Given the abundant stroma of the liver and that cirrhosis or hepatic fibrosis is the premalignant condition of most hepatocellular carcinomas (HCC), underscores the critical interaction between extracellular matrix (ECM) stiffness and the tumor microenvironment (TME) in the initiation, progression, and immunotherapy of HCC. This review presents a comprehensive exploration of the factors that regulate matrix stiffness, including the activation of cancer-associated fibroblasts (CAFs), the excessive deposition of ECM proteins, and cross-linking. Furthermore, this review explores the underlying molecular pathways through which matrix stiffness affects the prevalence of tumors and immune cells. Based on these premises, we delve into the potential targets and roles of pharmacological interventions targeting matrix stiffness in HCC and its immunotherapy, and highlight the considerable potential of biomaterials for the development of ECM stiffness-targeted agents. The potential exists for such agents to enhance the efficacy of immunotherapy and prolong the survival of patients diagnosed with HCC.

Diffuse large B cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma (NHL), with approximately 30

Hepatocellular carcinoma (HCC) is one of the most common cancer types globally, which is characteristically aggressive, with a poor prognosis and a high mortality rate. The pathways leading to the development and progression of this fatal disease have been studied at the macro and micromolecular levels, where the interplay of multiple factors has been observed in multistep processes. Invariably, all factors at some point trigger mutations in specific genes that contribute to the development and progression of hepatic tumors. Decades of research have demonstrated that, among all genetic variations, mutation in the TP53 gene is the most frequent phenomenon, attracting global interest in cancer research. Driven by certain external and internal factors, the mutation transforms TP53 into an active oncogene with both gain-of-function (GOF) and loss-of-function (LOF) properties, collectively exerting a robust carcinogenic effect. The key mechanisms involved in this process include the P53-MDM2 negative feedback loop, the CDK4/cyclin D1-PIN1-FBW7a-c-Myc axis, profound immune modulation, and the development of cancer stemness, collectively shaping tumor behavior. Given that patients with p53 mutations often present with advanced-stage, it is crucial to adopt mutation-centric subgroup stratification to achieve prognostic precision and therapeutic success. However, emerging techniques are facing significant challenges due to the diverse heterogeneity and immune modulation caused by the mutation, making it difficult to design an effective management scheme. In recent years, several strategies have shown promising results in preclinical and early clinical settings, and combining them with established frontline therapies or incorporating them into preventive measures may open new possibilities. Existing studies largely highlight the mutation from molecular and clinicopathological perspectives, rather than undertaking an inclusive examination and meaningful translation for prospective clinical advancement. This review attempts to fully capture the unfolding role of p53 mutations, primarily based on the literature from the last 10 years, and provides a comprehensive perspective on both mechanistic insights and translational aspects.

Natural extracellular vesicles (EVs) and extruded membrane vesicles (MVs) have emerged as a promising platform for cancer vaccination by co-delivering tumor antigens and adjuvant. However, conventional designs rely on a single class of adjuvant, which often fail to adequately activate dendritic cells (DCs), resulting in inefficient cross-priming and weak cytotoxic T lymphocyte (CTL) activation. To address this, we designed a dual-adjuvant nanovaccine by modularly fusing interferon-alpha (IFNα)-displaying bacterial MVs (IFNα-BMVs) with programmed cell death protein 1 (PD1)-displaying cancer MVs (PD1-CMVs) to potentiate antitumor immune responses. In this design, IFNα-BMVs deliver dual-adjuvant pathogen-associated molecular patterns (PAMPs) and IFNα to promote DC maturation and cross-priming, thereby activating CTL. Concurrently, PD1-CMVs provide tumor-associated antigens (TAAs) and utilize membrane-anchored PD1 as a decoy receptor for targeted PD-L1 blockade, thus preventing CTL exhaustion. More importantly, this IFNα and PD1 co-displaying hybrid MVs (IP-HMVs) nanovaccine significantly upregulated costimulatory molecules and antigen-presenting molecules, thereby promoting DC maturation and CTL infiltration. Furthermore, RNA sequencing analysis validated that IP-HMVs robustly activated canonical antigen presentation pathways. In both subcutaneous and metastatic 4T1 tumor models, IP-HMVs significantly suppressed tumor progression and extended median survival to 35 days. The modular design offers a generalizable framework for developing next-generation cancer vaccines.

