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Cancer-associated adipocytes (CAAs), one of the primary stromal components, exhibit intimate crosstalk and release multiple cell factors mediating local and systemic biological effects. However, the role of CAAs in the regulation of systemic immune responses and their potential value in the clinical treatment of triple-negative breast cancer (TNBC) are not well described. Transcriptome sequencing was performed on CAA and normal adipocyte (NA) tissues isolated from surgically resected samples from TNBC patients and healthy controls. Cytokines, including C-X-C motif chemokine ligand 8 (CXCL8, also known as IL-8), secreted from NAs and CAAs were compared by transcriptome sequencing and enzyme-linked immunosorbent assay (ELISA). Proliferation, migration and invasion assays were employed to analyze the role of CAAs and CAA-derived CXCL8 (macrophage inflammatory protein-2 (MIP2) as a functional surrogate in mice). TNBC syngraft models were established to evaluate the curative effect of targeting CXCL8 in combination with anti-PD-1 therapies. Real-time quantitative polymerase chain reaction (RT-qPCR), western blotting (WB), polymerase chain reaction (PCR) array, flow cytometry, immunohistochemistry (IHC), and immunofluorescence (IF) were applied to analyze immune cell infiltration and epithelial–mesenchymal transition (EMT) markers. Specifically, we demonstrated that CAAs and CAA-derived CXCL8 played important roles in tumor growth, EMT, metastasis and tumor immunity suppression. CAA-derived CXCL8 remodeled the tumor immune microenvironment not only by suppressing CD4 + T and CD8 + T immune cell infiltration but also by upregulating CD274 expression in TNBC. The combination of targeting the CXCL8 pathway and blocking the PD-1 pathway synergistically increased the tumor immune response and inhibited tumor progression. Thus, our results highlight the molecular mechanisms and translational significance of CAAs in tumor progression and immune ecosystem regulatory effects and provide a better understanding of the potential clinical benefit of targeting CAA-derived CXCL8 in antitumor immunity and as a new therapeutic moiety in TNBC.

Serine/threonine kinase 16 (STK16) is crucial in on regulating tumor cell proliferation, apoptosis, and prognosis. Activated M1 macrophages regulate lung adenocarcinoma (LUAD) growth by releasing exosomes. This study aims to investigate the role of STK16 and then focus on the possible mechanisms through which exosomes derived from M1 macrophages play their roles in LUAD cells by targeting STK16. Clinical LUAD samples were used to evaluate the expression of STK16 and its association with prognosis. Exosomes were isolated from M0 and M1 macrophages by ultracentrifugation and were then identified by electron microscopy and western blotting. In vitro gain‐ and loss‐of‐function experiments with LUAD cells were performed to elucidate the functions of miR‐181a‐5p, ETS1, and STK16, and mouse xenograft models were used to verify the function of STK16 in vivo. Western blotting, quantitative real‐time PCR, CCK‐8 assay, cell apoptosis, immunohistochemistry staining, luciferase assay, ChIP assay, and bioinformatics analysis were performed to reveal the underlying mechanisms. High expression of STK16 was observed in LUAD tissues and cells, and higher expression of STK16 was associated with worse prognosis. Silencing STK16 expression inhibited cell proliferation and promoted apoptosis via the AKT1 pathway. Exosomes from M1 macrophages inhibited viability and promoted apoptosis by inhibiting STK16. Moreover, miR‐181a‐5p is the functional molecule in M1 macrophage‐derived exosomes and plays a vital role in inhibiting cell proliferation and promoting apoptosis by targeting ETS1 and STK16. Hence, exosomes derived from M1 macrophages were capable of inhibiting viability and promoting apoptosis in LUAD via the miR‐181a‐5p/ETS1/STK16 axis. The finding that MiR‐181a‐5p in exosomes from M1‐polarized macrophages inhibits STK16 by targeting ETS1 to regulate cell viability and apoptosis in LUAD provides guidance for the treatment of LUAD and deserves attention in the clinical practice of precision medicine.

