Background: The tumor-stroma proportion (TSP) was a critical factor influencing clinical outcomes in non-small cell lung cancer (NSCLC). However, the underlying molecular mechanisms driving TSP-associated aggressiveness and its contribution to immune checkpoint blockade (ICB) resistance remained poorly understood. Methods: Using H&E staining data from the TCGA-NSCLC cohort, patients were stratified into TSP-high and low groups. Transcriptomic profiling and single-cell RNA sequencing (scRNA-seq) were employed to identify the TSP signatures. Functional validation was conducted to investigate the role of SEMA3C in cancer-associated fibroblasts (CAFs) and its influence to tumor cells and T cells. Results: TSP-high status independently predicted worse overall survival (OS) and correlated with ICB resistance. Transcriptomic analysis identified seven TSP-related genes enriched in stromal fibroblasts. Among these signatures, SEMA3C emerged as the key TSP biomarker associated with an immunosuppressive tumor microenvironment (TME) and ICB resistance in NSCLC. Functionally, SEMA3C knockdown in CAFs suppressed their migratory capacity and collagen production. Co-culture experiments demonstrated that compared to SEMA3C-knockdown CAFs, control CAFs significantly enhanced tumor cell migration and invasion while suppressing the activation and proliferation of CD8⁺ T cells. Strikingly, in vivo targeting of SEMA3C inhibited tumor growth. Conclusion: TSP served as an independent prognostic biomarker and predictor of ICB resistance in NSCLC. SEMA3C was identified as a crucial mediator within this axis, promoting tumor malignancy and fostering an immunosuppressive TME characterized by stromal remodeling and excluded anti-tumor immunity. This study established TSP as a clinically relevant stratification tool and revealed stromal-immune crosstalk.

BACKGROUND:Neonatal inflammation increases the risk of adult depression, but the mechanisms remain unclear. Under the two-hit hypothesis, early-life inflammation may enhance vulnerability to later-life stress. Whether neonatal inflammation induces depression susceptibility via microglial priming, and the molecular basis of this process, remain unknown. METHODS:Neonatal mice (postnatal day 4) received intraperitoneal injections of lipopolysaccharide (LPS; 10, 50, or 100 μg/kg) or saline. In adulthood, mice were exposed to a subthreshold 2-week chronic unpredictable mild stress (CUMS) paradigm. Depression-like behaviors, microglial priming, molecular alterations, and DNA methylation were assessed. Genetic (Bag3 knockout) and pharmacological (minocycline; S-adenosylmethionine, SAM) interventions were applied. RESULTS:Neonatal exposure to a moderate dose of LPS (50 μg/kg), but not lower or higher doses, selectively increased susceptibility to adult depression-like behaviors and induced microglial priming in the ventral hippocampus (vHPC). Subthreshold CUMS alone failed to induce microglial activation or depressive phenotypes, but robustly activated primed vHPC microglia, triggered neuroinflammation, and precipitated depressive-like behaviors in neonatally LPS-exposed mice; these effects were fully reversed by minocycline. Neonatal moderate LPS induced sustained BAG3 upregulation in the vHPC. Genetic deletion of Bag3 abolished microglial priming and depression susceptibility. At the epigenetic level, neonatal moderate LPS caused persistent hypomethylation of the Bag3 promoter, which was reversed by SAM supplementation. CONCLUSION:Moderate neonatal inflammation establishes a BAG3-dependent microglial primed state in the vHPC via persistent epigenetic remodeling, thereby enhancing vulnerability to adult stress-induced depression. These findings identify BAG3-centered epigenetic-microglial crosstalk as a critical mechanistic hub linking early-life inflammation to later depression susceptibility.

