Cellular Oncology最新文献

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.

Background: Ovarian cancer (OC) is a lethal gynecologic malignancy with limited therapeutic success due to late diagnosis and therapy resistance. Endoplasmic reticulum (ER) stress and ER-associated degradation (ERAD) are key to tumor adaptation, yet the mechanisms sustaining ER homeostasis in OC remain poorly defined.

Methods: We combined multi-omics analyses, tissue microarrays, and in vitro and in vivo models. Functional assays involved COPB2 knockdown or overexpression in OC cells, xenografts in nude mice, and mechanistic studies including protein interaction and glycoproteomic analyses.

Results: COPB2 was significantly upregulated in OC and associated with poor prognosis. It promoted cell proliferation and survival by alleviating ER stress and suppressing apoptosis. Mechanistically, COPB2 interacted with EDEM3, a key ERAD enzyme, enhancing its ER localization and mannose-trimming function. COPB2 depletion impaired EDEM3 activity, resulting in glycan processing defects and ER stress accumulation. In vivo, COPB2 overexpression accelerated tumor growth.

Conclusions: This study identifies a novel COPB2-EDEM3 axis that maintains ER homeostasis and drives OC progression. Targeting this axis may offer new opportunities for therapeutic intervention and biomarker development.

Background: Immune checkpoint inhibitors (ICIs), such as anti-programmed cell death protein-1 (PD-1) immunotherapy, have emerged as promising treatments for advanced hepatocellular carcinoma (HCC), significantly improving clinical outcomes. However, resistance to ICIs remains a major challenge, and the underlying mechanisms of this resistance are not yet fully understood. This study aimed to investigate the role of S100 calcium-binding protein A9 (S100A9) in mediating resistance to anti-PD-1 therapy.

Approach and results: We conducted RNA sequencing (RNA-seq) on tumor samples from anti-PD-1 responders and non-responders in HCC patients. Differential expression analysis identified S100A9 as a potential driver gene of resistance to anti-PD-1 therapy. Subcutaneous tumor models and an orthotopic HCC model established via hydrodynamic transfection were utilized to evaluate the impact of S100A9 on the efficacy of PD-1 therapy. Our findings revealed that S100A9 promotes resistance to anti-PD-1 therapy in HCC. Mechanistically, S100A9 directly interacted with PARP1 and induced its degradation via the ubiquitin-proteasome pathway. This process increased STAT3 phosphorylation at Tyr705, thereby enhancing PD-L1 transcription. Notably, treatment with the S100A9 inhibitor Tasquinimod significantly improved the efficacy of anti-PD-1 therapy in HCC.

Conclusions: Our study reveals that S100A9 facilitates immune evasion in HCC by enhancing PARP1 ubiquitination, STAT3 phosphorylation, and PD-L1 expression. Furthermore, combining S100A9 inhibitors with anti-PD-1 antibodies markedly enhances the therapeutic efficacy of ICIs in HCC. These findings highlight S100A9 as a potential therapeutic target for overcoming resistance to immunotherapy in HCC.