Hepatocellular carcinoma (HCC) is one of the most malignant tumors worldwide. This study aimed to investigate the role of protein arginine methyltransferase 5 (PRMT5) in HCC. Gene expression was determined using reverse transcription-quantitative polymerase chain reaction, Western blot, and immunohistochemistry. The interaction between genes were determined using chromatin immunoprecipitation, glutathione-S-transferase pull-down, co-immunoprecipitation, and luciferase assays. m6A levels were determined using m6A dot assay. N6-methyladenosine (m6A) enrichment was determined using methylated RNA immunoprecipitation assay. Cellular functions were determined using Cell Counting Kit-8 assay and propidium iodide staining. Xenograft assay was conducted to further verify the role of PRMT5 in HCC. We found that overexpressed PRMT5 was upregulated in tumor protein p53 (TP53)-mutated HCC patients. TP53 epigenetically in activated PRMT5. PRMT5 deficiency promoted the ferroptosis of HCC cells in vitro and inhibited tumor growth in vivo. Moreover, PRMT5 could interact with RNA binding motif protein 15 (RBM15) to activate ferritinophagy signaling. RBM15-mediated m6A modification of ferritin heavy chain 1 (FTH1), promoting its mRNA expression and stability. However, overexpression of FTH1 suppressed ferroptosis and promoted tumor growth. Taken together, PRMT5/RBM15/ferritinophagy signaling can be a potential target for HCC.

Background: Acute kidney injury (AKI) is a severe and prevalent nephrotic syndrome which lack of definitive therapies. Alpha-amino-β-carboxymuconic acid-ε-semialdehyde decarboxylase (ACMSD) is a metabolic enzyme mainly expressed in the kidney which exacerbated AKI injury by promoting TCA cycle and inhibiting nicotinamide adenine dinucleotide (NAD+) production, whereas lack of effective intervention strategies for ACMSD-targeted therapy. Methods: Herein, we knocked out ACMSD in vitro through CRISPR-Cas9 method, and developed a reactive oxygen species (ROS)-responsive neutrophil-derived cellular vesicles (CVs) drugs (RNAi@ROS-CVs), which efficiently mediated ACMSD knockdown in vivo, exploring the mechanism of ACMSD-induced ferroptosis process in AKI. Results: ACMSD knockout effectively alleviated cisplatin (CP)-induced mitochondrial damage, suppressed TCA cycle progression, promoted NAD+ synthesis, and inhibited ferroptosis in HK2 cells. In mice AKI model, RNAi@ROS-CVs effectively targeted the injured kidneys, downregulated ACMSD expression in renal tubular epithelial cells, reduced ROS production and lipid peroxidation, and alleviated CP or ischemia/reperfusion (I/R)-induced ferroptosis. Conclusion: These findings highlight the therapeutic potential of ACMSD-targeted knockout in AKI intervention and introduce a versatile and efficient controlled-release drug delivery platform for AKI-targeted therapy, with potential applicability to other acute renal diseases.

