Cancer Cell International最新文献

Background: Immune checkpoint inhibitors (ICIs), such as anti-programmed cell death protein 1 (PD-1) and anti-cytotoxic T-lymphocyte associated protein 4 (CTLA-4), have transformed the management of stage III melanoma in the neoadjuvant setting. However, a substantial proportion of patients do not derive benefit from ICI therapy. To improve clinical outcomes, there remains a critical unmet need to identify early biomarkers of response to neoadjuvant immunotherapy in stage III melanoma.

Methods: In this study, we performed longitudinal serum proteomic profiling in 39 patients undergoing neoadjuvant combination anti-PD-1 and anti-CTLA-4 therapy. Using a multiplex proximity extension assay, we measured 702 proteins at three timepoints: baseline, early on-treatment (3-4 weeks after treatment initiation), and pre-surgery (4-8 weeks post-treatment).

Results: The most pronounced differences between major pathological responders (MPR) and non-MPR patients were detected at baseline and were linked to interferon gamma (IFNγ) signalling, but these differences diminish at later timepoints. A 10-protein IFNγ-associated signature derived from baseline serum profile achieved an AUC of 0.68 for predicting pathological response, comparable to a previously reported tumour-based IFNγ gene signature (AUC = 0.67).

Conclusions: These findings support the use of circulating protein signatures as minimally invasive, scalable biomarkers to inform early treatment decisions in the neoadjuvant setting.

Background: Pancreatic cancer, recognized as a refractory tumor, has an overall survival rate of less than 10%, and its mortality rate continues to rise. Due to the low immune activity induced by its unique tumor microenvironment, pancreatic cancer is classified as a "cold" tumor and is insensitive to current immunotherapies. However, little is still known about the identification and functional mechanisms of key regulatory molecules in the formation of "cold" tumors.

Methods: In this study, we identified the pancreatic ductal cell niche through single-cell sequencing. By calculating CNV scores using inferCNV to distinguish malignant from non-malignant cells and analyzing differences in transcriptional levels, we constructed a 15-gene model. The inhibitory effect of UBE2H on the immune microenvironment was studied through single-cell sequencing analysis, including the inhibition of T cell function, impairment of antigen presentation in macrophages and neutrophils, and activation of neutrophil extracellular traps (NETs).

Results: Our results revealed the presence of a UBE2H+ cell population within the pancreatic ductal cell niche, primarily observed in pancreatic cancer samples. Notably, single-cell sequencing analysis of UBE2H overexpression revealed an enhanced T cell PD-L1 interaction axis and a downregulation of antigen presentation pathways in macrophages and neutrophils (antigen processing and presentation, macrophage activation, and neutrophil activation). Further in vivo experiments confirmed that high UBE2H expression promotes tumor progression, leading to increased T cell exhaustion (PD1) and decreased activation (CD69, GZMB, IFNR) in the immune microenvironment, impaired antigen presentation of macrophages and neutrophils (H2Kb, I-Ab, I-A/E), and increased neutrophil extracellular trap formation (MPO, NE, CITH3).

Conclusions: This study revealed the presence of a UBE2H+ cell population within the pancreatic ductal cell niche and analyzed the inhibition of UBE2H on the immune microenvironment of pancreatic cancer through single-cell sequencing and in vivo experiments, providing important clues for the formation of "cold" tumors in pancreatic cancer and opening new directions for exploring new treatment strategies.

The solute carrier (SLC) family is one of the largest families of membrane transport proteins, essential for cellular metabolism and communication. Studies have shown that the SLC family plays a critical role in the metabolic processes and intrinsic biological behaviors of hepatocellular carcinoma (HCC). SLC38s contribute to the progression of HCC through signaling pathways such as PI3K/AKT/mTOR and Wnt/β-catenin/MYC. The regulation of upstream factors like miR-10b-5p, the LINC01559-miR-511-SLC38A1 axis, miRNA-432, and other genes are also implicated in HCC development. Additionally, SLC7A11 influences the proliferation of HCC cells via pathways such as SMYD3/SLC7A11 and JAK/STAT/SLC7A11. Other members of the SLC family also play significant roles in HCC through various mechanisms. Given the importance of SLCs in HCC and the lack of a comprehensive understanding of their molecular mechanisms, this study explores metabolic alterations in liver cancer cells and their surrounding immune cells. It also examines how the metal ions in liver cancer impact HCC growth and the efficacy of anticancer immunotherapy. Furthermore, we discuss the vital role of SLCs as key transporters for the hepatic uptake of anionic anticancer drugs, highlighting novel therapeutic opportunities.

Background: Macrophage play a dual role in tumor progression. However, the mechanisms underlying tumor-associated macrophage (TAM) polarization in the hepatocellular carcinoma (HCC) microenvironment remain elusive.

Methods: We analyzed the proportions of tumor-infiltrating immune cells in The Cancer Genome Atlas Liver Hepatocellular Carcinoma cohort. Subsequently, a risk prediction model was constructed for patients with HCC. The expression patterns and clinical relevance of G protein-coupled receptor 34 (GPR34) were evaluated. The potential functions and mechanisms of GPR34 in macrophages were also investigated. Additionally, HCC mouse models were used to assess the therapeutic potential of a GPR34 inhibitor in enhancing immune checkpoint blockade (ICB) therapy.

Results: A novel prognostic prediction model based on macrophage-related genes was established to predict the outcomes of patients with HCC. In this model, GPR34 was identified as significantly upregulated and associated with a poor clinical prognosis in HCC. Mechanistically, GPR34 facilitated M2 macrophage polarization by activating the PI3K/AKT signaling axis. The pharmacological inhibition of GPR34 effectively suppressed tumor growth. Moreover, the combination of a GPR34 inhibitor with a PD-1 inhibitor demonstrated synergistic antitumor effects.

