Journal of Cancer最新文献

Immune checkpoint inhibitors are effective treatments for many tumors. However, existing biomarkers can benefit only a small selection of colorectal cancer patients. Super-enhancers are associated with various tumor characteristics. We wondered whether super-enhancer-related genes could be novel biomarkers for immunotherapy. We screened super-enhancer-related genes that were highly correlated with immune infiltration through weighted gene co-expression network analysis on the basis of chromatin immunoprecipitation sequencing data. A prognostic risk signature was established using least absolute shrinkage and selection operator and cox regression models. By analyzing the correlations between the expression of model genes and the immunophenotypic and microsatellite instability scores, we determined that PLAU and GSDMC expression had high predictive value for immunotherapy efficacy. Moreover, we predicted the sensitivity of the PLAU and GSDMC proteins to drugs by virtual docking. Finally, we validated the effect of the super-enhancer activity on PLAU and GSDMC expression. Overall, our study identified super-enhancer-based biomarkers for predicting survival and immunotherapy efficacy in colorectal cancer.

Colorectal cancer (CRC) is the third most common malignancy and leading cause of mortality worldwide. Tumor microenvironment (TME) strongly influences CRC growth, immune evasion, and metastasis. Among various immune cells, tumor-associated macrophages (TAMs) act as key regulators of cancer progression. Although traditionally classified as M1 (pro-inflammatory, anti-tumor) or M2 (anti-inflammatory, pro-tumor), single-cell RNA sequencing and spatial transcriptomics have revealed that macrophage phenotypes exist along a continuum, challenging the classic dichotomy. This review investigates macrophages throughout CRC development, from normal mucosa to adenoma, primary tumor, and liver metastasis. Early adenomas feature M1-like macrophages that drive local inflammation, whereas advanced adenomas and invasive CRC comprise M2-like macrophages promoting angiogenesis, extracellular matrix remodeling, and immunosuppression. TAMs are crucial in CRC metastasis, particularly to the liver. M2-polarized Kupffer cells express CD206 and CD163, secrete hepatocyte growth factor, and activate PI3K/AKT signaling, thus aiding extravasation, survival, and proliferation of metastatic cells. They also foster lymphangiogenesis and immunosuppression through release of IL-10 and TGF-β. CRC's consensus molecular subtype (CMS) impacts the profile of TAMs: CMS1 (microsatellite instability-high) tumors typically harbor an anti-tumor M1 macrophages, while CMS4 (mesenchymal) tumors are enriched in M2-like TAMs, which facilitate stromal remodeling and angiogenesis, ultimately contributing to a poor prognosis. Spatial distribution also matters. Abundant M1 macrophages at the invasive margin correlate with better outcomes, whereas M2 macrophages in tumor centers and metastatic sites drive disease progression. Some CD206+ macrophages, however, support vascular normalization, which can limit metastasis. These findings underscore the complexity of TAMs in CRC and highlight the necessity of multi-marker phenotyping. Given the limitations of the M1/M2 paradigm, advanced techniques such as spatial transcriptomics and single-cell RNA sequencing offer novel insights into TAM heterogeneity. Future therapeutic strategies targeting TAMs, including metabolic reprogramming, epigenetic modulators, and immune checkpoint inhibitors, hold promise for improving CRC patient outcomes by shifting the balance toward an anti-tumor immune response.

Lung cancer remains the leading cause of cancer mortality. The AP-1 adaptor complex, including AP1AR, AP1S1, AP1S2, AP1S3, AP1M1, AP1M2, AP1B1, and AP1G1, functions as a conserved hub of vesicular trafficking, selecting cargo and coordinating clathrin-mediated transport. By shaping receptor recycling, membrane composition, and signal duration, AP-1 influences core cancer phenotypes such as proliferation, migration, and therapy response. However, the family-level role of AP-1 adaptors in lung cancer is incompletely defined. We systematically profiled all eight AP-1 adaptor genes using multi-omics datasets, survival resources, pharmacogenomic panels, Human Protein Atlas data, pathway enrichment, and single-cell RNA sequencing with cell-cell communication modeling. AP1AR was consistently upregulated in lung adenocarcinoma and independently associated with poorer overall survival. It was linked to cell-cycle progression, DNA replication checkpoints, hypoxia, and epithelial-to-mesenchymal transition (EMT). At single cell resolution, AP1AR also regulate malignant epithelial and fibroblast cell types. Pseudotime analyses revealed progressive activation along proliferative and EMT axes, and CellChat modeling indicated enhanced stromal and epithelial signaling. AP1S3 and AP1S1 showed complementary roles, associated with oncogenic/inflammatory signaling and immune-metabolic programs, respectively. These findings identify AP1AR as a clinically relevant biomarker and highlight AP-1 adaptor biology as an underexplored contributor to lung adenocarcinoma progression and therapeutic stratification.