OBJECTIVES:To investigate the expression patterns and prognostic value of lipid metabolism-related genes in breast cancer. METHODS:RNA sequencing data and clinical information were obtained from The Cancer Genome Atlas breast cancer-related gene (TCGA-BRCA) cohort, including 1100 breast cancer tissue samples and 112 normal breast tissue samples. Differentially expressed lipid metabolism-related genes were screened from a predefined set of 2043 genes using Bioconductor in R, with a false discovery rate <0.05 and |log2(fold change)|>2. Breast cancer tissue samples were randomly divided into a training cohort (n=651) and a validation cohort (n=431) at a 6∶4 ratio. Prognostic lipid metabolism-related genes were identified using univariate Cox regression (P<0.01) and further refined via least absolute shrinkage and selection operate (LASSO) regression. A risk score model was constructed using multivariate Cox regression, and patients were stratified into high- and low-risk groups based on the median risk score. The model's performance was evaluated using Kaplan-Meier survival analysis with the log-rank test and time-dependent receiver operator characteristic (ROC) curves. A nomogram integrating age, TNM stage, clinical grade, and risk score was developed and validated using calibration curves and the concordance index. Immune cell infiltration was quantified using an immune scoring algorithm, and weighted gene co-expression network analysis (WGCNA) was applied to identify key modules associated with immune cell infiltration. Finally, to validate the function of the key gene ALDH2, small interfering RNA targeting ALDH2 was transfected into breast cancer cells (MDA-MB-231), and its effects on invasion and migration were assessed using Transwell invasion and wound healing assays. RESULTS:A total of 185 differentially expressed lipid metabolism-related genes were identified. Univariate Cox and LASSO regression analyses identified three genes-ALDH2, CYP21A2, and IL24-which were incorporated into the multivariate Cox model. The prognosis forecasting model based on these genes demonstrated good predictive performance in both cohorts: patients in the high-risk group had significantly shorter overall survival (both P<0.01), and the areas under the ROC curve for predicting 1-, 3-, and 5-year survival rates were all greater than 0.64. Analysis of the tumor microenvironment revealed a dysfunctional state in the high-risk group, characterized by reduced infiltration of several anti-tumor immune cells and downregulation of key immune checkpoint molecules such as PDCD1 and CTLA-4. WGCNA suggested an association between ALDH2 and immune cell infiltration. Functional experiments confirmed that ALDH2 knockdown significantly enhanced the migration and invasion abilities of breast cancer cells. CONCLUSIONS:This study established and validated a prognosis forecasting model for breast cancer based on lipid metabolism-related genes. It revealed that reduced ALDH2 expression is closely associated with poor prognosis and immunosuppression.

Objectives We aimed to investigate the antitumor effects of isoforsythiaside (IFY), a novel natural small compound, on osteosarcoma (OS) and breast cancer (BC), and to explore whether IFY exerts its activity by directly targeting the formin homology 2 domain (FH2) of dishevelled-associated activator of morphogenesis 1 (DAAM1).Methods Public data from The Human Protein Atlas (HPA) were analyzed for DAAM1 expression. Molecular docking (PyMOL) and microscale thermophoresis (MST) were used to confirm the direct binding of IFY to the FH2 domain of DAAM1 in vitro. Cell Counting Kit-8 (CCK8) assay, wound healing assay, Boyden chamber assay, Western blotting and microfilament assembly (immunofluorescence) were assessed in OS and BC cell lines. Antitumor efficacy was further evaluated in a 4T1 mouse breast cancer xenograft model.Results DAAM1 was highly expressed in OS and BC tissues and cells. IFY directly bound the FH2 domain of DAAM1. IFY (10-15 mu mol/L) significantly reduced cell viability, migration, invasion, microfilament assembly, and DAAM1 protein expression levels in OS and BC cell lines. In vivo, IFY (10 mg/kg, i.p., q.2d) markedly suppressed tumor growth in BC-bearing mice.Conclusions IFY is a novel DAAM1 inhibitor that directly targets the FH2 domain and effectively suppresses the viability, motility, and microfilament assembly of OS and BC cells and inhibits tumor growth, suggesting its potential as a promising therapeutic candidate targeting the Wnt/PCP pathway.

