The role of dendritic cells in tertiary lymphoid structures: implications in cancer and autoimmune diseases.

Tertiary Lymphoid Structures (TLS) are organized aggregates of immune cells such as T cells, B cells, and Dendritic Cells (DCs), as well as fibroblasts, formed postnatally in response to signals from cytokines and chemokines. Central to the function of TLS are DCs, professional antigen-presenting cells (APCs) that coordinate the adaptive immune response, and which can be classified into different subsets, with specific functions, and markers. In this article, we review current data on the contribution of different DC subsets to TLS function in cancer and autoimmunity, two opposite sides of the immune response. Different DC subsets can be found in different tumor types, correlating with cancer prognosis. Moreover, DCs are also present in TLS found in autoimmune and inflammatory conditions, contributing to disease development. Broadly, the presence of DCs in TLS appears to be associated with favorable clinical outcomes in cancer while in autoimmune pathologies these cells are associated with unfavorable prognosis. Therefore, it is important to analyze the complex functions of DCs within TLS in order to enhance our fundamental understanding of immune regulation but also as a possible route to create innovative clinical interventions designed for the specific needs of patients with diverse pathological diseases.

NF-κB signaling pathway in tumor microenvironment.

The genesis and progression of tumors are multifaceted processes influenced by genetic mutations within the tumor cells and the dynamic interplay with their surrounding milieu, which incessantly impacts the course of cancer. The tumor microenvironment (TME) is a complex and dynamic entity that encompasses not only the tumor cells but also an array of non-cancerous cells, signaling molecules, and the extracellular matrix. This intricate network is crucial in tumor progression, metastasis, and response to treatments. The TME is populated by diverse cell types, including immune cells, fibroblasts, endothelial cells, alongside cytokines and growth factors, all of which play roles in either suppressing or fostering tumor growth. Grasping the nuances of the interactions within the TME is vital for the advancement of targeted cancer therapies. Consequently, a thorough understanding of the alterations of TME and the identification of upstream regulatory targets have emerged as a research priority. NF-κB transcription factors, central to inflammation and innate immunity, are increasingly recognized for their significant role in cancer onset and progression. This review emphasizes the crucial influence of the NF-κB signaling pathway within the TME, underscoring its roles in the development and advancement of cancer. By examining the interactions between NF-κB and various components of the TME, targeting the NF-κB pathway appears as a promising cancer treatment approach.

TMEM164 promotes ferroptosis by selectively mediating ATG5-dependent autophagosome formation to inhibit the progression of LUAD.

The study focuses on lung adenocarcinoma (LUAD), a predominant type of lung cancer. Despite advancements in diagnostics and molecular therapies, treatment remains challenging due to its low five-year survival rate. This study aims to investigate the role of the transmembrane protein TMEM164 in ferroptosis and anti-tumor immunity in LUAD, and to evaluate its potential as a therapeutic target. Through cellular experiments (such as QPCR, WB, CCK-8, EdU, Transwell, flow cytometry, CO-IP) and animal model experiments (including HE staining and IHC analysis), the relationship between TMEM164 expression and LUAD progression was explored, with particular attention to its mechanisms in ferroptosis and autophagy. The results show that TMEM164 expression is downregulated in LUAD and is associated with poor prognosis. Increasing TMEM164 expression significantly inhibits cell proliferation, migration, and invasion, while promoting an autophagy process dependent on ATG5 for autophagosome formation, thus facilitating ferroptosis. In mouse models, high TMEM164 expression combined with anti-PD-1 antibodies demonstrated synergistic anti-tumor effects. These findings highlight the critical role of TMEM164 in LUAD, suggesting that modulating TMEM164 expression could open new avenues for LUAD treatment.

LAMTOR1 ablation impedes cGAS degradation caused by chemotherapy and promotes antitumor immunity.