BackgroundTriple-negative breast cancer (TNBC) is a heterogeneous disease that is characterized by metabolic disruption. Metabolic reprogramming and tumor cell immune escape play indispensable roles in the tumorigenesis that leads to TNBC.MethodsIn this study, we constructed and validated two prognostic glutamine metabolic gene models, Clusters A and B, to better discriminate between groups of TNBC patients based on risk. Compared with the risk Cluster A patients, the Cluster B patients tended to exhibit better survival outcomes and higher immune cell infiltration. In addition, we established a scoring system, the glutamine metabolism score (GMS), to assess the pattern of glutamine metabolic modification.ResultsWe found that solute carrier family 7 member 5 (SLC7A5), an amino acid transporter, was the most important gene and plays a vital role in glutamine metabolism reprogramming in TNBC cells. Knocking down SLC7A5 significantly inhibited human and mouse TNBC cell proliferation, migration, and invasion. In addition, downregulation of SLC7A5 increased CD8+ T-cell infiltration. The combination of a SLC7A5 blockade mediated via JPH203 treatment and an anti-programmed cell death 1 (PD-1) antibody synergistically increased the immune cell infiltration rate and inhibited tumor progression.ConclusionsHence, our results highlight the molecular mechanisms underlying SLC7A5 effects and lead to a better understanding of the potential benefit of targeting glutamine metabolism in combination with immunotherapy as a new therapy for TNBC.

Background Metabolic reprogramming is a hallmark in cancer. Pyrimidine metabolism (PM), a part of nucleotide metabolism, has been shown to be associated with the progression of various cancers, and the prognostic predictive ability of pyrimidine metabolism-related genes (PMG) in breast cancer has not been elucidated. This paper was designed to identify pyrimidine metabolism-related prognostic marker of breast cancer and potential targeted therapeutic options. Methods The cohort in the TCGA-BRCA dataset was used for patient information, and 108 pyrimidine metabolism-related genes were identified from the MSigDB KEGG pathways. We identified PM clusters in breast cancer and established a PM risk score model based on 10 pyrimidine metabolism-related genes. The status of immune infiltration was assessed in different groups. Further we identified the relevant hub gene and analyzed its significance for breast cancer metastasis and explored patterns of combination therapy. Results We identified three types of PM clusters in breast cancer and clarified that PM cluster C with inferior prognosis possessed activation of tumor proliferation-associated pathways. The high-risk group in PM risk score model was found to be characterized by an immunosuppressive microenvironment. The hub gene POLR2C (RNA polymerase II subunit C) was further identified and verified as a potential prognostic marker. Furthermore, targeting POLR2C in combination with anti-PD-1 and anti-angiogenic therapies demonstrated a promising tumor suppression effect, suggesting a potential therapeutic direction. Conclusions These findings provide additional insights into the link between breast cancer and PMG, offering potential strategies for breast cancer management and treatment.

Our previous study demonstrated that SIRT6 is upregulated in papillary thyroid cancer (PTC) and enhances tumor aggressiveness. In this study, we further researched its influence in the Warburg effect. SIRT6-upregulated and downregulated BCPAP cells and negative control BCPAP-NC groups were generated with lentiviral vectors. In these two cell lines, reactive oxygen species (ROS) were detected by dichlorodihydrofluorescein diacetate. Expression of the key Warburg effect genes including GLUT1, HK2, GAPDH, PGK1, ENO1, PKM2 and LDHA was measured by quantitative real-time PCR and western blotting. Glucose uptake, lactate production and the ATP content of cells were detected with assay kits. The ROS scavenger -acetylcysteine was used for treatment of BCPAP-SIRT6, and the same measurements as described above were detected again. Compared with the BCPAP-NC group, expression of the key Warburg effect genes including Glut1, HK2 and GAPDH and their protein products was upregulated in the BCPAP-SIRT6 group, whereas BCPAP-shSIRT6 showed significant downregulation. Meanwhile, ROS, glucose uptake, lactate production and ATP content of the BCPAP-SIRT6 group were also significantly increased, and BCPAP-shSIRT6 showed significant downregulation. Furthermore, upregulation of key Warburg effect genes and glucose uptake, lactate production and ATP content were all rescued after treatment with ROS scavenger. SIRT6 promoted the Warburg effect of PTC cells via upregulation of ROS. Inhibition of ROS in SIRT6-upregulated cells could rescue activation of the Warburg effect.