IntroductionIntratumoral collagen deposition is a hallmark of solid cancers and plays a critical role in shaping the tumor microenvironment (TME). This study aimed to characterize the clinical and molecular implications of collagen deposition and elucidate its role in modulating TME components and signaling pathways.MethodsIn this research, we analyzed transcriptomic data from public databases and our in-house clinical samples to expore the correlation between collagen deposition and TME features. In addition, the findings were validated through in vitro and in vivo assays.ResultsWe found that high levels of intratumoral collagen deposition were related to poor clinical outcomes and advanced tumor stages in gastric cancer. Collagen deposition showed strong positive correlations with the abundance of vascular endothelial cells and M2-polarized macrophages, suggesting its role in promoting angiogenesis and immunosuppression. In addition, the correlations between collagen deposition and endothelial cells as well as M2-polarized macrophages were also confirmed in lung cancer. Moreover, pathway analysis revealed that collagen activated the MAPK signaling pathway, and in vitro and in vivo functional assays confirmed that collagen-mediated MAPK activation enhanced tumor cell invasion, angiogenesis, and M2 macrophage polarization.ConclusionOur findings demonstrate that intratumoral collagen deposition is a key regulator of the TME in gastric cancer, promoting tumor progression through MAPK signaling pathway activation. These results demonstrate the promise of collagen as both a prognostic indicator and a therapeutic target, offering fresh perspectives on the underlying mechanisms of TME remodeling and tumor progression across various solid tumors.

Purpose:Bladder cancer (BLCA) is one of the most common urogenital malignancies in the world. The stroma of the tumor microenvironment (TME) largely affects the progression of BLCA. However, a stroma-relevant biomarker for predicting BLCA progression is still lacking. Methods:We obtained gene expression profiles and clinical data from the Cancer Genome Atlas (TCGA) datasets via UCSC Xena. The amount of stroma was evaluated using a stromal score and a stroma-tumor ratio (STR). The STR was independently assessed by two pathologists. The stromal score, derived from the R package "ESTIMATE," was used to calculate the relative proportions of the stroma. We performed cell viability, wound healing, and Boyden chamber assays to determine cell behavior and utilized a BLCA in-house cohort to validate the results of our bioinformatics analysis. Results:Patients with a higher stromal content showed a worse prognosis. We found that to the high amount of stroma shaped a more immunosuppressive TME in BLCA. Next, we found that stroma could predict molecular subtypes and different therapy options in BLCA. A high stromal content shaped an immune overdrive TME. Cytological experiments revealed that collagen, the main component of the stroma, elevates BLCA cell viability, migration, and invasion. The results from the BLCA in-house cohort also showed that a high stromal content is associated with a worse prognosis and a higher PDL1 expression. Conclusion:A high stromal content shapes a more immunosuppressive tumor microenvironment and can predict not only the immune phenotypes but also the clinical phenotypes in BLCA. A high stromal content predicts a worse prognosis. STR exhibits great potential as a biomarker for evaluating the immunogenicity of BLCA and its likelihood of responding to immunotherapy.

Solid tumors are characterized by extensive extracellular matrix (ECM) remodeling prominently featuring massive collagen deposition. This dense collagen network does not act as inert scaffolding but actively orchestrates critical aspects of tumor progression and therapy resistance, thereby shaping the fate of cancer cells. Collagen influences cellular behavior through multiple mechanisms, including providing structural rigidity, modulating mechanotransduction signaling pathways, creating physical barriers to immune cell infiltration and drug penetration, and serving as a reservoir for signaling molecules. Here, we discuss recent findings regarding the critical roles of collagen in tumors and potential therapies for armored and cold tumors, a refractory subset demonstrating high collagen deposition and low immune infiltration.

BACKGROUND:The immunosuppressive tumor microenvironment (TME) is a key characteristic of human cancer. Immunotherapy has emerged as a promising treatment strategy to overcome immune escape and has gained widespread use in recent years. In particular, the blockade of PD-1/PD-L1 interaction holds significant importance in oncotherapy. Combining anti-PD-1/PD-L1 with small molecule inhibitors targeting key pathways represents an emerging trend in therapeutic development. METHODS:To validate our findings biologically, we employed qRT-PCR or Western blotting and immunofluorescence staining techniques to assess the expression levels of DIAPH1 and PD-L1 in cells. Additionally, CCK8 and clone formation assays were utilized to evaluate cell proliferation ability, while flow assays were conducted to detect apoptosis in T cells. RESULTS:Knockdown of DIAPH1 restored the tumor-killing capacity of T cells, effectively suppressing tumor immune escape. We observed a highly positive correlation between the expression levels of DIAPH1 and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), which can be competitively inhibited by lovastatin. Through Sybyl analysis followed by confirmation via micro scale thermophoresis, we identified lovastatin as a potential inhibitor targeting DIAPH1. Lovastatin downregulated DIAPH1 expression both in tumor cell lines and xenograft lung cancer tissues within a mouse lung cancer model. Furthermore, we found that lovastatin degraded DIAPH1 through lysosomal degradation pathway. Treatment with lovastatin was strongly associated with improved response rates and prolonged overall survival among patients with lung adenocarcinoma. Finally, overexpression of DIAPH1 reversed the inhibitory effects mediated by lovastatin on tumor development. CONCLUSIONS:Lovastatin downregulates PD-L1 expression by targeting DIAPH1 and restores the tumor-killing ability of T cells to block tumor immune escape. Lovastatin may become a potential drug for cancer patients to enhance immunotherapy response in the clinic.

