Cellular Oncology最新文献

Purpose: Helicobacter pylori (Hp) markedly elevates the risk of gastric cancer (GC) through the induction of chronic inflammation, which facilitates the accumulation of cancer-associated fibroblasts (CAFs) within the immune microenvironment of GC. CAFs contribute to the progression of GC and adversely affect subsequent therapeutic outcomes for patients. However, there is a paucity of research concerning the impact of Hp on CAFs or the identification of potential targets for therapeutic intervention.

Methods: We analyzed public microRNA and transcriptome sequencing data to identify key microRNAs and signaling pathways in Hp + GC. We also used single-cell sequencing to explore cellular localization and interaction mechanisms. Molecular biology experiments, in vitro cell co-culture, and in vivo cell-derived xenograft (CDX) and patient-derived xenograft (PDX) models validated our findings and assessed the pathway's impact on GC proliferation and therapeutic potential.

Results: We identified the "TLR/miR-148a-5p/CALD1/collagen VI" signaling pathway in Hp-stimulated cancer-associated fibroblasts (CAFs) as a critical signaling pathway influencing the proliferation of Hp + GC. These CAFs contributed to GC cell proliferation by releasing substantial amounts of collagen VI, which interacted with tumoral SDC4 receptors. Administration of miR-148a-5p agomir in vivo effectively inhibited the proliferative effects and concurrently enhanced the efficacy of chemotherapy in Hp + GC mice models.

Conclusion: Hp-stimulated CAFs played a significant role in promoting tumor proliferation in Hp + GC. Targeting its "TLR/miR-148a-5p/CALD1/collagen VI" pathway was a promising method to ease the collagen-rich microenvironment and inhibit the proliferation of GC cells. Furthermore, miR-148a-5p agomir might serve as a safer and more efficacious chemotherapeutic sensitizer for patients with Hp + GC.

Background: Xp11.2 translocation renal cell carcinoma (Xp11.2 tRCC) is a very rare and aggressiveness malignancy with poor outcome. Previous studies suggested that programmed cell death protein-1 ligand 1 (PDL1) was characterized with high mRNA and low protein in Xp11.2 tRCC, however, the potential mechanism is still blurry.

Methods: Immunohistochemistry was conducted to verify Cyclin D1 and PDL1 expression in Xp11.2 tRCC. ChIP and dual-luciferase reporter gene assay were applied to evaluate transcriptional-regulation of TFE3 fusion proteins on CCND1/Cyclin D1 and NR1D1, we used RNA-seq to detect the regulation role of NR1D1 on CCND1/Cyclin D1, half-life experiment and autophagy flux were employed to demonstrate Cyclin D1-CDK4 speeded PDL1 degradation.

Results: Here, we demonstrated that CCND1/Cyclin D1 was not only a direct target gene for positive regulation of TFE3 fusion proteins, but also up-regulated by nuclear receptor subfamily 1 group D member 1 (NR1D1) which was positively transcriptional regulation of TFE3 fusion proteins. Besides, TFE3 fusion proteins reduced the degradation of Cyclin D1 by activating the AKT/mTOR pathway. As a result, the high-expression of CCND1/Cyclin D1 mediated degradation of PDL1 protein through ubiquitin-proteasome system and autophagy pathway.

Conclusion: This research found that CCND1/Cyclin D1 was upregulated in Xp11.2 tRCC through three mechanisms, high-expression CCND1/Cyclin D1 inducing PDL1 degradation. Overall, the study provided a theoretical basis for sequentially using CDK4 inhibitors and anti-PDL1 for Xp11.2 tRCC treatment.

Clinical trial number: Not applicable.

Background: Eukaryotic translation regulators have emerged as pivotal modulators of cancer progression and immune evasion. However, their mechanistic contributions in hepatocellular carcinoma (HCC) remain poorly understood. EIF2B4, the δ-subunit of the eukaryotic initiation factor 2B (eIF2B) complex, has not been previously characterized in HCC.