Chemotherapy resistance remains a significant obstacle that limits the long-term efficacy of cancer therapy, necessitating further investigations into the underlying mechanisms. Here, we find that DNA fragments induced by chemotherapeutic agents trigger the degradation of cGAS, a potent double-strand DNA (dsDNA) sensor, by lysosomes. Mechanically, the lysosome-localized protein LAMTOR1 is up-regulated, and the interaction between LAMTOR1 and cGAS is enhanced upon exposure to DNA fragments, boosting the accumulation and digestion of cGAS in lysosomes through the receptor protein p62. LAMTOR1 deficiency increases cGAS abundance and promotes activation of the cGAS-STING pathway, leading to subsequent production of type I interferons induced by cytosolic DNA stimulation. Loss of LAMTOR1 synergizes with immunotherapy and chemotherapy to inhibit tumor growth and prolong the survival time of tumor-bearing mice by promoting the infiltration of effective T lymphocytes. Thus, our study reveals a regulation of cGAS abundance and provides a potential strategy to overcome chemotherapy resistance by targeting LAMTOR1.

Bioinformatic-Experimental Screening Uncovers Multiple Targets for Increase of MHC-I Expression through Activating the Interferon Response in Breast Cancer.

Expression of major histocompatibility complex I (MHC-I) on tumor cells is extremely important for the antitumor immune response for its essential role in activating various immune cells, including tumor-specific CD8+ T cells. Cancers of lower MHC-I expression commonly exhibit less immune cell infiltration and worse prognosis in clinic. In this study, we conducted bioinformatic-experimental screening to identify potential gene targets to enhance MHC-I expression in breast cancer (BRCA). Through a combination of MHC-I scoring, gene expression correlation analysis, survival prognostication, and Cibersort tumor-infiltrated lymphocytes (TILs) scoring, we identify 144 genes negatively correlated with both MHC-I expression and TILs in breast cancer. Furthermore, we verified partially according to KEGG functional enrichment or gene-dependency analysis and figured out multiple genes, including PIP5K1A, NCKAP1, CYFIP1, DIS3, TBP, and EXOC1, as effective gene targets for increasing MHC-I expression in breast cancer. Mechanistically, knockout of each of these genes activated the intrinsic interferon response in breast cancer cells, which not only promoted MHC-I expression but also caused immunogenic cell death of breast cancer. Finally, the scRNA-seq confirmed the negative correlation of PIP5K1A et al. with TILs in breast cancer patients. Collectively, we identified multiple gene targets for an increase in MHC-I expression in breast cancer in this study.

Carvacrol potentiates immunity and sorafenib anti-cancer efficacy by targeting HIF-1α/STAT3/ FGL1 pathway: in silico and in vivo study.

Hypoxia and tumor cell immunological escape greatly hinder the hepatocellular carcinoma (HCC) treatment efficiency. This study is designed to investigate the capability of carvacrol (CVR) to enhance sorafenib (SOR) anti-cancer efficacy and modulate anti-HCC immunity. CVR target and biological activities were predicted using Swiss Target Prediction website and PASS web server. UALCAN and LinkedOmics databases were used to examine hypoxia-inducible factor 1-alpha (HIF-1α) expression and the relationship between studied genes and tumor clinical features. Kaplan-Meier plotter (KM plotter) and TISIDB databases were used to illustrate correlation of HIF-1α with HCC prognosis and immune infiltration. The binding affinities of CVR to p300, KAT2B, CREBBP, and Hsp90 were demonstrated by molecular docking. In vivo analysis was performed in male Sprague-Dawley rats. The STAT3, JAK2, and fibrinogen-like protein 1 (FGL1) expressions were assessed by qRT-PCR. FGL1 was determined by ELISA. CD8+ T cell number was counted by flow cytometry. HIF-1α was determined by immunohistochemistry. CVR showed an HIF-1α inhibitory potential, which is highly expressed in HCC tissues. Also, elevated HIF-1α expression has been found to be correlated with clinicopathological characteristics, poor survival in HCC patients, and tumor immune cell infiltration. CVR/SOR enhanced liver functions and decreased AFP level. CVR/SOR hindered HCC progression by downregulating STAT3, JAK2, and FGL1. CVR/SOR induced tumor immunity via increasing CD8+ T cells. CVR/SOR is a powerful combination for tumor repression and enhancing SOR efficiency in HCC by modulating FGL1. Moreover, CVR/SOR might exert the aforementioned effects through HIF-1α/STAT3/FGL1 pathway.

