A pivotal factor in the immune evasion of hepatocellular carcinoma (HCC) is the excessive exhaustion of CD8⁺ T cells; however, the molecular drivers of this phenomenon remain incompletely understood. In this study, we discovered that B7-H3 is markedly overexpressed in HCC and actively promotes CD8⁺ T cell exhaustion. Through high-resolution mass spectrometry and site-directed mutagenesis, we identified asparagine 215 (N215) as a critical N-linked glycosylation site of B7-H3. By employing dual orthogonal strategies-pharmacological inhibition via tunicamycin and targeted genetic ablation (N215Q mutation)-we provided strong evidence that, upon N215 glycosylation, B7-H3 maintains its cell-surface abundance through RAB11-mediated recycling of the endosomal pathway. Conversely, when glycosylation is impeded through either intervention, B7-H3 undergoes accelerated degradation via the endosome-lysosome route, thereby enhancing the cytotoxic activity of CD8⁺ T cells. Finally, murine experiments confirmed that both the specific genetic disruption of N215 and systemic blockade with tunicamycin enhance the antitumor effects of anti-PD-1, anti-PD-L1, and anti-CTLA-4 antibodies. Collectively, our data reveal that the "B7-H3 Glycosylation-RAB11 Axis" preserves membrane expression of B7-H3, constituting an intrinsic mechanism of immune evasion in HCC, and uncover the intricate crosstalk between B7-H3 glycosylation and the immunosuppressive tumor microenvironment.

Triple-negative breast cancer (TNBC) is an aggressive subtype with poor prognosis and limited treatment options owing to the lack of expression of common therapeutic targets such as hormone receptors and HER2. Recent advances in immunopeptidomics have enabled the identification of tumor-associated antigen peptides that can elicit tumor-specific immune responses. We identified four novel HLA class I-restricted peptides derived from nucleolin (NCL), a protein overexpressed in TNBC that is associated with poor outcomes. We predicted and validated pNCL-01 through pNCL-04 because of its strong binding affinity to common HLA alleles (A*02:01 and B*15:01), with pNCL-04 demonstrating broad HLA-binding potential across 20 HLA alleles. Peripheral blood mononuclear cells (PBMCs) from both healthy donors and patients with TNBC were pulsed with these peptides, generating NCL-specific CD8⁺ T cells that effectively targeted and killed NCL⁺/PD-L1⁺ TNBC cell lines in vitro (MDA-MB-231 and HCC70). These T cells exhibited robust IFN-γ secretion and expressed effector memory markers (CD107a), particularly in cancer tissues of patients with high NCL expression. Notably, pNCL-04 functioned as a shared immunogenic peptide, activating T cells in the majority of TNBC patients (7/10) which was predicted to bind up to 20 different HLA class I alleles, supporting its use as a broadly applicable immunogenic peptide. Furthermore, the combination of NCL-specific T cells with atezolizumab enhanced anti-tumor activity, suggesting the potential benefit of combining NCL-targeted immunotherapy with immune checkpoint blockade. In conclusion, this study demonstrates the potential of HLA-restricted NCL peptides in combination with atezolizumab as a rational peptide-based therapeutic strategy for clinical translation in TNBC patients with high NCL.

C-type lectin domain family 3 member B (CLEC3B), also known as tetranectin, is a secreted protein associated with extracellular matrix remodeling and tumor microenvironment regulation. However, its expression pattern and clinical significance in breast cancer tissues remain unclear. This study aimed to investigate CLEC3B expression in breast cancer tissues and its associations with clinicopathological characteristics and the tumor microenvironment.

Ninety-eight women with newly diagnosed breast cancer who underwent surgical treatment at our hospital between September 2023 and December 2024 were included in this study. Tumor and adjacent non-tumorous tissues, including vascular regions, were obtained from the enrolled patients and processed for immunohistochemical analysis. CLEC3B expression was semiquantitatively graded from 1 to 4. Associations between CLEC3B expression, clinicopathological and biochemical variables were analyzed using the chi-square test, Spearman correlation, and multivariable logistic regression. Double immunofluorescence staining was performed to assess colocalization of CLEC3B with CD68 (macrophages) and CD31 (endothelial cells).