Objective: Neoadjuvant chemotherapy regimens have shown encouraging efficacy characterized by high objective response rate (ORR), pathologic complete response (pCR) rate, and major pathologic response (MPR) rate, alongside acceptable safety. This single-center retrospective study aimed to evaluate the safety and efficacy of neoadjuvant pembrolizumab plus chemotherapy in patients with locally advanced resectable oral and oropharyngeal squamous cell carcinomas (LA-OSCC/OPSCC). Materials and methods: A total of 50 patients were included. The patients received 2-4 cycles of neoadjuvant therapy with pembrolizumab, albumin-bound paclitaxel and cisplatin before surgery, followed by adjuvant radiotherapy or immunotherapy. Results: The median follow-up time was 31.7 months (95%CI, 29.4-34.0). The ORR was 85.4%, and the MPR rate was 65.8%. The 1-year event-free survival (EFS) rate was 88.8% (95%CI, 79.8%-98.8%). Patients with moderate programmed cell death ligand 1 (PD-L1) expression (combined positive score (CPS) 1 to <10) achieved the highest MPR rate (71.4%), underscoring the potential predictive value of PD-L1 expression. Treatment-related adverse events (TRAEs), most commonly alopecia, anemia, neutropenia, and nausea, were manageable. No treatment-related deaths occurred. Conclusion: This retrospective analysis indicates that neoadjuvant pembrolizumab combined with chemotherapy is a promising strategy for patients with LA-OSCC/OPSCC. Future prospective studies with larger cohorts and longer follow-up are warranted to confirm these findings.

Thyroid carcinoma (TC) is the most prevalent malignancy of the endocrine system, with its incidence rising annually worldwide. Post-translational modifications and epigenetic changes have been documented to be pivotal in the initiation, progression, and malignant transformation of TC. In addition to mediating biological processes such as cell recognition, signal transduction, and immune regulation, these modifications can also significantly impact the development and metastasis of various cancers. Among these, sialylation is identified as a key post-translational modification, showing close associations with the invasiveness and metastatic potential of TC. This review aims to provide an overview of the current understanding of sialylation in TC, highlighting its underlying mechanisms and examining its roles in cell proliferation, invasion, and immune evasion. Additionally, this study intends to explore the potential of targeting sialylation as a novel therapeutic approach, providing new perspectives for TC prevention and treatment, as well as the development of new therapeutic agents.

For patients with recurrent or metastatic clear cell renal cell carcinoma (ccRCC), immunotherapy has demonstrated substantial antitumor activity. However, accurately predicting which patients will benefit from these therapies remains a major challenge. This study aims to elucidate the regulatory role of the hypoxic tumor microenvironment in immune suppression and immune escape, to develop a hypoxia-based prognostic model, and to identify key biomarkers to guide personalized treatment decisions. We applied weighted gene co-expression network analysis (WGCNA) to screen hypoxia-related genes and constructed a hypoxia risk score (HRS) model using LASSO-Cox regression. We found that the HRS model effectively predicted immunotherapy response and prognosis, with patients in the high-HRS group exhibiting significantly shorter overall survival. A high HRS was associated with immune escape by reshaping the T-cell-infiltrated tumor microenvironment (TME), and showed strong positive correlations with cancer-immunity cycle activity, PD-L1/CTLA-4 immune checkpoint expression, and T-cell inflammation scores. Importantly, cell-based and animal experiments demonstrated that PLOD2, a key gene in the HRS model, plays a critical role in hypoxia-induced immune escape in ccRCC. PLOD2 significantly promoted ccRCC cell growth and migration in vitro and in vivo. High PLOD2 expression in clinical samples was associated with ccRCC progression and potentially enhanced sensitivity to immunotherapy by modulating tumor mutational burden and immune escape-related pathways. In summary, our study successfully constructed an HRS model to predict the efficacy of immune checkpoint inhibitor (ICI)-based immunotherapy. PLOD2 was identified as a dual-functional biomarker with both prognostic and predictive value for immunotherapy. The HRS model provides a quantitative tool for immunotherapy stratification. Notably, high PLOD2 expression indicates tumor progression yet paradoxically associates with enhanced immunotherapy response through activation of immune escape pathways, thereby offering a potential therapeutic target for converting "cold tumors" into "hot tumors".