Background:Concurrent chemoradiotherapy (CCRT) for abdominal cancer frequently induces muscle loss, weight loss, and malnutrition. Objective:This exploratory randomized phase II trial evaluated whether a multidisciplinary, mobile health (mHealth)-based multimodal rehabilitation program could preserve handgrip strength and muscle mass in patients with abdominal cancer undergoing CCRT. Methods:In this prospective, multicenter, randomized, open-label phase II trial (NCT05325554), 111 eligible patients with abdominal malignancies scheduled for CCRT were randomly assigned (1:1) to receive either multidisciplinary mHealth rehabilitation care (MRC; n=57) or standard care (SC; n=54). The MRC program was delivered by a dedicated multidisciplinary team using the AiNST mHealth platform and wearable heart rate monitors. The primary end point was handgrip strength at the end of CCRT (analyzed with analysis of covariance adjusting for baseline). Secondary end points were exploratory and analyzed without multiplicity adjustment; sensitivity analysis using false discovery rate (FDR) correction was performed. Results:Between February 2022 and April 2023, 111 patients were enrolled. Adherence was high (n=93, 83.9% achieved exercise targets). After adjusting for baseline handgrip strength, the MRC group had significantly higher handgrip strength at the end of CCRT than the SC group (adjusted mean difference 4.87 kg, 95% CI 3.36-6.38; P<.001). Exploratory analyses of secondary end points (without multiplicity adjustment) showed that the MRC group also had better preservation of body weight (P=.005), skeletal muscle mass (P<.001), serum albumin (P=.009), prealbumin (P=.02), and lower rates of hematological toxicity (P<.05), as well as improved psychological status (distress thermometer [DT] and Hospital Anxiety and Depression Scale [HADS]) and nutritional scores (Nutritional Risk Screening 2002 [NRS-2002] and Patient-Generated Subjective Global Assessment [PG-SGA]) at the end of CCRT (all P<.05). All nominally significant secondary end points remained significant after FDR correction (q<.05). These findings are preliminary and should be interpreted with caution due to the open-label design, population heterogeneity, and exploratory secondary analyses. Conclusions:In this exploratory phase II trial, a multidisciplinary, mHealth-based multimodal rehabilitation program was associated with better preservation of handgrip strength, muscle mass, and nutritional status, as well as lower rates of certain treatment toxicities, compared with SC. However, definitive conclusions are limited by the open-label design, heterogeneity of tumor types, and short follow-up. Larger, blinded phase III trials are needed to confirm these findings.

Programmed cell death protein 1/its ligand 1 (PD-1/PD-L1) blockade has revolutionized cancer immunotherapy, yet its efficacy is limited by incomplete checkpoint inhibition and persistent PD-L1 transcription. In this work, lysine acetyltransferase 8 (KAT8) is identified as a nucleator of liquid-liquid phase separation (LLPS)-mediated condensates that concentrate transcription factors to drive sustained PD-L1 transcription and promote immune resistance. Leveraging this mechanism, a PD-1-functionalized hybrid vesicle-liposome platform (PD-1-HVL-siKAT8) is developed to deliver small interfering RNA (siRNA) targeting KAT8 for LLPS modulation and enhanced cancer immunotherapy. In this platform, the PD-1-presenting vesicles enable tumor accumulation and PD-L1 blockade, while the fused liposomes provide efficient siRNA encapsulation and cytosolic release, leading to potent KAT8 silencing and condensate dissolution. This LLPS modulator platform markedly suppresses PD-L1 expression and reshapes the tumor immune microenvironment, augmenting type I interferon signaling, dendritic cell maturation, cytotoxic T-cell activation, and M1-like macrophage polarization. In subcutaneous and recurrent hepatocellular carcinoma models, PD-1-HVL-siKAT8 significantly inhibits tumor growth, prevents recurrence, and extends survival with negligible toxicity. Collectively, this approach integrates PD-L1 blockade with disruption of LLPS-dependent transcription for durable immunotherapy.

