Background Radiomic prediction of immunotherapy response has been widely reported, yet the nature and localization of the predictive signal remain unclear. We aimed to determine whether longitudinal delta-radiomics (change between serial scans) predicts short-term response in lung cancer, and to dissect the signal by benchmarking against pre-treatment and clinical models, separating texture from shape contributions, and localizing it across intratumoral and peritumoral compartments, and relating it to survival. Methods In a single-center cohort of 156 lung cancer patients receiving first-line immunotherapy, baseline and interim contrast-enhanced CT scans were analyzed. We extracted 1688 radiomic features from intratumoral, peritumoral (3/5/8/10-pixel shells), and combined ROIs, and computed delta features. Short-term response (RECIST 1.1) was modeled using stratified 5-fold cross-validation with all feature selection (univariate filtering, correlation pruning, LASSO) performed inside each training fold. Performance was evaluated by pooled out-of-fold AUC (mean over 5 seeds; 2000-sample bootstrap 95% CI). PFS and OS were assessed by C-index, Kaplan–Meier, and Cox models on cross-validation-averaged risk scores. Results Pre-treatment radiomics was uninformative across all ROIs (AUC 0.48–0.54), as were clinical variables (AUC 0.45). Intratumoral delta-radiomics predicted response with AUC 0.78 (95% CI 0.70–0.85). The signal was texture-driven: texture-only delta reproduced full performance (AUC 0.78), with five of six retained features being texture-based. The effect was consistent across all ROIs and peritumoral distances (AUC 0.74–0.78), and adding clinical, peritumoral, or multi-ROI features provided no improvement. The delta score modestly stratified PFS (HR 1.66, 95% CI 1.15–2.39; log-rank p = 0.006; C-index 0.56) but was not associated with OS (p = 0.28); prognostic signal resided specifically in intratumoral-containing ROIs. Conclusions The predictive information in serial CT is texture-driven, intratumoral, and exists only as change — it is not a restatement of tumor shrinkage, does not require peritumoral sampling, and is absent from static pre-treatment imaging. Longitudinal radiomics functions as an early response surrogate that partially tracks progression but does not predict overall survival.

BACKGROUND:Colon adenocarcinoma (COAD), although the third-most common type of gastrointestinal tumors, still lacks specific biomarkers for early diagnosis, treatment, and prognosis. AIMS:This study aimed to evaluate the CD276 in tumorigenesis, prognosis and immunity for colon adenocarcinoma. METHODS AND RESULTS:The CD276 expression in colon adenocarcinoma was established by using RNA-sequencing transcriptomic data of The Cancer Genome Atlas (TCGA) databases. The biological functions of CD276 were evaluated using the Metascape database and Gene Set Enrichment Analysis (GSEA). The association between CD276 and immune cell infiltration was investigated by TIMER website. Correlation analysis was performed between CD276 expression and clinicopathological characteristics. CD276 expression was significantly elevated in colon adenocarcinoma tumor (p < 0.0001). High CD276 was associated with microsatellite instability (MSI) status, patients' survival, and disease progression. Cox regression analysis revealed that CD276 was a risk factor for overall survival [hazard ratio (HR): 1.848, p = 2.64E-03], disease-specific survival (HR: 2.406, p = 5.35E-04), and progression-free interval (HR: 1.772, p = 2.04E-03). Moreover, CD276 level was significantly associated with tumor immune cell infiltration, biomarkers of immune cells, and immune checkpoint expression. CONCLUSIONS:Our analyses indicated that increased CD276 may contribute to colon adenocarcinoma development by activating tumor-promoting signal pathways and altering the immune microenvironment.