Basophils Induce Pro-Tumorigenic Cytokines from A549 Lung Adenocarcinoma via Mechanisms Requiring IgE, Galectin-3, and IL-3 Priming.

Galectin-3 (Gal-3) is implicated in innate immune cell activation in a host of diseases/conditions. We identified a unique response whereby human basophils secrete IL-4/IL-13 when co-cultured with A549 cells -a lung adenocarcinoma. While displaying parameters consistent with standard IgE-dependent activation, these Galectin-3-dependent responses occurred in the absence of specific IgE/allergen and required cell-to-cell contact. We now hypothesize that this mode of activation also impacts A549 function. Our findings show that cytokines are induced in basophil/A549 co-cultures that are not detected when either cell is cultured alone, in particular IL-6. As previously shown for IL-4/IL-13, IL-6 production also required cell-to-cell contact and was dependent on A549-Gal-3, since clones deficient of this lectin induced less cytokine. Using culture-derived basophils (CDBA), we demonstrate that the IL-6 response, and production of another tumorigenic factor, VEGF-A, are induced in CDBA/A549 co-cultures but only after passively sensitizing CDBA with IgE, in a manner similar to IL-4/IL-13. However, IgE-dependent activation of basophils/CDBA cultured alone failed to induce IL-6/VEGF. Importantly, IL-3-primed basophils, even those fixed with paraformaldehyde, readily induced IL-6/VEGF-A in co-cultures, thus verifying these cytokines are derived from A549. Overall, these results suggest a complex mechanism whereby Gal-3/IgE interactions between IL-3-primed basophils and A549 have the potential to modulate cytokine production by both cells. With Gal-3 implicated in many diseases ranging from asthma to cancer, but also in normal physiological conditions, such as wound healing, these findings are predicted to provide insight into the molecular mechanisms by which this lectin (and IgE) functions in these processes.

Exploring the impact of tertiary lymphoid structures maturity in NSCLC: insights from TLS scoring.

Tertiary Lymphoid Structures (TLS) are lymphoid structures commonly associated with improved survival of cancer patients and response to immunotherapies. However, conflicting reports underscore the need to consider TLS heterogeneity and multiple features such as TLS size, composition, and maturation status, when assessing their functional impact. With the aim of gaining insights into TLS biology and evaluating the prognostic impact of TLS maturity in Non-Small Cell Lung Carcinoma (NSCLC), we developed a multiplex immunofluorescent (mIF) panel including T cell (CD3, CD8), B cell (CD20), Follicular Dendritic cell (FDC) (CD21, CD23) and mature dendritic cell (DC-LAMP) markers. We deployed this panel across a cohort of primary tumor resections from NSCLC patients (N=406) and established a mIF image analysis workstream to specifically detect TLS structures and evaluate the density of each cell phenotype. We assessed the prognostic significance of TLS size, number, and composition, to develop a TLS scoring system representative of TLS biology within a tumor. TLS relative area, (total TLS area divided by the total tumor area), was the most prognostic TLS feature (C-index: 0.54, p = 0.04). CD21 positivity was a marker driving the favorable prognostic impact, where CD21+ CD23- B cells (C-index: 0.57, p = 0.04) and CD21+ CD23- FDC (C-index: 0.58, p = 0.01) were the only prognostic cell phenotypes in TLS. Combining the three most robust prognostic TLS features: TLS relative area, the density of B cells, and FDC CD21+ CD23- we generated a TLS scoring system that demonstrated strong prognostic value in NSCLC when considering the effect of age, sex, histology, and smoking status. This TLS Score also demonstrated significant association with Immunoscore, EGFR mutational status and gene expression-based B-cell and TLS signature scores. It was not correlated with PD-L1 status in tumor cells or immune cells. In conclusion, we generated a prognostic TLS Score representative of the TLS heterogeneity and maturity undergoing within NSCLC tissues. This score could be used as a tool to explore how TLS presence and maturity impact the organization of the tumor microenvironment and support the discovery of spatial biomarker surrogates of TLS maturity, that could be used in the clinic.