Concurrent chemoradiotherapy (CCRT) for abdominal cancer frequently induces chemoradiotherapy‑induced muscle loss, weight loss, and malnutrition. This randomized phase II trial evaluated whether a multidisciplinary, mHealth‑based multimodal rehabilitation program could preserve handgrip strength and muscle mass in abdominal cancer patients undergoing CCRT. In this prospective, multicenter, randomized, open‑label phase II trial (NCT05325554), 111 eligible patients with abdominal malignancies scheduled for CCRT were randomly assigned (1:1) to receive either multidisciplinary mHealth rehabilitation care (MRC, n=57) or standard care (SC, n=54). The MRC program was delivered by a dedicated multidisciplinary team comprising oncologists, rehabilitation physicians, nurses, clinical nutritionists, and psychologists. Using the AINST mHealth platform and wearable heart rate monitors, the team provided coordinated, individualized exercise, nutritional, and psychological interventions based on weekly assessments and real‑time data. The SC group received routine oncology care. The primary endpoint was change in handgrip strength from baseline to CCRT completion. Secondary endpoints included body weight, skeletal muscle mass, nutritional biomarkers, quality of life, psychological status, and adverse events. Between February 2022 and April 2023, 111 patients were enrolled. Adherence was high, with 83.9% (47/56) of MRC patients achieving preset exercise targets. Compared with SC, the MRC group demonstrated significantly less decline in handgrip strength at all time points (all p < 0.001). The MRC group also showed better preservation of body weight (mean difference 1.3 kg, p=0.005) and a significantly lower proportion of patients with >5% weight loss (10.7% vs. 32.7%, p=0.005). Skeletal muscle mass was also better preserved (mean difference 1.3 kg, p<0.001). The MRC group had less decline in serum albumin (p=0.009) and prealbumin (p=0.019), and lower incidences of ≥G3 leukopenia (5.4% vs. 19.2%, p=0.037) and ≥G1 thrombocytopenia (16.1% vs. 34.6%, p=0.026). Nutritional and psychological benefits persisted at 4‑week post‑CCRT follow‑up. A multidisciplinary, mHealth‑based multimodal rehabilitation program effectively preserves handgrip strength, muscle mass, and nutritional status while reducing treatment toxicity in abdominal cancer patients undergoing CCRT. The multicenter implementation using standardized digital tools supports its scalability and translation into real‑world clinical pathways. Clinical Trial Registration: ClinicalTrials.gov NCT05325554.Registration Date 03/08/2022.

BACKGROUND:Matrix stiffening is a hallmark of hepatocellular carcinoma (HCC), disrupting the tumor microenvironment (TME) and impairing anti-tumor immunity. Although the interferon-stimulated gene 2'-5'-oligoadenylate synthetase-like (OASL) is dysregulated in cancers, its role in stiffness-driven HCC progression remains unclear. METHODS:We constructed polyacrylamide gels (5 kPa soft, 16 kPa stiff) to mimic the mechanical TME. Transcriptome sequencing identified OASL as a stiffness-associated gene. We subsequently performed in vitro assays (CCK-8, Transwell, apoptosis) to assess HCC cell behaviors. Furthermore, Co-IP, ELISA, Western blot, and immunofluorescence were utilized to explore molecular interactions. For in vivo validation, we established a subcutaneous HCC model in C57BL/6 mice and then employed immunohistochemistry and flow cytometry to evaluate OASL's effects on matrix stiffness, the cGAS-STING pathway, and macrophage polarization. RESULTS:OASL was up-regulated in HCC cells on stiff substrates, correlating with elevated stiffness markers (COL1A2, YAP, α-SMA) and poor prognosis. OASL knockdown reduced matrix stiffness, suppressed proliferation and migration, and promoted apoptosis. It activated the cGAS-STING pathway via direct interaction with cGAS and inhibition of cGAMP generation, enhancing M1 macrophage polarization. However, the STING inhibitor C-176 reversed all these effects. In vivo, OASL silencing attenuated tumor growth, down-regulated stiffness-related proteins, and boosted anti-tumor immunity. CONCLUSION:OASL promotes HCC progression by inhibiting the cGAS-STING pathway, sustaining high matrix stiffness, and suppressing M1 macrophage polarization. Targeting OASL may offer a novel therapeutic strategy to remodel TME stiffness and restore anti-tumor immunity in HCC.

