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Background The regulatory role of N6-methyladenosine (m6A) modification in the onset and progression of cancer has garnered increasing attention in recent years. However, the specific role of m6A modification in pulmonary metastasis of colorectal cancer remains unclear. Methods This study identified differential m6A gene expression between  primary colorectal cancer and its pulmonary metastases using transcriptome sequencing and immunohistochemistry. We investigated the biological function of METTL3 gene both in vitro and in vivo using assays such as CCK-8, colony formation, wound healing, EDU, transwell, and apoptosis, along with a BALB/c nude mouse model. The regulatory mechanisms of METTL3 in colorectal cancer pulmonary metastasis were studied using methods like methylated RNA immunoprecipitation quantitative reverse transcription PCR, RNA stability analysis, luciferase reporter gene assay, Enzyme-Linked Immunosorbent Assay, and quantitative reverse transcription PCR. Results The study revealed high expression of METTL3 and YTHDF1 in the tumors of patients with pulmonary metastasis of colorectal cancer. METTL3 promotes epithelial-mesenchymal transition in colorectal cancer by m6A modification of SNAIL mRNA, where SNAIL enhances the secretion of CXCL2 through the NF-κB pathway. Additionally, colorectal cancer cells expressing METTL3 recruit M2-type macrophages by secreting CXCL2. Conclusion METTL3 facilitates pulmonary metastasis of colorectal cancer by targeting the m6A-Snail-CXCL2 axis to recruit M2-type immunosuppressive macrophages. This finding offers new research directions and potential therapeutic targets for colorectal cancer treatment.

Immune-checkpoint inhibitors (ICIs) have shown unprecedented success in a subset of immunogenic tumors, however a host of patients with advanced solid tumors fail to respond well or at all to immunotherapy. Refractory tumors commonly display a tumor microenvironment (TME) rich in immunosuppressive macrophages (M2-like) that suppress adaptive immunity and promote tumor progression. The ability to reprogram macrophages in the TME into an immune-active state holds great promise for enhancing responses to ICIs. Lucicebtide (previously referred to as ST101) is a peptide antagonist of the transcription factor C/EBPβ, a key activator of the transcriptional program in immunosuppressive macrophages. Here we show that lucicebtide exposure reprograms human immunosuppressive M2-like macrophages to a pro-inflammatory M1-like phenotype, restores cytotoxic T cell activation in immunosuppressed co-culture assays in vitro , and further increases T-cell activity in M1-like/T cell co-cultures. In immunocompetent, macrophage-rich triple-negative breast and colorectal cancer models, lucicebtide induces repolarization of tumor-associated macrophages (TAMs) to a pro-inflammatory M1-like phenotype and suppresses tumor growth. Lucicebtide synergizes with anti-PD-1 therapy and overcomes resistance to checkpoint inhibition in anti-PD-1-refractory tumors, but in vivo responses are impaired by systemic macrophage depletion, indicating that macrophage reprogramming is integral to lucicebtide activity. These results identify lucicebtide as a novel immunomodulator that reprograms immunosuppressive macrophage populations to enhance anti-tumor activity and suggests its utility for combination strategies in cancers with poor response to ICIs.

Gynecologic tract melanoma is a malignant tumor with poor prognosis. Because of the low survival rate and the lack of a standard treatment protocol related to this condition, the investigation of the mechanisms underlying melanoma progression is crucial to achieve advancements in the relevant gynecological surgery and treatment. Mitochondrial transfer between adjacent cells in the tumor microenvironment regulates tumor progression. This study investigated the effects of endothelial mitochondria on the growth of melanoma cells and the activation of specific signal transduction pathways following mitochondrial transplantation. Mitochondria were isolated from endothelial cells (ECs) and transplanted into B16F10 melanoma cells, resulting in the upregulation of proteins associated with tumor growth. Furthermore, enhanced antioxidation and mitochondrial homeostasis mediated by the Sirt1-PGC-1α-Nrf2-HO-1 pathway were observed, along with the inhibition of apoptotic protein caspase-3. Finally, the transplantation of endothelial mitochondria into B16F10 cells promoted tumor growth and increased M2-type macrophages through Nrf2/HO-1-mediated pathways in a xenograft animal model. In summary, the introduction of exogenous mitochondria from ECs into melanoma cells promoted tumor growth, indicating the role of mitochondrial transfer by stromal cells in modulating a tumor’s phenotype. These results provide valuable insights into the role of mitochondrial transfer and provide potential targets for gynecological melanoma treatment.