Metabolic mediators: microbial-derived metabolites as key regulators of anti-tumor immunity, immunotherapy, and chemotherapy.

The human microbiome has recently emerged as a focal point in cancer research, specifically in anti-tumor immunity, immunotherapy, and chemotherapy. This review explores microbial-derived metabolites, emphasizing their crucial roles in shaping fundamental aspects of cancer treatment. Metabolites such as short-chain fatty acids (SCFAs), Trimethylamine N-Oxide (TMAO), and Tryptophan Metabolites take the spotlight, underscoring their diverse origins and functions and their profound impact on the host immune system. The focus is on SCFAs' remarkable ability to modulate immune responses, reduce inflammation, and enhance anti-tumor immunity within the intricate tumor microenvironment (TME). The review critically evaluates TMAO, intricately tied to dietary choices and gut microbiota composition, assessing its implications for cancer susceptibility, progression, and immunosuppression. Additionally, the involvement of tryptophan and other amino acid metabolites in shaping immune responses is discussed, highlighting their influence on immune checkpoints, immunosuppression, and immunotherapy effectiveness. The examination extends to their dynamic interaction with chemotherapy, emphasizing the potential of microbial-derived metabolites to alter treatment protocols and optimize outcomes for cancer patients. A comprehensive understanding of their role in cancer therapy is attained by exploring their impacts on drug metabolism, therapeutic responses, and resistance development. In conclusion, this review underscores the pivotal contributions of microbial-derived metabolites in regulating anti-tumor immunity, immunotherapy responses, and chemotherapy outcomes. By illuminating the intricate interactions between these metabolites and cancer therapy, the article enhances our understanding of cancer biology, paving the way for the development of more effective treatment options in the ongoing battle against cancer.

The emerging roles of liquid-liquid phase separation in tumor immunity.

Recent advancements in tumor immunotherapy, particularly PD-1 targeted therapy, have shown significant promise, marking major progress in tumor treatment approaches. Despite this, the development of resistance to therapy and mechanisms of immune evasion by tumors pose considerable obstacles to the broad application of immunotherapy. This necessitates a deeper exploration of complex immune signaling pathways integral to tumor immunity. This review aims to critically analyze the role of liquid-liquid phase separation (LLPS) within tumor immunity, specifically its impact on immune signaling pathways and its potential to foster the development of novel cancer therapies. LLPS, a biophysical process newly recognized for its ability to spontaneously segregate and organize biomacromolecules into liquid-like condensates through weak multivalent interactions, offers a novel perspective on the formation of signaling clusters and the functionality of immune molecules. The review delves into the micromolecular mechanisms behind the creation of signaling condensates via LLPS and reviews recent progress in adjusting signaling pathways pertinent to tumor immunity, including the T cell receptor (TCR), B cell receptor (BCR), immune checkpoints, and innate immune pathways such as the cGAS-STING pathway, stress granules, and the ADP-heptose-ALPK1 signaling axis. Furthermore, it considers the prospects of utilizing LLPS to generate groundbreaking cancer therapies capable of navigating past current treatment barriers. Through an extensive examination of LLPS's impact on tumor immunity, the review seeks to highlight novel therapeutic strategies and address the challenges and future directions in this rapidly evolving field.

Unveiling the impact of Cancer-IgG on glioma: Insights into biological behavior and macrophage polarization dynamics.

Gliomas are the most common malignant brain tumor in the central nervous system. They are characterized by high invasiveness and heterogeneity. In recent years, cancer-derived immunoglobulin G (Cancer-IgG) has received significant attention from researchers. Cancer-IgG, identified from tumors, can promote tumorigenesis and tumor progression. In this study, we explored the expression patterns of Cancer-IgG using available datasets and validated these patterns in our patient samples. Several loss-of-function and gain-of function assays were performed to investigate the roles of Cancer-IgG. Potential mechanisms underlying these roles were investigated using co-immunoprecipitation and RNA sequencing. Our result demonstrated that Cancer-IgG is expressed in gliomas. Furthermore, the expression of Cancer-IgG is associated with a poor prognosis and malignant molecular characterization. Functional assays confirmed that Cancer-IgG can promote glioma cells proliferation, migration, invasion, and resistant to apoptosis. The cGMP/PKG/VASP pathway is potentially involved in the effects of Cancer-IgG. Evidence from co-culture assay suggest that Cancer-IgG can induce M2 polarization of macrophages. In conclusion, Cancer-IgG can be identified in glioma cells and promotes the development of a malignant biological phenotype in vivo and in vitro. In glioma microenvironment, Cancer-IgG can induce M2 polarization of macrophages.