Extracellular matrix (ECM) stiffness-mediated mechanotransduction is a common signaling scheme in both physiological and pathological contexts; however, its molecular mechanisms remain incompletely understood. Polycystin-1 is a transmembrane protein that is known to participate in mechano-transduction. Here, it is demonstrated that, in response to extracellular collagen and increased ECM stiffness, polycystin-1 interacts with disheveled-associated activator of morphogenesis 1 (Daam1), a cytoskeletal regulator, thereby promoting microfilament remodeling, cellular protrusion formation, and enhanced motility of tumor cells through activating the RhoA signaling axis. Wild-type polycystin-1 is susceptible to proteolytic cleavage at the G protein-coupled receptor proteolysis site. Using atomic force microscopy-based single-molecule force spectroscopy, direct evidence is provided that polycystin-1 variants R3039H and L3048H exhibit reduced cleavage susceptibility in vitro. Notably, R3039H is associated with lymphatic and distant metastasis in breast cancer and augments mechanotransduction by facilitating the nuclear translocation of Yes-associated protein and upregulating the expression of connective tissue growth factor and collagen in tumor cells and cancer-associated fibroblasts, respectively. Collectively, our findings identify polycystin-1 as a mechanosensor of collagen and ECM stiffness that modulates tumor cell migration via the Daam1/RhoA/YAP signaling cascade.

Dishevelled-associated activator of morphogenesis1 (DAAM1) is a member of the evolutionarily conserved Formin family and plays a significant role in the malignant progression of various human cancers. This study aims to explore the clinical and biological significance of DAAM1 in pancreatic cancer. Multiple public datasets and an in-house cohort were utilized to assess the clinical relevance of DAAM1 in pancreatic cancer. The LinkedOmics platform was employed to perform enrichment analysis of DAAM1-associated molecular pathways in pancreatic cancer. Subsequently, a series of in vitro and in vivo experiments were conducted to evaluate the biological roles of DAAM1 in pancreatic cancer cells and its effects on intratumoral T cells. DAAM1 was found to be upregulated in pancreatic cancer tissues, with higher expression levels observed in tumor cells. Additionally, high expression of DAAM1 was associated with poor prognosis. DAAM1 acted as an oncogene in pancreatic cancer, and its inhibition suppressed tumor cell proliferation, migration, and invasion, while promoted apoptosis. Furthermore, DAAM1 was involved in the JAK1/STAT1 signaling pathway and regulated PD-L1 expression in pancreatic cancer cells. The inhibition of DAAM1 also significantly reduced the exhaustion levels of CD8+ T cells. In conclusion, DAAM1 functions as an oncogene and is immunologically implicated in pancreatic cancer, these findings suggest that DAAM1 may serve as a promising therapeutic target for the clinical management of pancreatic cancer.