Lung cancer ranks as the leading cause of cancer-related mortality worldwide, characterised by complex molecular mechanisms and high therapeutic resistance. Ubiquitin-specific proteases, as core members of the deubiquitinating enzyme family, extensively participate in the initiation, progression, metastasis, and treatment resistance of lung cancer by regulating the stability of key proteins. Recent studies indicate that multiple Ubiquitin-Specific Proteases (USP) family members play pivotal roles in lung cancer: Ubiquitin-Specific Peptidase 7 (USP7) promotes proliferation and osimertinib resistance in non-small cell lung cancer by stabilising proteins such as ERβ, c-Abl, and KRAS; Ubiquitin-Specific Peptidase 9, X-linked (USP9X) mediates radiotherapy resistance by regulating KDM4C and REV1; USP10 influences cellular metabolism and chemotherapy sensitivity via PTEN/AKT/mTOR and HDAC6 pathways; Ubiquitin-Specific Peptidase 14 (USP14) enhances tumour migration by regulating β-catenin and Acf7 stability; Ubiquitin-Specific Peptidase 22 (USP22) amplifies tumour stem cell properties and suppresses ferroptosis via EGFR and BMI1 signalling; Ubiquitin-Specific Peptidase 35 (USP35) and Ubiquitin-Specific Peptidase 38 (USP38) respectively modulate apoptosis resistance and proliferation through BIRC3 and KLF5; while Ubiquitin-Specific Peptidase 39 (USP39) influences mitochondrial metabolism via PDHA, thereby promoting tumour growth. This paper systematically reviews the mechanisms of action of the aforementioned USPs in multiple key signalling pathways, including KRAS, TGF-β/SMAD, ferroptosis, and DNA damage repair. It further explores the potential value of small-molecule inhibitors targeting USPs (such as P5091, IU1, and gentiopicroside) in reversing drug resistance, inducing apoptosis, and enhancing immunotherapy. Nevertheless, current research remains subject to certain limitations, including insufficient systematic and synergistic understanding of USP family members’ functions, poor inhibitor selectivity and preclinical toxicity concerns, as well as unresolved functional heterogeneity across different molecular subtypes of lung cancer. This paper reviews the molecular mechanisms and targeting strategies of USPs in lung cancer based on a systematic literature search of PubMed and Web of Science databases. It further explores their potential applications in precision lung cancer therapy, providing theoretical foundations and directional guidance for future research.

Breast cancer (BRCA) is the most common type of cancer among women. The tumor immune microenvironment (TIM) influences the early progression of BRCA and is related to its clinical characteristics and outcomes. But the underlying mechanisms remain unclear. In this study, four synergistic TIM-prognosis-related genes (CD1C, CD40LG, CXCR3, CD69) were obtained which were significantly associated with tumor purity, and higher TIM-related immune activity was associated with improved prognosis in BRCA patients. A microRNA-mRNA-transcription factor regulatory network was established, revealing upstream regulators of these genes. Furthermore, fourteen candidate drugs targeting this network were predicted, and structural analogs of Lumacaftor and Ivosidenib showed promising docking affinities to CD1C and CXCR3, respectively. These findings provide preliminary insights into TIM-associated prognostic pathways and suggest candidate compounds for further investigation in BRCA.

Background:Airborne microplastic polyethylene terephthalate (PET) accumulates in human lungs and is linked to respiratory pathologies; however, its molecular role in lung adenocarcinoma (LUAD) remains unclear. This study aims to explore the potential carcinogenic mechanisms of PET exposure in LUAD. Methods:We integrated single-cell RNA sequencing, machine learning algorithms [including Classification and Regression Trees (CART), Naïve Bayes (NB), random forest (RF), and support vector machine (SVM)], molecular docking, survival analysis, and multi-omics data. Through differential expression screening across datasets combined with Venn analysis, we identified seven PET-associated oncogenic targets. Seven PET-associated oncogenic targets were identified via differential gene screening and Venn analysis. Results:MYL9 was validated as a downregulated, LUAD-protective biomarker associated with significant survival benefit [hazard ratio (HR) =0.59, 0.16, 0.23; all P<0.05]. These findings were consistent across the Human Protein Atlas (HPA) database, co-expression networks, and three independent LUAD datasets. SPI1 was identified as a key transcriptional regulator, showing strong co-expression with MYL9 (R=0.556, P<0.05) and concurrent downregulation in LUAD. Molecular docking revealed that PET bound to the DNA-binding pocket of SPI1 (ΔG =-5.30 kcal·mol-1), suggesting its transcriptional inhibition of MYL9. Conclusions:Our integrated bioinformatics approach supports a novel "PET-SPI1-MYL9" transcriptional axis, revealing a potential non-genotoxic carcinogenic pathway for PET. While the computational evidence is robust, further wet-lab experiments are needed to validate the binding and transcriptional inhibition mechanism. This model provides a framework for understanding airborne microplastic toxicity in LUAD. We propose that PET promotes LUAD by disrupting the SPI1-MYL9 transcriptional axis, highlighting a potential environmental trigger and candidate targets for diagnostic and therapeutic strategies.