Antagonistic roles of cGAS/STING signaling in colorectal cancer chemotherapy.

FOLFOX, composed of 5-FU, oxaliplatin and leucovorin, is a first line chemotherapy regimen for colorectal cancer (CRC) treatment. In this study, we show that 5-FU and oxaliplatin induce DNA damage and activate cGAS/STING signaling leading to enhanced expression of interferon (IFN) ß, IFN-stimulated genes and inflammatory cytokines in mouse and human colon cancer cells as well as increased intratumoral CD8+ T cells in mice. Crucially, 5-FU and oxaliplatin increase PD-L1 expression at the mRNA and protein levels, which has been shown to inhibit CD8+ T cell function. Depletion of cGAS, STING, IRF3, or IFNα/ß receptor 1 (IFNAR1) abolishes this increase, indicating that 5-FU/oxaliplatin mediated upregulation of PD-L1 expression is dependent on tumor cell intrinsic cGAS/STING signaling. These results imply opposing roles for FOLFOX during cancer treatment. On one hand, 5-FU and oxaliplatin activate the innate immune response to facilitate anti-tumor immunity, and conversely upregulate PD-L1 expression to evade immune surveillance. Analysis of TCGA colon cancer dataset shows a positive correlation between expression of PD-L1 and components of the cGAS/STING pathway, supporting a role for cGAS/STING signaling in upregulating PD-L1 expression in colon cancer patients. Tumor studies in syngeneic immune competent mice demonstrate that the combination of 5-FU/oxaliplatin and anti-PD-1 significantly reduced tumor growth of colon cancer cells compared to 5-FU/oxaliplatin treatment alone. Taken together, our studies have identified a unique pathway leading to chemoresistance and provide a rationale to combine FOLFOX with anti-PD-1/PD-L1 as an effective CRC treatment.

Multi-omics analysis identifies PTTG1 as a prognostic biomarker associated with immunotherapy and chemotherapy resistance.

BACKGROUND: Pituitary tumor-transforming gene 1 (PTTG1) is an important gene in tumour development. However, the relevance of PTTG1 in tumour prognosis, immunotherapy response, and medication sensitivity in human pan-cancer has to be determined. METHODS: TIMER, GEPIA, the human protein atlas, GEPIA, TISCH2, and cBioportal examined the gene expression, protein expression, prognostic value, and genetic modification landscape of PTTG1 in 33 malignancies based on the TCGA cohort. The association between PTTG1 and tumour immunity, tumour microenvironment, immunotherapy response, and anticancer drug sensitivity was investigated using GSCA, TIDE, and CellMiner CDB. Molecular docking was used to validate the possible chemotherapeutic medicines for PTTG1. Additionally, siRNA-mediated knockdown was employed to confirm the probable role of PTTG1 in paclitaxel-resistant cells. RESULTS: PTTG1 is overexpressed and associated with poor survival in most tumors. Functional enrichment study revealed that PTTG1 is involved in the cell cycle and DNA replication. A substantial connection between PTTG1 expression and immune cell infiltration points to PTTG1's possible role in the tumour microenvironment. High PTTG1 expression is associated with tumour immunotherapy resistance. The process could be connected to PTTG1, which mediates T cell exhaustion and promotes cytotoxic T lymphocyte malfunction. Furthermore, PTTG1 was found to be substantially linked with sensitivity to several anticancer medications. Suppressing PTTG1 with siRNA reduced clone formation and migration, implying that PTTG1 may play a role in paclitaxel resistance. CONCLUSION: PTTG1 shows potential as a cancer diagnostic, prognostic, and chemosensitivity marker. Increased PTTG1 expression is linked to resistance to cancer treatment. The mechanism could be linked to PTTG1's role in promoting cytotoxic T lymphocyte dysfunction and mediating T cell exhaustion. It is feasible to consider PTTG1, which is expressed on Treg and Tprolif cells, as a new therapeutic target for overcoming immunotherapy resistance.