Target therapy is effective for epidermal growth factor receptor (EGFR) mutation in non-small cell lung cancer (NSCLC). However, resistance often occurs after treatment for several months. Macrophages have difficulty in devouring resistant cells. Ganoderma immunomodulatory protein (GMI) exhibits anti-tumour and immunomodulatory activities. This study aimed to investigate whether GMI overcomes Osimertinib (Tagrisso) and Gefitinib (Iressa) resistance via enhancing macrophage polarization. GMI attenuated signal transducer and activator of transcription 3 (STAT3) phosphorylation and downstream CD47 expression in parental and resistant cells via Western blot and RT-qPCR. Overexpressed STAT3 restored GMI-induced apoptosis and GMI-reduced transcription of CD47 in HCC827 and H1975 lung cancer cells. Phospho-STAT3 inhibitor (W1131) also reduced the expression of CD47 in NSCLC cells. The interaction between GMI and W1131 was effective in reducing phosphorylated STAT3 and CD47. ImageXpress Pico analysis revealed that GMI enhanced phagocytotic activity of macrophages toward tumour cells with Red CMTPX and Green CMFDA dyes. The results showed that GMI enhanced macrophage phagocytosis of lung cancer cells by inhibiting STAT3 and reducing CD47 expression. In addition, GMI enhanced M1 inhibition of M2 polarization but had no effect on M1 differentiation. This is the first study to demonstrate that GMI enhances macrophage phagocytosis and modulates the STAT3-CD47 axis to overcome EGFR-TKI resistance in NSCLC, highlighting its potential as a novel adjunct immunotherapeutic agent.

Urothelial cancer (UC) remains a highly recurrent and heterogeneous malignancy in which reliable biomarkers for recurrence and prognosis are needed, particularly in the metastatic setting. In recent years, the identification and validation of biomarkers have become an essential pillar for improving the diagnosis, monitoring, and prognosis of this disease. This review summarizes and analyzes recent advances in the study of serological, urinary, histological, genetic, and microRNA biomarkers, as well as emerging tools such as circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA). Together, these non-invasive markers show significant potential to complement conventional diagnostic techniques, optimize risk stratification, and support a more personalized therapeutic approach. Furthermore, the integration of new sequencing technologies and liquid biopsy methods is opening new perspectives for the early detection of recurrence and the dynamic assessment of treatment response. However, the routine clinical implementation of these biomarkers still requires validation through standardized prospective studies.

Hepatocellular carcinoma (HCC) represents a major public health issue globally, necessitating the urgent development of new therapies. The therapeutic efficacy of disulfiram (DSF) and copper (Cu) in HCC was investigated in the present study, focusing on cytotoxicity, mitochondrial function, and apoptosis to clarify the mechanistic basis of this drug combination. Our findings revealed a significant, dose-dependent reduction in HCC cell viability with DSF/Cu treatment. Further investigation showed increased reactive oxygen species (ROS) levels, decreased adenosine triphosphate (ATP) production, and a decline in mitochondrial membrane potential (MMP). These events culminated in the activation of caspase-9 and caspase-3, key enzymes in the apoptotic pathway, leading to cell death. Mechanistically, DSF/Cu synergistically increased the expression of activating transcription factor 3 (ATF3), a known tumor suppressor, in HCC cells. In vivo studies using a mouse tumor model supported these findings, demonstrating significantly inhibited tumor growth in the DSF/Cu group compared with the control group. Overall, our study findings suggest that the DSF/Cu combination exhibits significant therapeutic potential against HCC by modulating the ATF3-dependent mitochondrial apoptosis pathway, a strategy that warrants further preclinical exploration.

Sulforaphane-cysteine (SFN-Cys) is a naturally-occurring form of plant-derived isothiocyanate metabolites that displays several tumor-suppressive properties. However, the oncostatic potential of SFN-Cys on oral squamous cell carcinoma (OSCC) is mostly elusive. In this study, we tried to test whether SFN-Cys affects OSCC to progress and further explored the underlying array of molecular cues that SFN-Cys mediates. Our results demonstrate that SFN-Cys was an effective inducer of cytotoxicity to OSCC cells, accompanied with blockage of cell cycling and promotion of apoptotic events. Moreover, treatment of OSCC cells with SFN-Cys attuned an apoptosis-associated protein regulatory program, underlined by downregulation of apoptosis suppressors (cIAP-1 and XIAP) and activation of caspase cascades. Furthermore, caspase activations in SFN-Cys-treated OSCC cells were affected by the pre-incubation with a specific c-Jun N-terminal kinase (JNK) inhibitor, suggesting a functional link of JNK pathway to SFN-Cys's actions in OSCC cells. Collectively, our data revealed that SFN-Cys hampered cell cycle progression and elicited apoptotic responses in OSCC via a JNK-mediated activation of caspase pathways. These findings provide possible avenues for the application of a natural compound in the management of oral malignancies.