Among the most common malignant tumors, hepatocellular carcinoma (HCC) is a primary liver cancer type that has a high mortality rate. HCC often presents insidiously, is prone to recurrence, and has limited treatment efficacy. Ferroptosis regulates tumorigenesis, progression, and metastasis, which is a novel form of iron-dependent cell death. Numerous studies suggest that HCC is sensitive to ferroptosis, indicating that targeted therapies aimed at inducing ferroptosis may represent a promising new approach to cancer treatment. This study aims to find genes associated with HCC and ferroptosis, as well as to screen for potential agents that may cause ferroptosis in HCC. Transcriptome and clinical sample data were obtained from the TCGA database to identify differentially expressed genes related to ferroptosis. Using various regression and survival analysis techniques, we developed a prognostic model based on four core genes and evaluated its predictive potential. Subsequently, we screened for potential therapeutic agents in the Connective Map (CMap) database, designated as compound Atorvastatin, based on differential genes from two risk groups and related to ferroptosis. Through experiments conducted in vivo and in vitro, we demonstrated that Atorvastatin can induce ferroptosis in HCC cells while inhibiting their growth and migration. In conclusion, this research targets ferroptosis therapy and provides new insights for improving the prediction and prevention of HCC.

BACKGROUND:Primary liver cancer is a malignant tumor of the digestive system and ranks as the sixth most commonly diagnosed cancer globally. It has also risen to become the third leading cause of cancer-related deaths globally, following lung and colorectal cancers. Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancer, approximately 75 to 85 %. Several studies suggest that NSMCE2 contributes to cancer through its SUMO E3 ligase activity, yet its specific role in HCC remains poorly understood. METHODS:We gathered data from various databases and obtained 10 pairs of tissue samples from HCC patients to detect the NSMCE2 expression levels. Additionally, we conducted both in vivo and in vitro experiments to confirm the impact of NSMCE2 on the development and progression of HCC. We further analyzed the potential mechanism of NSMCE2 regulation on HCC by bioinformatics, and detected the specific mechanism of NSMCE2 regulating PPARα by co-immunoprecipitation. RESULTS:Our study shows that NSMCE2 is an important tumor promoter in HCC and acts through the PPARα-CYP7A1 axis. Specifically, NSMCE2 affects the occurrence and progression of HCC by SUMOylating PPARα, reducing its ubiquitination degradation, and activating the PPARα-CYP7A1 axis. CONCLUSIONS:Our study uncovered the role of NSMCE2 in the development and progression of HCC, providing new insights into the pathogenesis and potential therapeutic strategies of HCC.

BackgroundThe Glasgow Prognostic Score (GPS) is a well-established prognostic indicator that effectively reflects the inflammatory, nutritional, and immune status of cancer patients. GPS has been shown to be associated with survival outcomes in many different cancers. However, its prognostic significance in biliary tract cancer (BTC) remains unclear. This meta-analysis aims to explore the prognostic value of GPS in BTC patients.MethodsA systematic search was conducted in PubMed, Embase, and Web of Science to identify relevant studies. Survival data including overall survival (OS), disease-free survival (DFS) and recurrence-free survival (RFS) were the main observation indicators. Hazard ratios (HRs) with 95% confidence intervals (CIs) were extracted and pooled for meta-analysis.ResultsA total of 16 articles incorporating 1919 patients were included in the study. High GPS was associated with poor OS (HR:2.00, 95% CI:1.62-2.48) and DFS/RFS (HR:2.50, 95% CI:1.71-3.65). Subgroup analysis further confirmed the prognosis value of GPS in BTC patients.ConclusionsGPS could serves as a valuable prognostic marker in BTC patients and may aid in risk stratification and treatment decision-making.