Inhibition of O-GlcNAc transferase activates type I interferon-dependent antitumor immunity by bridging cGAS-STING pathway.

The O-GlcNAc transferase (OGT) is an essential enzyme that mediates protein O-GlcNAcylation, a unique form of posttranslational modification of many nuclear and cytosolic proteins. Recent studies observed increased OGT and O-GlcNAcylation levels in a broad range of human cancer tissues compared to adjacent normal tissues, indicating a universal effect of OGT in promoting tumorigenesis. Here, we show that OGT is essential for tumor growth in immunocompetent mice by repressing the cyclic GMP-AMP synthase (cGAS)-dependent DNA sensing pathway. We found that deletion of OGT (Ogt-/-) caused a marked reduction in tumor growth in both syngeneic mice tumor models and a genetic mice colorectal cancer (CRC) model induced by mutation of the Apc gene (Apcmin). Pharmacological inhibition or genetic deletion of OGT induced a robust genomic instability (GIN), leading to cGAS-dependent production of the type I interferon (IFN-I) and IFN-stimulated genes (ISGs). As a result, deletion of Cgas or Sting from Ogt-/- cancer cells restored tumor growth, and this correlated with impaired CD8+ T-cell-mediated antitumor immunity. Mechanistically, we found that OGT-dependent cleavage of host cell factor C1 (HCF-1) is required for the avoidance of GIN and IFN-I production in tumors. In summary, our results identify OGT-mediated genomic stability and activate cGAS-STING pathway as an important tumor-cell-intrinsic mechanism to repress antitumor immunity.

Inducing disulfidptosis in tumors:potential pathways and significance.

Regulated cell death (RCD) is crucial for the elimination of abnormal cells. In recent years, strategies aimed at inducing RCD, particularly apoptosis, have become increasingly important in cancer therapy. However, the ability of tumor cells to evade apoptosis has led to treatment resistance and relapse, prompting extensive research into alternative death processes in cancer cells. A recent study identified a novel form of RCD known as disulfidptosis, which is linked to disulfide stress. Cancer cells import cystine from the extracellular environment via solute carrier family 7 member 11 (SLC7A11) and convert it to cysteine using nicotinamide adenine dinucleotide phosphate (NADPH). When NADPH is deficient or its utilization is impaired, cystine accumulates, leading to the formation of disulfide bonds in the actin cytoskeleton, triggering disulfidptosis. Disulfidptosis reveals a metabolic vulnerability in tumors, offering new insights into cancer therapy strategies. This review provides a detailed overview of the mechanisms underlying disulfidptosis, the current research progress, and limitations. It also highlights innovative strategies for inducing disulfidptosis and explores the potential of combining these approaches with traditional cancer therapies, particularly immunotherapy, to expedite clinical translation.

Unraveling Th subsets: insights into their role in immune checkpoint inhibitor therapy.

T helper (Th) cell subsets play pivotal roles in regulating immune responses within the tumor microenvironment, influencing both tumor progression and anti-tumor immunity. Among these subsets, Th1 cells promote cytotoxic responses through the production of IFN-γ, while Th2 cells and regulatory T cells (Tregs) exert immunosuppressive effects that support tumor growth. Th9 and Th17 cells have context-dependent roles, contributing to both pro-inflammatory and regulatory processes in tumor immunity. Tumor antigen-specific T cells within the tumor microenvironment often exhibit a dysfunctional phenotype due to increased expression of inhibitory receptors such as CTLA-4 and PD-1, leading to reduced antitumor activity. Monoclonal antibodies that block these inhibitory signals-collectively known as immune checkpoint inhibitors (ICIs)-can reactivate these T cells, enhancing their ability to target and destroy cancer cells. Recent advancements have highlighted the critical role of T helper subsets in modulating responses to ICIs, with their interactions remaining a focus of ongoing research. Both positive and negative effects of ICIs have been reported in relation to Th cell subsets, with some effects depending on the type of tumor microenvironment. This review summarizes the crucial roles of different T helper cell subsets in tumor immunity and their complex relationship with immune checkpoint inhibitor therapy.