Triple-negative breast cancer (TNBC) is a highly heterogeneous tumor that lacks effective treatment and has a poor prognosis. Exosomes carry abundant genomic information and have a significant role in tumorigenesis, metastasis, and drug resistance. However, further exploration is needed to investigate the relationship between exosome-related genes and the heterogeneity and tumor immune microenvironment of TNBC. Based on the exosome-related gene sets, multiple machine learning algorithms, such as Cox boost, were used to screen the risk score model with the highest C-index. A 9-gene risk score model was constructed, and the TNBC population was divided into high- and low-risk groups. The effectiveness of this model was verified in multiple datasets. Compared with the low-risk group, the high-risk group exhibited a poorer prognosis, which may be related to lower levels of immune infiltration and immune response rates. The gene mutation profiles and drug sensitivity of the two groups were also compared. By screening for genes with the most prognostic value, the hub gene, CLDN7, was identified, and thus, its potential role in predicting prognosis, as well as providing ideas for the clinical diagnosis, treatment, and risk assessment of TNBC, was also discussed. This study demonstrates that exosome-related genes can be used for risk stratification in TNBC, identifying patients with a worse prognosis. The high-risk group exhibited a poorer prognosis and required more aggressive treatment strategies. Analysis of the genomic information in patient exosomes may help to develop personalized treatment decisions and improve their prognosis. CLDN7 has potential value in prognostic prediction in the TNBC population.

Background In our previous study, we demonstrated that Sirtuin 6 (SIRT6) is upregulated and associated with papillary thyroid cancer (PTC) progression (Qu et al. in Int J Oncol 50(5):1683–92, 2017 ). This study examined whether SIRT6 promotes epithelial–mesenchymal transition (EMT) of papillary thyroid cancer through hypoxia inducible factor-1α (HIF-1α). Methods SIRT6-upregulated TPC-1 and B-CPAP cells were generated by lentivirus. Western blotting, RT-qPCR, immunofluorescence was performed to detect the following EMT associated markers: E-cadherin, Vimentin, Snail, and TWIST. Cell proliferation was detected by CCK8, and cell invasion and migration were detected by transwell and wound healing assays, respectively. HIF-1α expression was further detected by western blotting in both normoxia and hypoxia conditions. A HIF-1α inhibitor was then used to block HIF-1α expression in SIRT6-upregulated PTC cells. The same parameters were then assessed and compared with control HIF-1α cells. Results E-cadherin was significantly decreased, whereas Vimentin, Snail, and TWIST were increased in SIRT6-upregulated PTC cells. Additionally, SIRT6 promoted the invasion and migration of PTC cells. We found that SIRT6 enhanced HIF-1α stability and synthesis and prolonged the protein half-life. The changes in the EMT associated markers and in the invasion and migration ability were rescued after inhibition of HIF-1α expression. Furthermore, we found that SIRT6 increased PTC resistance to HIF-1α inhibitor-mediated proliferation changes. Conclusion These results confirm that the SIRT6/HIF-1α axis promotes papillary thyroid cancer progression by inducing EMT.