192 Background: We have demonstrated that neoadjuvant SCRT followed by PD-1 inhibitor plus CAPOX for LARC patients (pts) showed a higher pCR rate and a well-tolerated safety profile in phase III UNION study. Fruquintinib is a potent and highly selective VEGFR inhibitor, which had been approved for previously treated mCRC pts. This study aimed to investigate the efficacy and safety of SCRT followed by fruquintinib plus adebrelimab and CAPOX as a total neoadjuvant therapy for high-risk LARC pts. Methods: In this prospective, open-label, multi-centers, single-arm phase 2 study (NCT06234007), pts diagnosed with newly diagnosed and high risk LARC were recruited. Pts received SCRT (25Gy/5f) followed by six cycles of fruquintinib (4mg, qd, po, q3w,for the initial 6 pts in the safety run-in period, dosage would be adjusted based on dose-limited toxicities in the 1st cycle) combined with adebrelimab (1200mg, iv, d1, q3w) and CAPOX (q3w). Primary endpoint was CR rate (including clinical CR & pathologic CR). Secondary endpoints included 3-year EFS rate, OS, R0 resection rate and safety. Results: As of 30 Aug 2024, 45 pts were enrolled (median age 59 years [range: 24-75], 26 males, 23 clinical T4 stage and 20 clinical N2 stage, 36 with EMVI positive, 31 with MRF positive, 22 tumor located ≤5cm from the anal verge). Up to 20 Sep 2024, all pts completed SCRT, 73.33% (33/45), 57.78% (26/45) and 31.11% (14/45) pts completed two, four and six cycles of combination therapy, respectively. At data cut-off, of 33 pts included in the efficacy analysis, 28 pts underwent MRI examination and mrTRG results were available, the remaining 5 pts had early surgery due to AEs/serious AEs. 35.7% (10/28) and 46.43% (13/28) pts were classified as mrTRG1 and mrTRG2, respectively. Of 19 pts who underwent surgery, R0 rate was achieved in all 19 pts (100%) and pCR was achieved in 12 pts (63.16%). Moreover, 1 pt achieved cCR during neoadjuvant therapy, thus the treatment strategy provided a CR rate of 65% (1 cCR plus 12 pCR divided by 20). Grade 3/4 adverse effects (AEs) occurred in 16 pts (47.06%), and most commonly were lymphocyte count decreased (n=6, 18.18%), diarrhea (n=5, 15.15%) and AST increased (n=2, 6.06%). 4 serious AEs reported with intestinal perforation and all achieved pCR after surgery therapy. No treatment related death was reported. Conclusions: SCRT followed by fruquintinib combined with adebrelimab and CAPOX as a total neoadjuvant therapy showed promising CR rate and favorable pCR for high-risk LARC pts, and the safety profile was generally manageable. This treatment strategy might be a potential option as neoadjuvant therapy for high-risk LARC pts. Updated data will be presented in the future. Clinical trial information: NCT06234007 .

Radiotherapy (RT) has great potential on activating antitumor immunity for combination therapy, yet this effect is limited by immunosuppressive tumor microenvironment (TME) and the potential toxicity in immune cells from high-dose radiation. Herein, we developed engineered nanoparticles (NPs) (CVs@MgMn) composed of genetically edited cellular vesicles (CVs), MnO2 and MgCO3 for enhanced radioimmunotherapy by remolding TME and activating the stimulator of the interferon genes (STING) pathway. In the TME, the efficiently enriched CVs@MgMn were decomposed to generate hydroxyl (‧OH) and oxygen (O2) for radiosensitization. Subsequently, reduced Mn2+ activated the STING pathway to promote dendritic cell (DC) maturation, and the released Mg2+ boosted antitumor immunity by regulating CD8+ T cell metabolism and tumor-associated macrophage polarization. PD1-displayed CVs increased the targeting effect of NPs and mediated the PD-L1 blocking, all synergistically triggering antitumor immune responses. In both in situ and distant re-challenge models of melanoma, the combination of RT and nanocomposites demonstrated a strong radioimmunotherapy effect, resulting in an increased survival time and long-term immunological memory of tumor bearing mice. Moreover, MgCO3 NPs synergistically promoted anti-PD-1 mAb immunotherapy. These findings highlight the importance of Mg/Mn combined supplementation and TME remolding during RT and immunotherapy, offered a simple and readily therapeutic strategy for patients with any type of solid tumor.