APOBEC family reshapes the immune microenvironment and therapy sensitivity in clear cell renal cell carcinoma.

Emerging evidence suggests that the APOBEC family is implicated in multiple cancers and might be utilized as a new target for cancer detection and treatment. However, the dysregulation and clinical implication of the APOBEC family in clear cell renal cell cancer (ccRCC) remain elusive. TCGA multiomics data facilitated a comprehensive exploration of the APOBEC family across cancers, including ccRCC. Remodeling analysis classified ccRCC patients into two distinct subgroups: APOBEC family pattern cancer subtype 1 (APCS1) and subtype 2 (APCS2). The study investigated differences in clinical parameters, tumor immune microenvironment, therapeutic responsiveness, and genomic mutation landscapes between these subtypes. An APOBEC family-related risk model was developed and validated for predicting ccRCC patient prognosis, demonstrating good sensitivity and specificity. Finally, the overview of APOBEC3B function was investigated in multiple cancers and verified in clinical samples. APCS1 and APCS2 demonstrated considerably distinct clinical features and biological processes in ccRCC. APCS1, an aggressive subtype, has advanced clinical stage and a poor prognosis. APCS1 exhibited an oncogenic and metabolically active phenotype. APCS1 also exhibited a greater tumor mutation load and immunocompromised condition, resulting in immunological dysfunction and immune checkpoint treatment resistance. The genomic copy number variation of APCS1, including arm gain and loss, was much more than that of APCS2, which may help explain the tired immune system. Furthermore, the two subtypes have distinct drug sensitivity patterns in clinical specimens and matching cell lines. Finally, we developed a predictive risk model based on subtype biomarkers that performed well for ccRCC patients and validated the clinical impact of APOBEC3B. Aberrant APOBEC family expression patterns might modify the tumor immune microenvironment by increasing the genome mutation frequency, thus inducing an immune-exhausted phenotype. APOBEC family-based molecular subtypes could strengthen the understanding of ccRCC characterization and guide clinical treatment. Targeting APOBEC3B may be regarded as a new therapeutic target for ccRCC.

Programmed death receptor (PD-)1/PD-ligand (L)1 in urological cancers : the "all-around warrior" in immunotherapy.

Programmed death receptor-1 (PD-1) and its ligand, programmed death ligand-1 (PD-L1) are essential molecules that are key in modulating immune responses. PD-L1 is constitutively expressed on various immune cells, epithelial cells, and cancer cells, where it functions as a co-stimulatory molecule capable of impairing T-cell mediated immune responses. Upon binding to PD-1 on activated T-cells, the PD-1/PD-L1 interaction triggers signaling pathways that can induce T-cell apoptosis or anergy, thereby facilitating the immune escape of tumors. In urological cancers, including bladder cancer (BCa), renal cell carcinoma (RCC), and prostate cancer (PCa), the upregulation of PD-L1 has been demonstrated. It is linked to poor prognosis and enhanced tumor immune evasion. Recent studies have highlighted the significant role of the PD-1/PD-L1 axis in the immune escape mechanisms of urological cancers. The interaction between PD-L1 and PD-1 on T-cells further contributes to immunosuppression by inhibiting T-cell activation and proliferation. Clinical applications of PD-1/PD-L1 checkpoint inhibitors have shown promising efficacy in treating advanced urological cancers, significantly improving patient outcomes. However, resistance to these therapies, either intrinsic or acquired, remains a significant challenge. This review aims to provide a comprehensive overview of the role of the PD-1/PD-L1 signaling pathway in urological cancers. We summarize the regulatory mechanism underlying PD-1 and PD-L1 expression and activity, including genetic, epigenetic, post-transcriptional, and post-translational modifications. Additionally, we discuss current clinical research on PD-1/PD-L1 inhibitors, their therapeutic potential, and the challenges associated with resistance. Understanding these mechanisms is crucial for developing new strategies to overcome therapeutic limitations and enhance the efficacy of cancer immunotherapy.