Background: Imbalances in the intestinal microbiome are closely associated with the occurrence and development of cancer, and can affect tumorigenesis by influencing the inflammatory response, regulating the immune system, producing specific metabolites, and participating in tumor signaling pathways. Methods: This study investigated the relationships among intestinal microbial dynamics, metabolite profiles, and neoadjuvant chemotherapy (NAC) outcomes in patients with breast cancer. Patients were stratified by Miller-Payne (MP) grade into good (MP 4–5) or poor (MP 1–3) responders. Fecal samples from patients (pre- and post-NAC) were analyzed via 16S rRNA sequencing and untargeted metabolic analysis. Results: After neoadjuvant chemotherapy, the species diversity and abundance of the intestinal microbiome significantly decreased, and these trends were not correlated with neoadjuvant chemotherapy efficacy. Fusobacterium abundance remained significantly higher in poor responders than good responders post-NAC, thus suggesting its association with chemoresistance. The Firmicutes/Bacteroidetes ratio was lower in patients with breast cancer than healthy controls, and was correlated with the therapeutic response: this ratio rose post-NAC but remained suboptimal in poor responders. Untargeted metabolomics identified upregulated amino acids (Thr-Thr and histidine) in poor responders and elevated lipids (C17-sphinganine) in good responders. ROC (receiver operating characteristic curve) analysis validated these metabolites (AUC >0.7) as predictive biomarkers. KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis highlighted enrichment in mTOR signaling, endocrine resistance, and estrogen signaling pathways. Conclusions: These findings underscore the intestinal microbiome’s potential as a predictor of NAC efficacy and a therapeutic target. Modulating Fusobacterium or metabolite pathways may enhance chemotherapy response.

In the previous study, patients with tumors based on collagen deposition and immunoreactivity are classified and identified the armored & cold subtype as the most treatment-refractory tumor type. Triple-negative breast cancer (TNBC) is the most lethal tumor type globally, making it critical to overcome the armored and cold tumor microenvironment (TME) for effective treatment of these patients. In this study, the transcriptomic collagen activity and immune profiles of cancer patients treated with immune checkpoint blockade (ICB) are analyzed, and found that intratumoral collagen is associated with an unfavorable immunotherapeutic response and T cell exhaustion. Additionally, collagen is shown to regulate IGF1R expression at both transcriptional and post-translational levels via SOX4 and DDR1, respectively. It is also found that IGF1R promotes tumor cell migration and invasion, as well as T cell exhaustion, with these effects mediated through collagen. Moreover, in vivo inhibition of IGF1R reversed the armored & cold TME, thereby enhancing anti-PD-1 therapy. In conclusion, this study identified IGF1R as a novel therapeutic target for the immuno-collagenic subtype, and combining IGF1R inhibition with anti-PD-1 therapy provides a promising foundation for a novel combination immunotherapy regimen for TNBC.

Background: The tumor stroma has been reported to be associated with worse prognosis in several solid tumors, but its prognostic value in breast cancer (BRCA) is still undefined. Methods: In this research, multiple public and in-house patient cohorts were collected to demonstrate the clinical and immune correlations of tumor-stroma proportion (TSP) in BRCA. In addition, in vitro assays uncovered the oncogenic role of TSP-related collagen in BRCA. Results: High TSP status based on hematoxylin and eosin (HE) staining was associated with positive hormone receptor status, advanced clinical stages, and poor immune checkpoint blockade (ICB) response. In addition, we developed a RNA-sequencing (RNA-seq)-based stromal score based on four critical genes expression (AEBP1, COL6A3, CTSK, and PLAC9). Both TSP status and stromal score were positively associated with increased M2 macrophage abundance in BRCA. Moreover, tumor collagen has been found to be enriched in samples with the high TSP status, and collagen promoted BRCA cells aggressiveness and macrophage M2 polarization. Conclusions: The tumor stroma was found to be notably related to poor ICB response in patients with BRCA as a result of tumor stroma-macrophage interactions. Thus, the TSP status could predict the clinical outcomes of BRCA patients receiving ICB therapy.

BackgroundLung cancer, particularly non-small cell lung cancer (NSCLC), remains a leading cause of cancer-related mortality worldwide. While immune checkpoint blockade (ICB), such as PD-1/PD-L1 inhibitors, have revolutionized treatment for advanced NSCLC, not all tumor patients respond to ICB therapy. Our recent investigations highlight the role of collagens synthesized by cancer-associated fibroblasts (CAFs) in immune evasion. Angiotensin II receptor blocker (ARB) has shown potential in reshaping the tumor microenvironment (TME) by inhibiting collagens, making tumors more susceptible to immunotherapy. This study aims to evaluate the effect of ARB on the efficacy and safety of Camrelizumab, an anti-PD-1 antibody, in combination with chemotherapy for first-line treatment of advanced NSCLC.MethodsThe ARMOR I trial is a prospective, real-world, multicenter, intervention clinical study designed to assess the synergistic effect of ARBs on Camrelizumab plus chemotherapy in patients with advanced NSCLC. Eligible patients include those with stage IV or unresectable locally advanced NSCLC, who have been diagnosed with hypertension and are receiving standard treatment for it. The study will enroll approximately 180 patients over a 12-month recruitment period, with a 12-month follow-up phase. The primary endpoint is the objective response rate (ORR), with secondary endpoints including progression-free survival (PFS), overall survival (OS), and safety.DiscussionThe interplay between collagens, ARB, and cancer is still complex and worth further study. ARMOR I will provide crucial preliminary data on ARB’s role in first-line therapy for advanced NSCLC. The potential application of ARB in other tumor types may also become an important area to explore.