Triple-negative breast cancer (TNBC) is a clinically aggressive subtype with limited therapeutic strategies. Although long non-coding RNAs (lncRNAs) are increasingly linked to tumor progression, their regulatory role in macrophage polarization during TNBC remains unclear. This study investigates the molecular interplay between lncRNA PVT1 and PPARγ in driving macrophage reprogramming during TNBC progression. Utilizing an orthotopic TNBC mouse model, single-cell RNA sequencing (scRNA-seq) identified nine distinct cell types, with pseudotime trajectory analysis revealing macrophage accumulation in advanced tumor stages. Reannotation of macrophages highlighted M2-like polarization dominance during TNBC development. Bulk sequencing of TNBC macrophages and integrated GEO/TCGA analyses identified PPARγ as a key regulator and PVT1 as a differentially expressed lncRNA in TNBC versus normal tissues. In vitro experiments with THP-1/U937 macrophages demonstrated that PVT1 knockdown or PPARγ modulation altered macrophage polarization, subsequently affecting MDA-MB-231 and MCF-7 breast cancer cell proliferation and invasion. Mechanistically, RNA/DNA pulldown and luciferase assays confirmed that PVT1 recruits NOP56 and E2F1 to form a transcriptional complex, enhancing E2F1-driven PPARγ expression. In vivo, orthotopic tumors generated from PVT1-silenced THP-1/MDA-MB-231 cell mixtures exhibited suppressed growth, increased M1-like macrophages, and elevated apoptosis (TUNEL assay), whereas PPARγ overexpression accelerated tumor progression with M2-dominant infiltration (flow cytometry). These findings establish lncRNA PVT1 as a critical epigenetic scaffold coordinating NOP56-E2F1-PPARγ signaling to polarize macrophages toward a pro-tumorigenic M2 phenotype, thereby fueling TNBC aggressiveness. This study unveils novel therapeutic targets for TNBC by disrupting the PVT1-PPARγ axis to rebalance macrophage dynamics and induce tumor-suppressive immunity.

Lung adenocarcinoma (LUAD) is a highly aggressive cancer with limited treatment options. This study investigated key genes linking ferroptosis and amino acid metabolism in LUAD using bioinformatics and experimental validation. Analysis of TCGA and GEO datasets identified GOT1 (upregulated) and CDO1 (downregulated) as core regulators. High GOT1 expression was associated with advanced clinicopathological characteristics and poor survival (log-rank P < 0.05). Functional studies demonstrated that GOT1 knockdown suppressed LUAD cell proliferation and clonogenic growth while promoting apoptosis, and also reduced tumor growth in vivo (P < 0.001). In addition, CDO1 showed an expression pattern consistent with a potentially protective role in LUAD and was inversely correlated with GOT1 (Spearman’s R = − 0.177, P < 0.001). Finally, a prognostic model incorporating GOT1 showed strong predictive accuracy (C-index = 0.705). These findings highlight the important role of GOT1 in LUAD progression and suggest that it may contribute to ferroptosis-related amino acid metabolic reprogramming, supporting its potential as a prognostic biomarker and therapeutic target.