Primary and secondary bile acid (BA) levels are elevated in patients with hepatocellular carcinoma (HCC). BAs are important signaling molecules that regulate CYP8B1 expression by targeting nuclear and membrane receptors. In this study, we aimed to determine the function of CYP8B1 in HCC. Examination of HCC tissue and bioinformatic analysis revealed that CYP8B1 expression is downregulated in HCC tissues and is associated with good prognosis. Cholic acid promoted Huh7 cell proliferation and migration by inhibiting CYP8B1 expression. Both in vitro and in vivo, CYP8B1 inhibited the proliferation, invasion, and migration of HCC cells. Nanopore long-read RNA-sequencing analysis identified PAK4 as a potential target of CYP8B1, and the MAPK pathway was associated with CYP8B1 expression. CYP8B1 inhibited PAK4 expression and Raf/MEK/ERK phosphorylation. Tissue microarray analysis also verified a strong correlation between CYP8B1 and PAK4 expression. In vitro Cell Counting Kit 8 assays and in vivo orthotopic liver tumor model analyses showed that CYP8B1 restores sorafenib sensitivity in resistant HC, suggesting its potential as a therapeutic target. IP-MS of CYP8B1 and transcription factor prediction of PAK4 revealed STAT1 as a potential transcription factor for PAK4, which may directly bind to CYP8B1. Chromatin immunoprecipitation confirmed that u-STAT1 directly binds to the PAK4 promoter, not p-STAT1. Overall, CYP8B1 binds to u-STAT1 in the cytoplasm, reducing the translocation of u-STAT1 from the cytoplasm to the nucleus, thereby inhibiting the transcription of PAK4 and ultimately inhibiting the phosphorylation of Raf/MEK/ERK. Our findings indicate that the CYP8B1/PAK4 axis is important in HCC progression and elucidate the mechanism by which BAs promote HCC. Thus, CYP8B1 is a potential therapeutic target for the clinical treatment of HCC.

The optimal number of examined lymph nodes (ELN) for accurate staging and prognosis for esophageal cancer patients receiving neoadjuvant therapy remains controversial. This study aimed to evaluate the impact of ELN count on pathologic staging and survival outcomes and to develop a predictive model for lymph node positivity in this patient population. Data were extracted from the Surveillance, Epidemiology, and End Results (SEER) database and a multicenter cohort. The inverse probability-weighting and propensity score-matching method was used to balance baseline characteristics. Patients were stratified into four ELN count groups based on quartiles: Q1 (1–9), Q2 (10–14), Q3 (15–20), and Q4 (≥ 21). A nomogram predicting pathologic lymph node positivity was constructed using least absolute shrinkage, selection operator regression, and multivariate logistic regression, incorporating variables such as age, sex, T stage, cN stage, and ELN count. The training cohort included 1736 patients from the SEER database. After matching, the Q4 group demonstrated significantly superior 5 year overall survival compared with the other three groups, whereas the Q2 and Q3 groups exhibited comparable outcomes. The Q1 group had the worst prognosis. The nomogram demonstrated strong discriminatory ability, with area under the curve values of 0.654 (training cohort) and 0.816 (validation cohort). Higher ELN counts, particularly in the Q4 group, were associated with increased detection of lymph node metastases. Examination of 21 or more lymph nodes significantly enhances the accuracy of pathologic lymph node staging and improves long-term survival for esophageal cancer patients undergoing neoadjuvant therapy.