Single-cell transcriptional atlas of tumor-associated macrophages in breast cancer.

BACKGROUND: The internal heterogeneity of breast cancer, notably the tumor microenvironment (TME) consisting of malignant and non-malignant cells, has been extensively explored in recent years. The cells in this complex cellular ecosystem activate or suppress tumor immunity through phenotypic changes, secretion of metabolites and cell-cell communication networks. Macrophages, as the most abundant immune cells within the TME, are recruited by malignant cells and undergo phenotypic remodeling. Tumor-associated macrophages (TAMs) exhibit a variety of subtypes and functions, playing significant roles in impacting tumor immunity. However, their precise subtype delineation and specific function remain inadequately defined. METHODS: The publicly available single-cell transcriptomes of 49,141 cells from eight breast cancer patients with different molecular subtypes and stages were incorporated into our study. Unsupervised clustering and manual cell annotation were employed to accurately classify TAM subtypes. We then conducted functional analysis and constructed a developmental trajectory for TAM subtypes. Subsequently, the roles of TAM subtypes in cell-cell communication networks within the TME were explored using endothelial cells (ECs) and T cells as key nodes. Finally, analyses were repeated in another independent publish scRNA datasets to validate our findings for TAM characterization. RESULTS: TAMs are accurately classified into 7 subtypes, displaying anti-tumor or pro-tumor roles. For the first time, we identified a new TAM subtype capable of proliferation and expansion in breast cancer-TUBA1B+ TAMs playing a crucial role in TAMs diversity and tumor progression. The developmental trajectory illustrates how TAMs are remodeled within the TME and undergo phenotypic and functional changes, with TUBA1B+ TAMs at the initial point. Notably, the predominant TAM subtypes varied across different molecular subtypes and stages of breast cancer. Additionally, our research on cell-cell communication networks shows that TAMs exert effects by directly modulating intrinsic immunity, indirectly regulating adaptive immunity through T cells, as well as influencing tumor angiogenesis and lymphangiogenesis through ECs. CONCLUSIONS: Our study establishes a precise single-cell atlas of breast cancer TAMs, shedding light on their multifaceted roles in tumor biology and providing resources for targeting TAMs in breast cancer immunotherapy.

Recombinant humanized type III collagen inhibits ovarian cancer and induces protective anti-tumor immunity by regulating autophagy through GSTP1.

Ovarian cancer (OC) is one of the leading causes of death from malignancy in women and lacks safe and efficient treatment. The novel biomaterial, recombinant humanized collagen type III (rhCOLIII), has been reported to have various biological functions, but its role in OC is unclear. This study aimed to reveal the function and mechanism of action of rhCOLIII in OC. We developed an injectable recombinant human collagen (rhCOL)-derived material with a molecular weight of 45 kDa, with a stable triple helix structure, high biocompatibility, water solubility and biosafety. The anti-tumor activity of rhCOLIII was comprehensively evaluated through in vitro and in vivo experiments. In vitro, our results showed that rhCOLIII inhibited the proliferation, migration, and invasion of ovarian cancer cells (OCCs), and induced apoptosis. In addition, rhCOLIII not only inhibited autophagy of OCCs but also increased the expression of MHC-1 molecule within OCCs. To further elucidate the mechanism of rhCOLIII in OC, we conducted joint analysis of RNA-Seq and proteomics, and found that rhCOLIII exerted anti-tumor function and autophagy inhibition by downregulating Glutathione S-transferase P1 (GSTP1). Furthermore, various rescue experiments were designed to demonstrate that rhCOLIII suppressed autophagy and proliferation of OCCs by mediating GSTP1. In vivo, we found that rhCOLIII could inhibit tumor growth and promote CD8+ T cell infiltration. Our results indicate that rhCOLIII has great anti-tumor potential activity in OC, and induces protective anti-tumor immunity by regulating autophagy through GSTP1. These findings illustrate the potential therapeutic prospects of rhCOLIII for OC treatment.