Conclusion: GPR34 is pivotal in driving macrophage M2 polarization, and inhibitor targeting GPR34 represents promising antitumor agent capable of augmenting the efficacy of anti-PD-1 therapy.

Ammonia, a toxic nitrogenous metabolic byproduct, has garnered increasing attention for its pivotal role in tumor biology. The human body has developed intricate detoxification mechanisms to regulate ammonia homeostasis and maintain acid‒base equilibrium. Through their adaptation mechanisms, cancer cells can exploit ammonia to facilitate their growth and modulate the tumor immune microenvironment. As ammonia is a toxic substance, it can have a toxic effect on tumor, thereby inhibiting tumor growth. This article critically examines the sources and destinations of ammonia within the tumor microenvironment (TME), offering an innovative synthesis of its dual roles in both promoting and inhibiting tumor progression. Additionally, it explores therapeutic strategies targeting ammonia metabolism and anticipates future research trajectories, thereby providing valuable insights and a theoretical framework for ammonia-based therapies in oncology.

Endometrial cancer (EC) is a leading cause of gynecological malignancy with poor prognosis in advanced stages. This study aimed to identify key eosinophil extracellular trap (EET) regulators involved in EC progression and explore their prognostic value using machine learning-based models. Through differential expression analysis, we identified 108 EET regulators whose expression was significantly altered in tumor tissues compared to normal tissues. Survival analysis further demonstrated that S100A9 and other EET-related genes, such as CCL26 and CD40, were significantly associated with poor patient outcomes. Unsupervised clustering analysis revealed two distinct molecular subtypes of EC, with Cluster A showing upregulation of most EET regulators and worse clinical outcomes. We assessed immune infiltration profiles and found elevated eosinophil infiltration in Cluster A. Machine learning models incorporating S100A9 achieved superior predictive performance, with the Lasso + RSF model demonstrating robust accuracy (C-index = 0.864) for predicting patient survival. Experimental validation of S100A9 function in endometrial cancer cell lines demonstrated that S100A9 knockdown effectively reduced its expression, leading to the disruption of the NF-κB pathway, as confirmed by Western blot analysis. Further, S100A9 overexpression in Ishikawa and KLE cells resulted in increased levels of apoptotic markers, indicating its role in apoptosis regulation. These findings suggest S100A9 as a potential prognostic biomarker for EC, influencing immune infiltration, NF-κB signaling, and tumor progression, with implications for new therapeutic strategies targeting EET-related pathways.

The limited clinical translation of preclinical anticancer drug efficacy underscores the urgent need for advanced models that faithfully replicate tumor pathophysiology. While three-dimensional (3D) tumor cultures improve the fidelity of microenvironmental modeling, most existing systems lack vascularization, which is a critical element influencing tumor progression and treatment resistance. In this study, a vascularized 3D lung cancer model was established by co-seeding decellularized lung scaffold with human embryonic stem cell-derived endothelial cells, pericytes, and A549 adenocarcinoma cells. This tri-culture system successfully formed a hierarchical vascular network and recapitulated key features of the tumor microenvironment, including hypoxia-driven lysyl oxidase (LOX) overexpression, and integrin-mediated fibronectin-rich desmoplastic niches accumulation. Compared to traditional cultures, this 3D bioengineered platform demonstrated excellent cell compatibility and architectural complexity, supporting enhanced cell migration and MUC5AC hypersecretion. Importantly, cancer cells cultured in this 3D vascularized system exhibited reduced chemosensitivity relative to monolayer cultures. Moreover, patient-derived lung cancer organoids were integrated into the pre-vascularized 3D compartment for individualized drug response testing. Mechanically, hypoxia-activated HIF-1α/LOX signaling promoted ITGA5/FN1-dependent extracellular matrix remodeling and contributed to a chemoprotective niche. This vascularized 3D lung cancer model offers a physiologically relevant and translationally valuable platform for investigating non-small cell lung cancer progression and optimizing patient-specific drug screening.

Background: Human papillomavirus (HPV) infection is associated with an increased risk of cutaneous squamous cell carcinoma (CSCC). A comprehensive understanding of the cellular heterogeneity of HPV-positive and -negative CSCC is crucial for improving diagnosis and preventing tumor progression.

Methods: We conducted an integrated analysis of single-cell RNA and spatial transcriptomic data from different skin tissue sources to map the cellular landscape of the tumor microenvironment (TME) in both HPV positive and negative CSCC. Results were validated through multiplex immunohistochemistry (mIHC) and in vitro experiments.

Results: We identified 10 major cell types in CSCC and normal skin samples, including epithelial cells, myeloid cells, T cells, fibroblasts, endothelial cells, B cells, smooth muscle cells, mast cells, melanocytes, and hair follicle cells. Notably, fibroblasts were found to be associated with tumor progression in CSCC with or without HPV infected. We further identified eight major CAF subtypes in CSCC, with iCAFs-CXCL2 promoting tumor progression, while iCAFs-PLA2G2A acted to suppress tumor growth. The MDK-ITGA6 pair was found to mediate interactions between fibroblasts and epithelial cells in CSCC. mIHC analysis confirmed elevated expression of MDK and ITGA6 in CSCC samples. Additionally, cell co-culture experiments confirmed that MDK-mediated CAFs were shown to enhance tumor cell migration and invasion in CSCC.

Conclusion: Our findings provide a comprehensive cellular atlas of CSCC, highlighting the association of CAFs in HPV infection and tumor progression of CSCC. These results also offer potential diagnostic and prognostic biomarkers for CSCC patients.