The oncogenesis and development of breast cancer is closely related to abnormal lipid metabolism. We focused on the identification of pivotal lipid metabolism-associated genes (LMAGs) and constructed a prognostic signature (ALDH2, CYP21A2, and IL24) by LASSO and Cox regression. Survival and time-dependent ROC analysis demonstrated the predictive accuracy of our signature in both training and validation cohort. Additionally, patients in high-risk group showed an immunosuppressive phenotype with lower abundance of immune cells and down-regulation of recognized immune checkpoints. Subsequent cellular experiments indicated that the downregulaiton of ALDH2 was correlated with the aggressive behavior of breast cancer cells. These findings offer crucial insights into understanding the interplay between lipid metabolism and breast cancer progression, potentially paving the way for innovative strategies to impede breast cancer metastasis.

Immunosuppression characterizes the tumour microenvironment in HCC, and recent studies have implicated RNA-binding proteins (RBPs) in the development of HCC. Here, we conducted a screen and identified RBM12 as a key protein that increased the expression of PD-L1, thereby driving immune evasion in HCC. Furthermore, RBM12 was found to be significantly upregulated in HCC tissues and was associated with a poor prognosis for HCC patients. Through various molecular assays and high-throughput screening, we determined that RBM12 could directly bind to the JAK1 mRNA via its 4th-RRM (RNA recognition motif) domain and recruit EIF4A2 through its 2nd-RRM domain, enhancing the distribution of ribosomes on JAK1 mRNA, which promotes the translation of JAK1 and the subsequent upregulation of its expression. As a result, the activated JAK1/STAT1 pathway transcriptionally upregulates PD-L1 expression, facilitating immune evasion in HCC. In summary, our findings provide insights into the significant contribution of RBM12 to immune evasion in HCC, highlighting its potential as a therapeutic target in the future. This graphical abstract shows that elevated expression of RBM12 in HCC can augment PD-L1-mediated tumour immune evasion by increasing the efficiency of JAK1 mRNA translation.

Melanoma is the most suitable tumor type for immunotherapy, but not all melanoma patients could respond to immunotherapy. B7 homolog 3 (B7-H3) belongs to the B7 family and is overexpressed in a number of malignant tumors, but the expression pattern of B7-H3 in melanoma has not been well summarized. The expression of B7-H3 was investigated in melanoma and its correlations with features of the tumor microenvironment (TME) by using various public databases, including the Cancer Genome Atlas (TCGA), the GEPIA, and the Human Protein Atlas databases. In addition, the in-house melanoma tissue microarray was applied to validate the results from public databases. Based on the public and in-house cohorts, we found that B7-H3 was overexpressed in melanoma tumor tissues and high B7-H3 expression was related to poor clinical outcome. Moreover, B7-H3 was negatively correlated with levels of tumor-infiltrating lymphocytes (TILs) and positively correlated with collagen infiltration. With clinical translational value, the predictive value of B7-H3 for conventional immunotherapy was detected using the Kaplan-Meier plotter tool, and the results showed that melanoma patients with high B7-H3 expression were insensitive to anti-PD-1 and anti-CTLA-4 immunotherapy. In conclusion, we first investigate the expression of B7-H3 in melanoma and its correlations with the TME features, and indicate B7-H3 as a promising therapeutic target in melanoma patients that are insensitive to conventional immunotherapy.