The expression of CLEC3B was identified in both tumor cell membrane and cytoplasm, and was significantly higher in breast cancer tissues than in adjacent non-tumorous tissues. CLEC3B expression was also significantly higher in blood vessels than in tumor parenchyma (p < 0.0001), indicating predominant vascular localization. High CLEC3B expression (grade 3-4) was associated with a tumor size of 2-5 cm, Ki-67 ≥14%, and the luminal B HER2-positive subtype. Spearman analysis showed that a high CLEC3B expression was correlated with larger tumor size, higher Ki-67 index, higher carcinoembryonic antigen level, and shorter prothrombin time. Multivariable logistic regression analysis further demonstrated that tumor size ≥2 cm and high Ki-67 (≥14%) were independently associated with high CLEC3B expression, whereas molecular subtype was not. CLEC3B was colocalized with CD68 and CD31, confirming its expression in macrophages and endothelial cells. CD4⁺ and CD8⁺ T-cell infiltration was abundant regardless of CLEC3B expression level.

The expression of CLEC3B was upregulated in breast cancer tissues and predominantly localized to the tumor vasculature and macrophages. Its expression was associated with aggressive clinicopathological features and certain biochemical parameters. No apparent differences in CD4⁺ or CD8⁺ T-cell infiltration were observed across different levels of CLEC3B expression. These findings suggest that CLEC3B expression may be associated with vascular and microenvironment-related characteristics of breast cancer.

Breast cancer is the second most common cancer worldwide and remains the leading cause of cancer-related deaths among women. Triple-negative breast cancer (TNBC) represents approximately 15-20% of all breast cancer cases and is characterized by an aggressive clinical course and a high risk of metastasis. Extracellular signal-regulated kinase 5 (ERK5) is a critical biomarker that promotes tumor progression through mechanisms involving cell proliferation, invasion, and metastasis; however, its precise role in epithelial-mesenchymal transition (EMT) in TNBC remains unclear. In this study, we analyzed data from 117 patients with TNBC and found that high ERK5 expression was significantly associated with tumor progression, shorter progression-free survival, and shorter overall survival. RNA sequencing of a highly metastatic TNBC cell line revealed that ERK5 knockdown modulated the expression of various gene clusters, particularly those associated with DNA repair, G2/M checkpoint regulation, and angiogenesis. In addition, ERK5 knockdown in a mouse xenograft model significantly suppressed tumor proliferation and lung metastasis, inhibited tumor cell migration, and reduced the expression of EMT-related proteins. Mechanistically, our data further demonstrated that ERK5 regulates the interaction between cellular JUN (c-JUN) and the vimentin promoter, thereby modulating vimentin expression and downstream signaling pathways. A significant positive correlation between ERK5 and vimentin expression in human TNBC tissue specimens further supported this regulatory association. These findings suggest that ERK5 mediates the recruitment of c-JUN to regulate vimentin expression, thereby promoting EMT and metastasis. Thus, the ERK5/c-JUN/vimentin axis may be a potential therapeutic target to improve clinical outcomes in patients with TNBC.

Arginine methylation, catalyzed by protein arginine methyltransferases (PRMTs), is a critical post-translational modification that modulates gene expression and signal transduction. Although the involvement of PRMTs in malignancy is increasingly recognized, a comprehensive pan-cancer synthesis of this family remains elusive. We sought to elucidate the multi-omic landscape of PRMTs and define their biological contributions to colorectal cancer (CRC) progression.

Using multi-omic data from TCGA and GTEx, we performed an integrative pan-cancer analysis of PRMT expression, genetic alterations, epigenetic modifications, and their associations with prognosis, genomic heterogeneity, stemness, the tumor microenvironment, and oncogenic pathways. After validating PRMT expression patterns across multiple independent CRC cohorts from the GEO database, PRMT1 was prioritized for further investigation. Its expression was assessed in a real-world CRC cohort using immunohistochemistry, while its oncogenic potential was scrutinized through in vitro proliferation assays.

PRMT family genes exhibit heterogeneous molecular profiles across cancers, which correlate significantly with genomic instability, stemness, immune infiltration, and oncogenic pathway activation. Clinical validation demonstrated that PRMT1 is markedly upregulated in CRC, where its overexpression correlates with larger tumor size, advanced T stage, and lymph node metastasis. Loss-of-function experiments demonstrated that PRMT1 is essential for maintaining CRC cell proliferation.

Our study highlights the multifaceted roles of PRMTs across the pan-cancer spectrum. By identifying PRMT1 as a key driver of CRC progression, this work provides a rationale for the development of PRMT-targeted therapies and personalized diagnostic biomarkers.