BackgroundDistant metastasis is a primary factor contributing to the significantly shorter survival time of patients with advanced lung adenocarcinoma. The transcription factor Kruppel-like factor 5 (KLF5) facilitates the progression of lung adenocarcinoma. However, the specific mechanism by which KLF5 is involved in the tumor metastasis of lung adenocarcinoma metastasis remains largely unclear.MethodsUsing bioinformatic analysis, Rhophilin Rho GTPase Binding Protein 2 (RHPN2) was identified as a potential downstream target gene for KLF5; it plays a crucial role in the regulation of the epithelial-mesenchymal transformation pathway in lung adenocarcinoma. Western blotting and immunohistochemistry were performed to examine RHPN2 expression in lung adenocarcinoma. In vivo and in vitro experiments were conducted to explore the regulatory role of RHPN2 on the cell growth and metastasis of lung adenocarcinoma. Chromatin immunoprecipitation sequencing was used to analyze the direct binding activity between KLF5 and RHPN2 promoter regions. Luciferase activity assay was performed to verify the transcriptional activation effect of KLF5 on RHPH2.ResultsRHPN2 was highly expressed in lung adenocarcinoma; patients with lung adenocarcinoma who showed high RHPN2 expression had a poor prognosis. In vivo and in vitro experiments showed that RHPN2 promoted cell growth and metastasis and activated the epithelial-mesenchymal transformation pathway in lung adenocarcinoma. KLF5 directly bound to the promoter region of RHPN2 and upregulated its expression in lung adenocarcinoma through transcriptional activation. In addition, rescue experiments confirmed that KLF5 facilitated the progression of lung adenocarcinoma in an RHPN2-dependent manner.ConclusionOur study offers insights into the potential mechanisms of metastasis in lung adenocarcinoma and highlights RHPN2 as a potential therapeutic target.

Although cadmium (Cd) exposure has been implicated in lung cancer development, systematic investigations into its association with cancer mortality, particularly lung cancer mortality remain limited, and the molecular mechanisms driving Cd-induced tumor progression are not fully understood. In this study, we first conducted a meta-analysis of existing cohort studies to quantitatively assess the association between Cd exposure and cancer- and lung cancer-specific mortality. We then employed an integrative approach combining bioinformatics analyses, LASSO regression, and Mendelian randomization to identify and validate DHX34 as a key gene implicated in Cd-related lung carcinogenesis. These findings were further supported by molecular docking, molecular dynamics simulations, in vitro functional assays, and in vivo tumor models. Our meta-analysis showed that long-term Cd exposure significantly increased cancer mortality risk, especially in males (RR = 1.49, 95 % CI: 1.13-1.96) and in lung cancer (RR = 1.86, 95 % CI: 1.36-2.54). Integration of GSE165549 and TCGA data identified 36 Cd-related genes enriched in tumor associated pathways including cell cycle and DNA replication. LASSO regression and Mendelian randomization suggested a causal role of DHX34 in lung cancer. Molecular docking demonstrated a strong binding affinity between Cd2 + and DHX34 (binding free energy = -5.34 kcal/mol), and molecular dynamics simulations confirmed the stability of this complex. Functional assays further showed that CdCl2 exposure upregulated DHX34, thereby promoting lung cancer cell proliferation and tumor growth both in vitro and in vivo. Together, these findings provide multi-level evidence that DHX34 mediates Cd-induced lung cancer progression, highlighting the carcinogenic potential of environmental heavy metal exposure and offering new insights into molecular targets for early prevention, risk stratification, and therapeutic intervention.

Increasing evidence suggests that key cancer-causing driver genes continue to exert a sustained influence on the tumor microenvironment (TME), highlighting the importance of immunotherapeutic targeting of gene mutations in governing tumor progression. TP53 is a prominent tumor suppressor that encodes the p53 protein, which controls the initiation and progression of different tumor types. Wild-type p53 maintains cell homeostasis and genomic instability through complex pathways, and mutant p53 (Mut p53) promotes tumor occurrence and development by regulating the TME. To date, it has been wildly considered that TP53 is able to mediate tumor immune escape. Herein, we summarized the relationship between TP53 gene and tumors, discussed the mechanism of Mut p53 mediated tumor immune escape, and summarized the progress of applying p53 protein in immunotherapy. This study will provide a basic basis for further exploration of therapeutic strategies targeting p53 protein.