Chronic pancreatitis (CP) is a fibro-inflammatory syndrome with unclear pathogenesis and futile therapy. CP's microenvironment disrupts the fine-tuned balance of macrophage polarization toward a predominance of the M2-like phenotype associated with fibrosis. S100A9 is mainly expressed in monocytes as a potent regulator of macrophage phenotype and function. Here, we investigated the S100A9-related mechanisms underlying CP pathology induced by macrophages polarization. knockout ( ) mice and an coculture system of macrophages overexpressing and primary PSCs were constructed to investigate the effects and mechanisms of S100A9-mediated macrophage polarization on pancreatic inflammation and fibrosis underpinning CP pathology. Furthermore, a variety of S100A9-targeted small-molecule compounds were screened from U.S. Food and Drug Administration (FDA)-listed drug libraries through molecular docking and virtual screening techniques. In CP progression, S100A9 upregulation induces M2 macrophage polarization to accelerate fibrosis via thousand-and-one amino acid kinase 3 (TAOK3)-c-Jun N-terminal kinase (JNK) signaling pathway, and loss of S100A9 reduces CP injury and . Coimmunoprecipitation (co-IP) and molecular docking experiments proved that S100A9 may interact directly with TAOK3 through salt bridges and hydrogen bonding interactions of the residues in the S100A9 protein. Furthermore, cobamamide and daptomycin, as inactivators of the S100A9-TAOK3 interaction, can improve CP by inhibiting the polarization of M2 macrophages. S100A9 is a significant promoter of M2-like macrophage-induced fibrosis in CP via the TAOK3-JNK signaling pathway. Cobamamide and daptomycin, targeted inhibitors of the S100A9-TAOK3 interaction, may become candidate drugs for CP immunotherapy.

Utilizing expression data of clear cell renal cell carcinoma (ccRCC) genes from the Cancer Genome Atlas (TCGA) database, this study employs weighted gene co-expression network analysis (WGCNA) and Cox regression analysis to identify genes associated with the occurrence and development of ccRCC, thereby providing a scientific basis for its treatment. Differentially expressed genes between tumor and control groups were identified by preprocessing and batch correction of ccRCC transcriptome data in the TCGA database using the Wilcoxon test. Prognostic prediction models were established through a combination of WGCNA analysis, univariate Cox regression analysis, and multivariate Cox regression analysis. The reliability of these prognostic models was evaluated by plotting Kaplan-Meier survival analysis and receiver operating characteristic (ROC) curves and by further analyzing the relationship between model gene expression levels, tumor staging, and tumor grading. Post-batch correction, M2-type macrophage infiltration was pronounced in tumor tissue, and 13 out of 290 screened relevant differential genes were included in the prognostic model. The Kaplan-Meier survival curves indicated that the 3- and 5-year overall survival rates were significantly higher in the low-risk group compared with the high-risk group (83.7 vs. 69.1%; 75.7 vs. 52.6%, p = 1.169e-08). The area under the ROC curve was 0.732, signifying strong predictive power for the survival curve. In this model, the expression levels of 11 genes were positively correlated with tumor stage and pathological grade, whereas the remaining 2 genes were negatively correlated. This model can predict the overall survival of patients with ccRCC and has the potential to become an important therapeutic target.