Background Immune checkpoint blockade (ICB) has made remarkable achievements, but newly identified armored and cold tumors cannot respond to ICB therapy. The high prevalence of concomitant medications has huge impact on immunotherapeutic responses, but the clinical effects on the therapeutic outcome of armored and cold tumors are still unclear.Methods In this research, using large-scale transcriptomics datasets, the expression and potential biological functions of angiotensin II receptor 1 (AGTR1), the target of angiotensin receptor blocker (ARB), were investigated. Next, the roles of ARB in tumor cells and tumor microenvironment cells were defined by a series of in vitro and in vivo assays. In addition, the clinical impacts of ARB on ICB therapy were assessed by multicenter cohorts and meta-analysis.Results AGTR1 was overexpressed in armored and cold tumors and associated with poor response to ICB therapy. ARB, the inhibitor for AGTR1, only suppressed the aggressiveness of tumor cells with high AGTR1 expression, which accounted for a very small proportion. Further analysis revealed that AGTR1 was always highly expressed in cancer-associated fibroblasts (CAFs) and ARB inhibited type I collagen expression in CAFs by suppressing the RhoA-YAP axis. Moreover, ARB could also drastically reverse the phenotype of armored and cold to soft and hot in vivo, leading to a higher response to ICB therapy. In addition, both our in-house cohorts and meta-analysis further supported the idea that ARB can significantly enhance ICB efficacy.Conclusion Overall, we identify AGTR1 as a novel target in armored and cold tumors and demonstrate the improved therapeutic efficacy of ICB in combination with ARB. These findings could provide novel clinical insight into how to treat patients with refractory armored and cold tumors.

BackgroundImmune checkpoint blockade (ICB) has revolutionized the treatment of various cancer types. Despite significant preclinical advancements in understanding mechanisms, identifying the molecular basis and predictive biomarkers for clinical ICB responses remains challenging. Recent evidence, both preclinical and clinical, underscores the pivotal role of the extracellular matrix (ECM) in modulating immune cell infiltration and behaviors. This study aimed to create an innovative classifier that leverages ECM characteristics to enhance the effectiveness of ICB therapy.MethodsWe analyzed transcriptomic collagen activity and immune signatures in 649 patients with cancer undergoing ICB therapy. This analysis led to the identification of three distinct immuno-collagenic subtypes predictive of ICB responses. We validated these subtypes using the transcriptome data from 9,363 cancer patients from The Cancer Genome Atlas (TCGA) dataset and 1,084 in-house samples. Additionally, novel therapeutic targets were identified based on these established immuno-collagenic subtypes.ResultsOur categorization divided tumors into three subtypes: "soft & hot" (low collagen activity and high immune infiltration), "armored & cold" (high collagen activity and low immune infiltration), and "quiescent" (low collagen activity and immune infiltration). Notably, "soft & hot" tumors exhibited the most robust response to ICB therapy across various cancer types. Mechanistically, inhibiting collagen augmented the response to ICB in preclinical models. Furthermore, these subtypes demonstrated associations with immune activity and prognostic predictive potential across multiple cancer types. Additionally, an unbiased approach identified B7 homolog 3 (B7-H3), an available drug target, as strongly expressed in "armored & cold" tumors, relating with poor prognosis.ConclusionThis study introduces histopathology-based universal immuno-collagenic subtypes capable of predicting ICB responses across diverse cancer types. These findings offer insights that could contribute to tailoring personalized immunotherapeutic strategies for patients with cancer.

The human microbiome interacts with the host mainly in the intestinal lumen, where putrefactive bacteria are suggested to promote colorectal cancer (CRC). In contrast, probiotics and their isolated components and secreted substances, display anti-tumor properties due to their ability to modulate gut microbiota composition, promote apoptosis, enhance immunity, resist oxidation and alter metabolism. Probiotics help to form a solid intestinal barrier against damaging agents via altering the gut microbiota and preventing harmful microbes from colonization. Probiotic strains that specifically target essential proteins involved in the process of apoptosis can overcome CRC resistance to apoptosis. They can increase the production of anti-inflammatory cytokines, essential in preventing carcinogenesis, and eliminate cancer cells by activating T cell-mediated immune responses. There is a clear indication that probiotics optimize the antioxidant system, decrease radical generation, and detect and degrade potential carcinogens. In this review, the pathogenic mechanisms of pathogens in CRC and the recent insights into the mechanism of probiotics in CRC prevention and therapy are discussed to provide a reference for the actual application of probiotics in CRC.