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Despite the exact biological role of HNF1 homolog A (HNF1A) in the regulatory mechanism of glioblastoma (GBM), the molecular mechanism, especially the downstream regulation as a transcription factor, remains to be further elucidated. Immunohistochemistry was used to detect the expression and clinical relevance of HNF1A in GBM patients. CCK8, TUNEL, and subcutaneous tumor formation in nude mice were used to evaluate the effect of HNF1A on GBM in vitro and in vivo. The correction between HNF1A and epidermal growth factor receptor pathway substrate 8 (EPS8) was illustrated by bioinformatics analysis and luciferase assay. Further mechanism was explored that the transcription factor HNF1A regulated the expression of EPS8 and downstream signaling pathways by directly binding to the promoter region of EPS8. Our comprehensive analysis of clinical samples in this study showed that upregulated expression of HNF1A was associated with poor survival in GBM patients. Further, we found that knockdown of HNF1A markedly suppressed the malignant phenotype of GBM cells in vivo and in vitro as well as promoted apoptosis of tumor cells, which was reversed by upregulation of HNF1A. Mechanistically, HNF1A could significantly activate PI3K/AKT signaling pathway by specifically binding to the promoter regions of EPS8. Moreover, overexpression of EPS8 was able to reverse the apoptosis of tumor cells caused by HNF1A knockdown, thereby exacerbating the GBM progression. Correctively, our study has clarified the explicit mechanism by which HNF1A promotes GBM malignancy and provides a new therapeutic target for further clinical application.

B7 -H3 is a common oncogene found in various cancer types. However, the molecular mechanisms underlying abnormal B7 -H3 expression and colorectal cancer (CRC) progression need to be extensively explored. B7 -H3 was upregulated in human CRC tissues and its abnormal expression was correlated with a poor prognosis in CRC patients. Notably, gain- and loss -of -function experiments revealed that B7 -H3 knockdown substantially inhibited cell proliferation, migration, and invasion in vitro, whereas exogenous B7 -H3 expression yielded contrasting results. In addition, silencing of B7 -H3 inhibited tumor growth in a xenograft mouse model. Mechanistically, our study demonstrated that the N6-methyladenosine (m6A) binding protein YTHDF1 augmented B7 -H3 expression in an m6A-dependent manner. Furthermore, rescue experiments demonstrated that reintroduction of B7 -H3 considerably abolished the inhibitory effects on cell proliferation and invasion induced by silencing YTHDF1. Our results suggest that the YTHDF1-m6A-B7-H3 axis is crucial for CRC development and progression and may represent a potential therapeutic target for CRC treatment.

Protein ubiquitination is a common post-translational modification and a critical mechanism for regulating protein stability. This study aimed to explore the role and potential molecular mechanism of ubiquitin-specific peptidase 38 (USP38) in the progression of lung adenocarcinoma (LUAD). USP38 expression was significantly higher in patients with LUAD than in their counterparts, and higher USP38 expression was closely associated with a worse prognosis. USP38 silencing suppresses the proliferation of LUAD cells in vitro and impedes the tumorigenic activity of cells in xenograft mouse models in vivo. Further, we found that USP38 affected the protein stability of transcription factor Krüppel-like factors 5 (KLF5) by inhibiting its degradation. Subsequent mechanistic investigations showed that the N-terminal of USP38 (residues 1-400aa) interacted with residues 1-200aa of KLF5, thereby stabilizing the KLF5 protein by deubiquitination. Moreover, we found that PIAS1-mediated SUMOylation of USP38 was promoted, whereas SENP2-mediated de-SUMOylation of USP38 suppressed the deubiquitination effects of USP38 on KLF5. Additionally, our results demonstrated that KLF5 overexpression restored the suppression of the malignant properties of LUAD cells by USP38 knockdown. SUMOylation of USP38 enhances the deubiquitination and stability of KLF5, thereby augmenting the malignant progression of LUAD.