Tumor-associated macrophages/M2-type (TAM/M2) play a key role in the metastasis and angiogenesis of cancer, and are considered to be critical targets for cancer treatment. However, it remains unclear whether α-programmed death-ligand 1 (αPD-L1; PD-L1 inhibitor) inhibits tumor progression via targeting TAMs. In the present study, it was demonstrated that αPD-L1 significantly inhibited IL-13-induced TAM/M2 polarization in vitro. Moreover, αPD-L1 inhibited the epithelial-mesenchymal transition (EMT) process and the stemness of triple-negative breast cancer (TNBC) cells, which were mediated via the reversal of TAM/M2 polarization. This therefore inhibited the migration and angiogenesis of TNBC cells. Furthermore, αPD-L1 prevented STAT3 phosphorylation and nuclear translocation, which resulted in the arrest of TAM/M2 polarization. In vivo experiments further demonstrated that αPD-L1 reduced the number of lung metastases without affecting tumor growth. Moreover, αPD-L1 reduced the expression levels of TAM/M2, EMT, stemness and vascular markers in tumor tissues. In summary, these data suggest that αPD-L1 plays a vital role in the anti-metastasis and anti-angiogenesis of TNBC in vitro and in vivo via the inhibition of TAM/M2 polarization. These findings may thus provide a novel therapeutic strategy for clinically refractory TNBC.

Background Endothelial-to-mesenchymal transition (EndoMT) can provide a source of cancer-associated fibroblasts which contribute to desmoplasia of many malignancies including pancreatic ductal adenocarcinoma (PDAC). We investigated the clinical relevance of EndoMT in PDAC, and explored its underlying mechanism and therapeutic implication. Methods Expression levels of 29 long non-coding RNAs were analyzed from the cells undergoing EndoMT, and an EndoMT index was proposed to survey its clinical associations in the PDAC patients of The Cancer Genome Atlas database. The observed clinical correlation was further confirmed by a mouse model inoculated with EndoMT cells-involved PDAC cell grafts. In vitro co-culture with EndoMT cells or treatment with the conditioned medium were performed to explore the underlying mechanism. Because secreted HSP90α was involved, anti-HSP90α antibody was evaluated for its inhibitory efficacy against the EndoMT-involved PDAC tumor. Results A combination of low expressions of LOC340340, LOC101927256, and MNX1-AS1 was used as an EndoMT index. The clinical PDAC tissues with positive EndoMT index were significantly correlated with T4-staging and showed positive for M2-macrophage index. Our mouse model and in vitro cell-culture experiments revealed that HSP90α secreted by EndoMT cells could induce macrophage M2-polarization and more HSP90α secretion to promote PDAC tumor growth. Furthermore, anti-HSP90α antibody showed a potent therapeutic efficacy against the EndoMT and M2-macrophages-involved PDAC tumor growth. Conclusions EndoMT cells can secrete HSP90α to harness HSP90α-overproducing M2-type macrophages to promote PDAC tumor growth, and such effect can be targeted and abolished by anti-HSP90α antibody.

Lung fibrosis is a dysregulated repair process caused by excessive deposition of extracellular matrix that can severely affect respiratory function. Macrophages are a group of immune cells that have multiple functions and can perform a variety of roles. Lung fibrosis develops with the involvement of pro-inflammatory and pro-fibrotic factors secreted by macrophages. The balance between M1 and M2 macrophages has been proposed to play a role in determining the trend and severity of lung fibrosis. New avenues and concepts for preventing and treating lung fibrosis have emerged in recent years through research on mitochondria, Gab proteins, and exosomes. The main topic of this essay is the impact that mitochondria, Gab proteins, and exosomes have on macrophage polarization. In addition, the potential of these factors as targets to enhance lung fibrosis is also explored. We have also collated the functions and mechanisms of signaling pathways associated with the regulation of macrophage polarization such as Notch, TGF-β/Smad, JAK-STAT and cGAS-STING. The goal of this article is to explain the potential benefits of focusing on macrophage polarization as a way to relieve lung fibrosis. We aspire to provide valuable insights that could lead to enhancements in the treatment of this condition.