Methods: EIF2B4 expression was analyzed using public datasets and validated in clinical HCC samples. Functional assays, including gain- and loss-of-function experiments, were performed to assess its impact on cell proliferation, apoptosis, migration, and the cell cycle. RNA immunoprecipitation (RIP), luciferase reporter assays, immunoblotting, and mutational rescue were employed to elucidate EIF2B4-mediated translational regulation of STAT3. In vivo mouse models and immune co-culture systems were used to investigate the role of EIF2B4 in antitumor immunity and response to anti-PD-1 therapy.

Results: EIF2B4 was significantly upregulated in HCC and associated with poor prognosis. EIF2B4 promoted oncogenic phenotypes, including proliferation, migration, and cell cycle progression, while suppressing apoptosis. Mechanistically, EIF2B4 enhanced STAT3 protein expression by directly binding its mRNA and facilitating translation without affecting mRNA levels. EIF2B4 interacted with the eIF2 complex and required GEF activity to promote STAT3 translation via the 5' untranslated region (5'UTR). GEF-inactivating mutations abolished EIF2B4's translational and tumor-promoting effects. In vivo, EIF2B4 impaired CD8⁺ T cell-mediated cytotoxicity, reduced immune infiltration, and diminished the efficacy of anti-PD-1 therapy. Conversely, EIF2B4 knockout restored antitumor immunity and sensitized tumors to immune checkpoint blockade.

Conclusions: EIF2B4 functions as a previously unrecognized translational regulator that promotes HCC progression and immune evasion by enhancing STAT3 translation through a GEF-dependent mechanism. These findings highlight EIF2B4 as a potential therapeutic target and biomarker to improve immunotherapy responsiveness in HCC.

Clinical trial number: Not applicable.

Purpose: Despite advancements in ¹⁷⁷Lu-based radiotherapy for cancer, its efficacy against refractory cold tumors remains limited. Targeted peptide-radionuclide conjugates (PRCs) combined with immunotherapy are emerging as promising theranostic strategies to maximize anti-tumor effectiveness.

Methods: Cyclic peptide CEMJ4 was identified via phage selection, and further conjugated with DOTA and radiolabeled with ⁶⁸Ga for diagnostic imaging and ¹⁷⁷Lu for cancer therapy. The druggability was assessed by in vitro cell experiments, in vivo PET/CT imaging and biodistribution. Additionally, the feasibility of combining ¹⁷⁷Lu-DOTA-CEMJ4 with a hematopoietic progenitor kinase 1 inhibitor (HPK1i) was evaluated in B16F10 tumor-bearing mice, focusing on the anti-tumor immune response and tumor growth.

Results: CEMJ4 exhibited high affinity for human erythropoietin-producing hepatocellular receptor A2 (EphA2; K_D = 0.3 ± 0.2 µM), a therapeutic target overexpressed in several solid tumors. Radiolabeled ⁶⁸Ga/¹⁷⁷Lu-DOTA-CEMJ4 specifically bound to EphA2-expressing B16F10 cells and tumor models, effectively inhibiting tumor growth. Notably, ¹⁷⁷Lu-induced T cell immunotoxicity was reversed by HPK1i, which modulated T cell dysfunction. Combining ¹⁷⁷Lu-DOTA-CEMJ4 with HPK1i significantly reduced tumor burden and increased tumor-infiltrating CD4⁺ T cells, CD8⁺ T cells, and M1 macrophages.

Conclusion: This study identifies CEMJ4 as a promising peptide ligand for tumor-targeted radionuclide delivery and emphasizes the clinical potential of radionuclide therapy combined with immunotherapy in theranostics to enhance therapeutic precision and efficacy.