Perioperative alterations in T lymphocyte subsets significantly impact tumor recurrence and postoperative recovery; therefore, identifying optimal strategies to maintain these immune parameters is essential for improving cancer surgery outcomes. The immunomodulatory effects of different tumor therapies, especially those on key T cell subsets, still lack systematic comparisons.

This study aims to systematically evaluate the impact of various treatment strategies (including systemic anti-cancer therapy (SACT), nutritional support, anesthesia, analgesia, and other methods) on key immune parameters (CD3⁺, CD4⁺, CD8⁺ cells, CD4⁺/CD8⁺ ratio, NK cells) in patients with solid tumors and provide a comparative ranking of their efficacy.

Systematic reviews and network meta-analyses were conducted on randomized controlled trials included in the PubMed, Embase and Cochrane CENTRAL databases using the PRISMA guidelines. Pairwise meta-analyses and network meta-analyses were completed using RevMan 5.3 and the gemtc package of R software. The efficacy was ranked by the area under the cumulative ranking curve (SUCRA), and the quality of the studies was evaluated using the Cochrane Risk of Bias Tool 2.0 and the Newnews-Ottawa Scale.

The analysis included 82 RCTs. In maintaining T lymphocyte subsets, immune-enhanced enteral nutrition combined with neoadjuvant chemotherapy (IEN+NACT), targeted therapy (TD), the Enhanced Recovery After Surgery (ERAS) protocol, anesthesia techniques incorporating Transcutaneous Electrical Acupoint Stimulation (TEAS), and analgesia with Dexmedetomidine (DEX) ranked as the most effective strategies, with IEN+NACT showing the greatest improvement in CD4+ counts (SMD 12.33, 95% CI 7.44-17.04). Safety analysis indicated that the risks associated with these top-ranking interventions were acceptable.

This network meta-analysis determined that for tumor surgery patients, the perioperative management plan should combine a multimodal strategy of IEN + NACT, ERAS, TD, TEAS and DEX to maintain postoperative T lymphocyte homeostasis and thereby protect immune function.

https://www.crd.york.ac.uk/PROSPERO/view/CRD420251233455, identifier CRD420251233455.

Ectopic hepatocellular carcinoma (EHCC) is an exceedingly rare malignancy characterized by its occurrence outside the liver without a detectable intrahepatic primary tumor. Owing to its rarity and the absence of standardized management guidelines, the diagnosis and treatment of EHCC pose significant challenges.

We report a case of unresectable, multifocal EHCC managed by a multidisciplinary team (MDT). Comprehensive molecular profiling, including whole-exome sequencing (WES) and RNA sequencing (RNA-seq), was performed to characterize the tumor's genetic and transcriptomic landscape. A systematic literature review of EHCC case reports in the PubMed database was also conducted.

A patient in his sixties was diagnosed with unresectable, multifocal EHCC localized within the abdominal cavity. The diagnosis was confirmed by laparoscopic biopsy and histopathological examination, which revealed hepatocellular carcinoma with fatty metaplasia, corroborated by positive immunohistochemical staining. Comprehensive genomic analysis using RNA-seq and WES identified key molecular features potentially involved in EHCC pathogenesis. Guided by the MDT, the patient received a multimodal regimen comprising lenvatinib (8 mg once daily), camrelizumab (200 mg every two weeks; an anti-PD-1 antibody), and stereotactic body radiotherapy (SBRT) targeting residual abdominal lesions. The patient achieved a progression-free survival (PFS) of 27 months and an overall survival (OS) of 30 months. A systematic review of 55 reported EHCC cases provided a comprehensive overview of the disease's demographic, clinical, management, and prognostic characteristics.

This study provides the molecular profiling of an EHCC case, offering descriptive insights into its genomic and transcriptomic landscape. Furthermore, the favorable clinical outcome associated with the combination therapy of lenvatinib, camrelizumab, and SBRT suggests the potential value of this multimodal strategy, indicating a potential therapeutic approach for future cases.

Colorectal cancer (CRC) with microsatellite-stable (MSS)/pMMR status resists immune checkpoint blockade due to its immunologically "cold" tumor microenvironment. We developed Lipo-LPS-Rg3, a dual-functional nanoliposome co-delivering lipopolysaccharide (LPS) and ginsenoside Rg3, to simultaneously ignite pyroptosis and attenuate PD-L1-associated immune suppression. LPS triggered GSDMD-mediated pyroptosis, releasing DAMPs and recruiting CD8⁺ T cells, while Rg3 reduced PD-L1 expression in vitro, at least partly by inhibiting NFATc1 nuclear translocation. In vivo, Lipo-LPS-Rg3 decreased PD-L1 protein expression in tumor tissues and promoted both CD8⁺ T-cell infiltration and IFN-γ-producing effector function. The nanoplatform achieved tumor-targeted delivery, induced near-complete regression in colorectal cancer, and exhibited minimal systemic toxicity. By converting "cold" tumors into "hot" and supporting antitumor T-cell activity, Lipo-LPS-Rg3 offers a promising strategy for MSS/pMMR CRC immunotherapy.