We aimed to assess the tolerability and efficacy of finotonlimab (an anti-programmed cell death protein-1 antibody) in combination with SCT510, a bevacizumab biosimilar, versus sorafenib in unresectable advanced HCC. This randomized phase 2 and 3 study (ClinicalTrials.gov, NCT04560894; Chinadrugtrials.org.cn, CTR20201976 and CTR20201974) was performed at 67 hospitals in China. HCC patients (n = 398) were included between 11 November 2020 and 28 September 2022. In phase 2, patients received intravenous finotonlimab (200 mg every 3 weeks) combined with SCT510 (15 mg/kg every 3 weeks). In phase 3, 346 patients were randomized (2:1) to either the finotonlimab plus SCT510 (dual-agent) group or the sorafenib group. The median follow-up time for the dual-agent therapy and sorafenib groups was 19.9 and 19.0 months, respectively. Median PFS, assessed by BICR according to RECIST 1.1, was significantly longer in the dual-agent group (7.1 months [95% confidence intervals {CI}: 6.1, 8.4]) than in the sorafenib group (2.9 months [95% CI: 2.8, 4.1]; stratified hazard ratio [HR]: 0.5, 95% CI: 0.38, 0.65, p < 0.0001). Median OS was also significantly longer in patients receiving finotonlimab plus SCT510 (22.1 months [18.6, not available]) than in those receiving sorafenib (14.2 months [95% CI: 10.2, 15.8]; HR: 0.60 [95% CI: 0.44, 0.81], p < 0.0008). Finotonlimab in combination with bevacizumab demonstrated favorable efficacy, in comparison to sorafenib, as a first-line treatment for unresectable HCC, with a manageable safety profile.

Hepatocellular carcinoma (HCC) is known for its aggressive nature and high mortality rates. Circular RNAs (circRNAs) have emerged as critical regulators of cancer progression, yet the role of the circRNA cell division cycle and apoptosis regulator 1 (circCCAR1) in HCC is poorly understood. This study aims to explore the mechanism of circCCAR1 in HCC progression. We measured the expression of circCCAR1, miR-641, and motor protein kinesin family member 5B (KIF5B) in HCC cell lines and normal hepatic cells, revealing that circCCAR1 was significantly overexpressed in HCC. Mechanistic analyses showed that the RNA methyltransferase YTH domain-containing protein 1 (YTHDC1) recognized N6-methyladenosine (m6A) modifications on circCCAR1, facilitating its transport from the nucleus to the cytoplasm. In the cytoplasm, circCCAR1 acted as a molecular sponge to sequester miR-641, relieving miR-641-mediated inhibition of KIF5B mRNA. CircCCAR1 directly bound to the RNA-binding protein polypyrimidine tract-binding protein 1 (PTBP1), which stabilized KIF5B mRNA. Functional experiments demonstrated that silencing circCCAR1 suppressed HCC cell proliferation, induced apoptosis, and reduced tumor growth in a xenograft mouse model, effects that were partially reversed after KIF5B overexpression or miR-641 inhibition. In conclusion, YTHDC1 promotes the cytoplasmic translocation of m6A-modified circCCAR1 and circCCAR1 facilitates HCC progression through the miR-641/KIF5B axis.

Tumor immunotherapy aims to harness the immune system to identify and eliminate cancer cells. However, its full potential is hindered by the immunosuppressive nature of tumors. Radiotherapy remains a key treatment modality for local tumor control and immunomodulation within the tumor microenvironment. Yet, the efficacy of radiotherapy is often limited by tumor radiosensitivity, and traditional radiosensitizers have shown limited effectiveness in hepatocellular carcinoma (HCC). To address these challenges, we developed a novel multifunctional nanoparticle system, ZIF-8@MnCO@DOX (ZMD), designed to enhance drug delivery to tumor tissues. In the tumor microenvironment, Zn²⁺ and Mn²⁺ ions released from ZMD participate in a Fenton-like reaction, generating reactive oxygen species (ROS) that promote tumor cell death and improve radiosensitivity. Additionally, the release of doxorubicin (DOX)-an anthracycline chemotherapeutic agent-induces DNA damage and apoptosis in cancer cells. The combined action of metal ions and double-stranded DNA (dsDNA) from damaged tumor cells synergistically activates the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, thereby initiating a robust anti-tumor immune response. Both in vitro and in vivo experiments demonstrated that ZMD effectively activates the cGAS-STING pathway, promotes anti-tumor immune responses, and exerts a potent tumor-killing effect in combination with radiotherapy, leading to regression of both primary tumors and distant metastases. Our work provides a straightforward, safe, and effective strategy for combining immunotherapy with radiotherapy to treat advanced cancer.