regulator of LMN in CCA. Proteomics analysis revealed upregulation of PDGF-BB in CAFs derived from patients with CCA with LMN (LN⁺CAFs). Clinically, the expression of CAF-PDGF-BB correlated with poor prognosis and increased LMN in patients with CCA, while CAF-secreted PDGF-BB enhanced lymphatic endothelial cell (LEC)-mediated lymphangiogenesis and promoted the trans-LEC migration ability of tumor cells. Co-injection of LN⁺CAFs and cancer cells increased tumor growth and LMN in vivo. Mechanistically, CAF-derived PDGF-BB activated its receptor PDGFR-β and its downstream ERK1/2-JNK signaling pathways in LECs to promote lymphoangiogenesis, while it also upregulated the PDGFR-β-GSK-P65-mediated tumor cell migration. Finally, targeting PDGF-BB/PDGFR-β or the GSK-P65 signaling axis prohibited CAF-mediated popliteal lymphatic metastasis (PLM) in vivo. Overall, our findings revealed that CAFs promote tumor growth and LMN via a paracrine network, identifying a promising therapeutic target for patients with advanced CCA.