Prostate cancer (PCa) is a prevalent malignancy in males with high morbidity and mortality. Although treatment modalities have evolved considerably, tumor resistance, recurrence, and metastasis persist, urgently requiring the exploration of alternative therapies for PCa. There is ongoing research on finding and identifying the use of traditional plant medicine (TPM). Cellular homeostasis comprises a sophisticated network of metabolic processes that functions cooperatively to preserve a stable intracellular environment. Programmed cell death (PCD) plays an important role in PCa mechanism. Thus, they represent an effective strategy for targeting PCa. TPM has been proven to induce PCD through multiple pathways and target in the treatment of PCa. Recent reviews have only focused on the one of the PCD, and autophagy, apoptosis, pyroptosis, ferroptosis, and necroptosis are not simultaneously reviewed.

The search strategy: articles with the title containing "prostate cancer", "therapeutic", "traditional medicine", "apoptosis", "pyroptosis", autophagy", "in vivo/in vitro", "active ingredients", "Herbal", "real modules", "dose", "pathway", "effects/mechanisms", "extract", "pure compound", "drug type", "anticancer activity", "Chinese herbal compounds", "necroptosis" and "ferroptosis" had been initially selected in the past five years databases of PubMed, Web of Science, and ScienceDirect. The references were screened according to the strategy.

Forty-two drugs in the TPM have been chosen in this review. The plant extract, Chinese herbal compound, and pure compound of TPM exhibit significant anticancer activity against PCa by regulating multiple kinds of PCD. More importantly, PI3K/AKT/mTOR, AMPK/mTOR pathways, AKT1/Bcl2/NF-κB, GPBAR1/NF-κB, Keap1/Nrf2/ARE, PINK1/Parkin signaling pathways serve as critical molecular targets mediating the anticancer activities of TPMs in PCD. Autophagy, apoptosis, and ferroptosis are research hotspots, while pyroptosis and necroptosis are less explored. Apoptosis is co-detected with autophagy, or necroptosis. Ferroptosis is co-detected with necroptosis, or pyroptosis. Notably, the interrelationships between these cell death modes are rarely investigated in depth in the treatment of TPM in PCa. TPM has been induced apoptosis, ferroptosis, necroptosis in PCa. But the effect of TPM on the autophagy and pyroptosis need further evidence to clarify the mechanism.

Hence, it is imperative to focus on elucidating the role of PCD modulators to refine therapeutic strategies of TPM in PCa.

Multiple myeloma remains largely incurable despite advances in proteasome inhibitors and monoclonal antibodies. Chimeric antigen receptor (CAR)-T-cell therapy targeting B-cell maturation antigen (BCMA) has achieved deep responses in relapsed/refractory multiple myeloma; however, its clinical utility is constrained by cytokine release syndrome (CRS). CRS is a multicellular hyperinflammatory process driven by CAR-T-derived cytokines, monocyte/macrophage activation, and amplification of the IL-1β-IL-6 axis, leading to endothelial dysfunction and metabolic reprogramming. While IL-6 blockade is the standard of care, severe CRS often persists due to redundant upstream inflammatory signalling. This mini-review evaluates the emerging roles of IL-37 and IL-38, anti-inflammatory members of the IL-1 superfamily, as endogenous regulators of CAR-T-associated hyperinflammation. IL-37 functions primarily as a systemic mediator that suppresses NF-κB/MAPK signalling, inflammasome activity, and endothelial injury. In contrast, IL-38 acts as a tissue-resident regulator that restrains early innate immune priming and modulates macrophage-dendritic cell interactions within the bone marrow microenvironment. We propose a phase-dependent regulatory axis wherein IL-38 limits inflammatory initiation while IL-37 suppresses systemic amplification during peak CRS. These pathways represent promising immunoregulatory checkpoints with translational potential as biomarkers and therapeutic targets. Leveraging these cytokines through recombinant proteins or "armoured" CAR-T-cells equipped with inducible regulatory circuits may improve the safety and efficacy of cellular immunotherapies in multiple myeloma.