BackgroundAccumulating evidence has shown that circular RNAs (circRNAs) are involved in gastric cancer (GC) tumorigenesis. However, specific functional circRNAs in GC remain to be discovered, and their underlying mechanisms remain to be elucidated.MethodsCircRNAs that were differentially expressed between GC tissues and controls were analyzed using a circRNA microarray dataset. The expression of circVDAC3 in GC was determined using quantitative real-time PCR (qRT-PCR), and the structural features of circVDAC3 were validated. Cell function assays and animal experiments were conducted to explore the effects of circVDAC3 on GC. Finally, bioinformatics analysis, fluorescent in situ hybridization, and dual luciferase assays were used to analyze the downstream mechanisms of circVDAC3.ResultsOur results showed that circVDAC3 was downregulated in GC and inhibited the proliferation and metastasis of GC cells. Mechanistically, circVDAC3 acts as a competing endogenous RNA (ceRNA) of miR-592 and deregulates the repression of EIF4E3 by miR-592. EIF4E3 is downregulated in GC and overexpression of miR-592 or knockdown of EIF4E3 in circVDAC3-overexpressing cells weakens the anticancer effect of circVDAC3.ConclusionOur study provides evidence that circVDAC3 affects the growth and metastasis of GC cells via the circVDAC3/miR-592/EIF4E3 axis. Our findings offer valuable insights into the mechanisms underlying GC tumorigenesis and suggest novel therapeutic strategies.

Objective The long non-coding RNA (lncRNA) PVT1 plays a significant role in regulating the development and progression of various cancers. However, its clinical relevance in triple-negative breast cancer (TNBC) and its immunoregulatory mechanisms in TNBC remain largely unexplored. Methods An orthotopic TNBC mouse model was established, and single-cell RNA sequencing was performed on tumor tissues to examine macrophage populations. Bulk RNA sequencing, differential expression analysis, and Weighted Gene Co-expression Network Analysis were integrated to identify key factors of interest. Experiments using the co-culture si-PVT1-transduced oe-PPARγ TNBC cells with macrophages were conducted to observe their effects on TNBC cell growth and on M1/M2 marker expression both in vivo and in vitro. Additionally, the interactions of PVT1, NOP56, and E2F1 and their influence on PPARγ transcription were analyzed using RNA/DNA immunoprecipitation, ChIP-qPCR, and luciferase reporter assays. Results Macrophage reprogramming occurred in the TNBC tissues of mice, characterized by a significant accumulation of M2-type macrophages in tumor tissues. Both PVT1 and PPARγ play pivotal roles in this reprogramming. PVT1 knockdown (KD) suppressed the expression of PPARγ and M2 macrophage markers, while oe-PPARγ partially restored M2 marker expression. In vitro, PVT1 enhances TNBC cell proliferation, invasion, and metastasis through PPARγ. Similarly, in vivo, PVT1 promotes TNBC tumor growth and M2 marker expression via PPARγ. Mechanistically, PVT1 functions as a scaffold to recruit NOP56 and E2F1, forming a PVT1–NOP56–E2F1 complex that facilitates the transcriptional upregulation of PPARγ. Conclusion LncRNA PVT1 significantly affects macrophage polarization and TNBC progression by regulating PPARγ transcription. These findings suggest novel molecular targets for TNBC therapy development.

Background: Germline HLA class I molecule supertypes are shown to correlate with response to anti-PD-1 therapy. Here, we investigate the significance of germline HLA-A and HLA-B supertypes in tumour microenvironment of non-small-cell lung cancer.Methods: Totally 278 NSCLC patients were collected retrospectively. HLA genotyping was conducted using next-generation sequencing. The evaluation of tumourinfiltrating lymphocytes was performed by multiplex immunohistochemistry assay. Correlations among HLA supertypes, tumour infiltrating lymphocytes, and clinicopathological characteristics were assessed.Results: HLA-A03 and HLA-B62 were the supertypes with the highest proportions, at 69.1% and 52.2%, respectively. HLA-A02 or HLA-B62, but not HLA-A03, associated with higher PD-L1+ tumour and stromal cells levels, CD68+ cells, and CD68+PD-L1+ cells. Patients with both HLAA02 and HLA-B62 supertypes displayed significantly higher PD-L1+ cells, CD68+ cells, and CD8+ cells levels than patients with other supertypes (P = 0.0301, P = 0.0479, P = 0.0192). These cells collectively constitute a hot but immunosuppressive tumour microenvironment. Accordingly, patients with both HLA-A02 and HLA-B62 supertypes had short progression-free survival after surgery (HR = 2.27, P = 0.0373).Conclusions: The HLA-A02B62 supertype could serve as a possible indicator of poor prognosis in early-stage lung cancer. However, it may also act as a favorable prognostic factor for immunotherapy, given its association with a PD-L1-positive tumour microenvironment.