BackgroundWhile adipose tissue constitutes a substantial proportion of breast composition, the functional characteristics and pathological relevance of the adipocyte microenvironment in breast carcinogenesis remain undercharacterized. This study employs single-nucleus RNA sequencing (snRNA-seq) to establish a comprehensive cellular atlas of adipocyte heterogeneity across molecular subtypes of breast cancer, aiming to elucidate subtype-specific adipocyte contributions to tumor microenvironment modulation.MethodssnRNA-seq was performed on breast adipose tissues isolated from individuals without cancer and treatment-naïve breast cancer. Various adipocyte and pre-adipocyte subclusters were identified. Comparative analyses of cellular distribution and transcriptional profiles were performed across disease states and molecular subtypes. Pseudotime, cell communication, and immunofluorescence analyses were further implemented to investigate cellular dynamics and microenvironment interactions.ResultssnRNA-seq data of 86,529 nuclei were obtained. Three adipocyte and seven pre-adipocyte subclusters were identified, of which Adi_LDLR, Pre_Adi_LDLR, and Pre_Adi_LGR4_TGFBR1 were restricted to cancer-associated adipose (CAAs). Adi_LDLR and Pre_Adi_LDLR were enriched in estrogen receptor (ER)-positive CAAs and related to cell senescence and immunosuppression. Pre_Adi_LGR4_TGFBR1 was predominantly present in triple-negative breast cancer, functionally pro-proliferative, immunosuppressive, and lacked normal adipose function. The immunofluorescence intensity of LDLR (p=0.031) and TGFBR1 (p=0.038) was positively associated with disease recurrence, suggesting the formation of immunosuppressive niches by these cancer-specific adipose subsets in both subtypes. Cell communication analyses revealed a specific (pre-) adipocyte-macrophage interaction via ligand-receptor pairs involved in stromal remodeling and tumor migration for ER-positive tumors, whereas tumor proliferation and metastasis for triple-negative ones likely contribute to tumor progression.ConclusionsThis study delineated a distinct adipocyte landscape in breast cancer and subtype-specific immunosuppressive niches fostered by CAAs and (pre-) adipocyte-macrophage interactions. These findings provide novel therapeutic targets for microenvironment-directed interventions in breast oncology.

Background Disulfidptosis represents a novel type of regulated cell death induced by excessively high intracellular levels of cystine. Targeting disulfide imbalance is considered a promising treatment approach for colorectal cancer (CRC). However, the involvement of disulfidptosis in CRC immunotherapy is undefined. Methods Unsupervised clustering was applied to The Cancer Genome Atlas (TCGA) datasets to classify disulfidptosis-related phenotypes. The tumor microenvironment (TME) was characterized using diverse bioinformatics algorithms, including gene set variation analysis (GSVA) for pathway enrichment analysis and CIBERSORT for immune cell profiling. A disulfidptosis-related gene (DRG) signature was generated for stratifying CRC cases, and univariate Cox regression was utilized for identifying prognostic DRGs. Filamin A (FLNA) was pinpointed as a pivotal regulator of disulfidptosis, and its functional impacts on tumor progression and immunotherapy response were further investigated. Results Two different groups were determined on the basis of the built disulfidptosis-related signature (DRS), showing distinct clinical outcomes, as well as different pathway activation, drug sensitivity, and immune infiltration patterns. The high-DRS subgroup correlated with poorer prognosis, elevated immunosuppressive cell activity, and reduced cytotoxic immune cell infiltration. FLNA emerged as a critical mediator of disulfidptosis in CRC, with its knockdown suppressing tumor cell migration and invasion in vitro. The FLNA inhibitor PTI-125 attenuated tumor growth and epithelial–mesenchymal transition (EMT), while FLNA depletion reversed glucose-driven metastasis. Notably, combined glucose transporter 1 (GLUT1) inhibition and anti-programmed cell death protein 1 (PD-1) therapy enhanced CD8 + T cell recruitment and suppressed EMT. Conclusions This study elucidates the interplay between disulfidptosis and the CRC immune landscape, highlighting FLNA as a therapeutic target. These findings suggest that modulating disulfidptosis in conjunction with immunotherapy may offer a novel treatment paradigm for CRC.