The increase of both M2-type macrophages and Tregs is closely associated with the development of colorectal cancer. However, the mechanism of their interaction is still unclear. In this study, we investigated the correlation of M2-type macrophages with Tregs and the possible mechanisms between them. Using immunohistochemistry, we analysed Smad3 (a key protein in the TGF-β/Smad signalling pathway) expression in colorectal cells, as well as infiltrating numbers of CD163 (a marker for M2-type macrophages), Foxp3 (a marker for Tregs) in 250 surgically resected colorectal cancer tissues, matched normal and paracancerous tissues. The relation of CD163 and Foxp3 was investigated in CRC with clinicopathological characteristics and preoperative tumour markers. CD163, Foxp3 and Smad3 were upregulated in CRC tissues compared to matched normal and paracancerous tissues. Interestingly, CD163 and Foxp3 were significantly positively correlated in CRC, and both were significantly positively correlated with Smad3. Both CD163 and Foxp3 were upregulated with increasing tumour TNM staging, increasing number of lymph node metastases and increasing vascular invasion. Additionally, CD163 was upregulated with increasing depth of infiltration. The number of M2-type macrophages and the expression levels of preoperative CEA, CA19-9 and CA72-4 were significantly positively correlated. The number of Tregs was significantly positively correlated with the expression levels of preoperative CEA and CA19-9. M2-type macrophages may induce Tregs generation through activation of the TGF-β/Smad signalling pathway, which can promote the development of colorectal cancer.

Background Diabetic nephropathy (DN) is a microvascular complication of diabetes and a major cause of chronic renal failure in adults. DN is characterized by the infiltration of inflammatory cells in the renal tubular interstitium, resulting in severe interstitial fibrosis, ultimately leading to end-stage renal disease. However, the exact timing at which different phenotypes of inflammatory cells contribute to interstitial fibrosis in DN remains unclear. Methods We collected 45 renal tissues diagnosed with DN through renal biopsy between January 2014 and April 2019 from the Pathology Department of Putuo Hospital, affiliated with the Shanghai University of Traditional Chinese Medicine and the Pathology Department of Shanghai Medical College Fudan University. Immunohistochemistry staining was performed on paraffin-embedded sections to analyze the expression patterns of M1 and M2 macrophages and regulatory T lymphocytes. The severity of renal function impairment was categorized into three groups: CKD stage 1 (16 cases), CKD stage 2 (13 cases), and CKD stages 3–5 (16 cases). The degree of tubulointerstitial fibrosis was divided into three groups: mild fibrosis (16 cases), moderate fibrosis (18 cases), and severe fibrosis (11 cases). Results Our findings revealed significant differences in the levels of inflammatory cell infiltration CD68, CD163, CD3, and CD4, as well as in the M1/M2 ratio among the different groups of tubulointerstitial fibrosis. While the severity of interstitial fibrosis did not impact urinary protein excretion, it demonstrated statistically significant differences in renal function decline. When the samples were categorized based on the degree of renal dysfunction, there were significant differences in the levels of CD68, CD163, CD3, CD4, and Foxp3 among the three groups. The infiltration levels of macrophages and lymphocytes increased significantly with renal function decline, with M2-type macrophages being the predominant subtype. The infiltration level of inflammatory cells was associated with renal function decline but not with the ratio of proteinuria to interstitial fibrosis. Macrophage and lymphocyte infiltration levels were consistent, while regulatory T lymphocytes showed a closer association with M1-type macrophages. The rate of interstitial fibrosis was correlated with renal function indicators and macrophage infiltration, with a positive correlation observed with M2-type macrophages. Discussion Our study demonstrated an association between regulatory T lymphocytes and M1-type macrophages, which may contribute to early lesions of DN. However, their impact was limited. In the late stage of DN, M2-type macrophages significantly increased, inhibiting the immune response but also producing and releasing numerous pro-fibrotic factors, ultimately exacerbating fibrosis and worsening renal function. The phenotypes of macrophages determined the development and prognosis of DN. Therefore, regulating macrophage polarization and subtype transformation represented a promising target for DN treatment.