Lung cancer remains the leading cause of cancer-related mortality worldwide, with limited treatment efficacy and frequent resistance to conventional therapies. Recent advances have uncovered the critical influence of the human microbiota-complex communities of bacteria, viruses, fungi, and other microorganisms-on lung cancer pathogenesis and therapeutic responses. This review synthesizes current knowledge on the compositional and functional roles of microbiota across multiple body sites, including the gut, lung, tumor microenvironment, circulation, and oral cavity, highlighting their contributions to tumor initiation, progression, metastasis, and immune regulation. We emphasize the bidirectional communication between microbial metabolites and host immune pathways, particularly the gut-lung axis, which modulates systemic and local antitumor immunity. Importantly, microbiota composition has been linked to differential responses and toxicities in chemotherapy, radiotherapy, targeted therapy, and immune checkpoint blockade. Microbiota-targeted interventions, such as probiotics, fecal microbiota transplantation, and selective antibiotics, show promising potential to enhance treatment efficacy and mitigate adverse effects. However, challenges remain in clinical translation due to interindividual microbiome variability, mechanistic complexities, and limited longitudinal data. Future research integrating multi-omics, microbial functional profiling, and controlled clinical trials is essential to harness the microbiome as a precision medicine tool in lung cancer management. This review provides a comprehensive overview of the emerging role of microbiota in lung cancer development and therapy, offering new perspectives for innovative therapeutic strategies.

Purpose: Glioblastoma (GBM), an aggressive brain malignancy with high recurrence rates and suboptimal response to conventional therapies, necessitates novel treatment strategies. Chimeric antigen receptor natural killer (CAR-NK) cell therapy represents a promising immunotherapeutic approach. CSPG4 (chondroitin sulfate proteoglycan 4), a tumor-associated antigen overexpressed in GBM and critically involved in tumor proliferation and metastasis, was investigated as a therapeutic target. This study aimed to evaluate the efficacy of CSPG4-targeted CAR-NK cells in GBM treatment.

Methods and results: We engineered a second-generation CAR construct incorporating the CSPG4-specific scFv 763.74, a CD8 transmembrane domain, and intracellular co-stimulatory/activation domains from CD28 and CD3ζ. The resulting CAR-NK cells were tested for anti-tumor activity in vitro and in vivo. Results demonstrated that CSPG4-directed CAR-NK cells selectively recognized and lysed CSPG4-positive GBM cells, significantly suppressing tumor growth in preclinical models compared to control NK cells. Mechanistic studies confirmed that cytotoxicity was mediated through specific CSPG4 antigen engagement.

Conclusion: CSPG4-targeted CAR-NK cells exhibit potent anti-GBM activity, highlighting their potential as a novel immunotherapy. These findings provide a robust preclinical foundation for advancing CSPG4-directed CAR-NK cell therapy into clinical trials, addressing the urgent need for effective treatments in GBM management.

Backgroud: Previous studies have identified B cell subpopulations with pro- and anti-tumoral activities, while the clinical relevance of B cell subpopulations-specific markers in pan-cancer remains understudied.

Methods: We integrated 14 scRNA-seq datasets (102,504 cells from 424 patients, 15 cancer types) to identify B cell subpopulations via unsupervised clustering. We characterized their functional dynamics and prognostic relevance through analyzing single-cell, bulk and spatial transcriptomic data. Moreover, using B cell subpopulations-specific gene signatures, we constructed models for predicting cancer prognosis and immunotherapy response.

Results: We identified eight B cell subpopulations (b00-b07) which were classified into naive, plasma, memory, germinal center (GC), and cycling B cells. Trajectory analysis revealed b02-naive and b04-GC cells in early phases, evolving into b01- and b03-plasma/b05- and b06-memory/b07-cycling and b05-memory subpopulations. Anti-tumor responses were activated in early pseudotime, complement/immunoglobulin pathways peaked in mid-pseudotime, and energy metabolism increased in late-pseudotime. The enrichment of b07-cycling and b04-GC was negatively correlated with cancer prognosis, while b02-naive had a positive correlation. Spatial transcriptomic analysis showed clustered b00-b06 versus dispersed b07 cells, with b04-GC and b07-cycling cells distant from tertiary lymphoid structure cores. Based on the expression profiles of 1,047 B cell subpopulations-specific signatures, we identified three pan-cancer subtypes with distinct clinical and molecular characteristics. Using 13 B cell subpopulations-specific signatures, we constructed models to accurately predict cancer survival outcomes and immunotherapy response.

Conclusions: Our study delineates eight B cell subpopulations with distinct prognostic relevance. Signature-based stratification and models underscore their clinical relevance in cancer outcomes and therapy response, advancing understanding of B cell heterogeneity in cancer.

Lactylation is a novel post-translational modification of proteins, which has attracted extensive attention since its discovery. Lactylation takes lactate, a common metabolite, as its substrate and mediates the modification under the action of lactyltransferases. Although lactylation modification was initially found to undergo in histones, subsequent studies have shown that this novel modification is not limited to specific protein classes, and can undergo in both histone and non-histone proteins. Lactylation has been proved to play an important regulatory role in a variety of diseases, including tumors, metabolic disorders, cardiovascular diseases, and neurodegenerative diseases. Given the tumor properties of its substrate lactate, lactylation has been most extensively studied in tumors, and as a result, we have gained a deeper understanding of the potential molecular mechanisms and regulatory roles of lactylation in tumors. In this paper, we will summarize the regulatory and functional mechanisms of lactylation, explain the cellular processes in which lactylation is involved and its association with various diseases, and look forward to the future clinical application of lactylation.

Introduction: Hepatoblastoma (HB) with hepatocellular carcinoma (HCC) features (HBHF) is a rare liver malignancy. Due to its rarity and diverse histological presentations, the prognosis of HBHF remains controversial, and diagnostic differentiation poses significant challenges. To enable more accurate outcome evaluation and targeted therapeutic strategies, rapid, comprehensive, and cost-effective methods are needed to complement histopathological evaluation.

Methods: In this study, we conducted transcriptomic profiling on an HBHF cohort from our center and developed a machine-learning algorithm to quantify HCC-like expression features in HB tumors. Given overlapping histopathological and molecular charateristicss between HBHF and HCC, we further investigated shared risk factors associated with HBHF prognosis.

Results: Significantly poorer outcomes in HBHF patients suggest fundamental biological distinctions from classical HB. Transcriptomic analysis revealed comparable somatic mutation profiles between HB and HBHF cohorts but identified inflammation activation, rather than specific mutations, as a key high-risk factor in HBHF. Clinical outcomes aligned with risk stratification generated by our quantification model.

Conclusions: HBHF represents a distinct transitional entity between HB and HCC, exhibiting markedly worse clinical outcomes than HB. Our transcriptome-based computational model effectively discriminates HBHF and predicts its prognostic risk. Importantly, inflammatory activation emerges as a critical driver of tumor aggressiveness in this subtype.

Purpose: Esophageal squamous cell carcinoma (ESCC) is aggressive with a poor prognosis. The tumor microenvironment (TME) significantly affects tumor progression and therapy resistance. Previous work has shown that fibroblasts in metastatic lymph nodes can confer cisplatin resistance to ESCC cells via PI16 (peptidase inhibitor 16). This study investigates the role of fibroblast-derived PI16 in the ESCC TME.

Methods: Public single-cell RNA sequencing (scRNA-seq) data for ESCC were analyzed. A cell co-culture assay was performed to evaluate regulatory T cells (Tregs) differentiation from naïve CD4⁺ T cells. Immunoprecipitation and mass spectrometry examined PI16's mechanism in Treg differentiation. In vitro and in vivo assays were conducted to explore fibroblast-derived PI16's function. Additionally, multiplex fluorescent immunohistochemistry (mfIHC) was performed.

Results: Analyses of the scRNA-seq dataset (GSE203115) reveal that fibroblasts can be classified into PI16 ⁺ and PI16^- subclusters based on PI16 expression levels. PI16 induces Treg differentiation from naïve CD4⁺ T cells through a DOCK2-dependent mechanism. Treatment with a DOCK2 inhibitor significantly inhibits PI16-induced Treg differentiation and increases Teff cell infiltration in vivo. Moreover, upregulation of PI16 in the tumor stroma is associated with poorer long-term survival outcomes in patients with ESCC.

Conclusions: PI16⁺ fibroblasts promote the differentiation of Tregs from naïve CD4⁺ T cells through interaction with DOCK2. Upregulation of PI16 in the tumor stroma is associated with poorer long-term survival outcomes in patients with ESCC. Given the accumulating evidence on the therapeutic impact of targeting the TME, PI16⁺ fibroblasts emerge as a promising novel therapeutic target to overcome tumor immune suppression.