Cancer of unknown primary (CUP) encompasses a highly heterogeneous group of cancers with limited therapeutic options and a dismal prognosis. To date, the pathogenesis and immune profiling of CUP have not been fully characterized which could provide more therapeutic targets.Samples of thirteen breast CUPs and five known metastatic breast cancers were subjected to gene expression analysis. The identified cancer stem cell (CSC) phenotype induced by the overexpression of T-cell leukemia/lymphoma-1 A (TCL1A) was validated via cytological experiments.Compared with known metastatic breast cancers, breast CUPs presented various genetic abnormalities mainly involving pluripotency in stem cells and upregulation of immune-related signaling pathways. CUPs also had significantly greater immune cell infiltration and tumor inflammation signature scores, accompanied by a higher trend of PD-L1 expression and tumor-infiltrating lymphocytes. TCL1A, a gene associated with stem cell-like features, was more highly expressed in various types of CUP than in metastases with known primary sites. In triple-negative breast cancer cell lines, overexpression of TCL1A promoted cell proliferation, invasion, and sphere formation and inhibited apoptosis; it also markedly upregulated CSC and epithelial-mesenchymal transition marker expression. Analysis of the downstream signaling pathways affected by TCL1A revealed notable enrichment of the AKT pathway.Breast CUP is characterized by complex genomic alterations and an inflamed immune microenvironment. The significant overexpression of TCL1A and the enrichment of CSC signatures suggest that the TCL1A-AKT axis may serve as a potential therapeutic target, highlighting the CSC phenotype as a critical biological mechanism in the tumorigenesis and progression of CUP.

ABSTRACT Circular RNAs (circRNAs) are ubiquitous in eukaryotes; dysregulated circRNA expression is linked to diseases, including lung cancer. In contrast to canonical circRNAs arising from exon-intron boundaries, noncanonical circRNAs originating within exonic, intronic, and intergenic regions have typically been dismissed as transcriptional noise or technical artifacts. To explore circRNA diversity and appreciate their functions, we developed an algorithm to identify both canonical and noncanonical circRNAs without relying on genome annotation, enabling the identification of circRNAs of all types and in newly sequenced or poorly annotated species. Results from lung cancer cells revealed that noncanonical circRNAs constituted over two-thirds of the circRNA population and were expressed more abundantly than canonical circRNAs, and genes with fewer and shorter exons were hotspots for noncanonical circRNA and circRNA isoform production. Further analyses showed that many noncanonical circRNAs were indeed endogenous circRNAs transcribed within cells rather than experimental artifacts, were potentially translated into proteins or peptides, and were conserved across species. Moreover, we validated 65 noncanonical circRNAs in NCI-H23 cells using multiple bioassays and demonstrated that both exonic and intergenic noncanonical circRNAs influenced cell viability. CircRNA profiles in tumor and tumor-adjacent tissues of lung cancer patients revealed tissue-specific expression and differentially expressed canonical and noncanonical circRNAs from cognate genes involved in cancer-related pathways, indicating their potential clinical relevance. This study confirmed the authenticity of noncanonical circRNAs and provided the first experimental evidence that noncanonical circRNAs influence cancer cell phenotypes. These findings broaden our understanding of circRNA biology, highlighting their widespread genomic distribution, diverse functions, and potential clinical relevance.

Autoimmune and inflammatory diseases are characterized by dysregulated T cell-mediated immune responses leading to tissue damage. Despite therapeutic advancements, patients remain resistant to treatment, highlighting the urgent need for alternative therapeutic strategies. Here, we identified neuritin (NRN), an immunosuppressive molecule, capable of restraining effector CD4+ T cell responses and mitigating autoimmune and inflammatory diseases. NRN is downregulated in CD4+ T cells of rheumatoid arthritis (RA) patients, driving T cell-mediated autoimmune pathology. Nrnfl/flCD4Cre mice exacerbate both experimental autoimmune encephalomyelitis (EAE) and dextran sulfate sodium (DSS)-induced colitis, characterized by regulatory T cell (Treg) depletion and expansion of interferon (IFN)-γ+ and interleukin (IL)-17+ pro-inflammatory cells. Mechanistically, NRN selectively binds to cannabinoid receptor 2 (CB2), but not to CB1, specifically through its threonine residues at positions T78 and T81. Meanwhile, mice lacking CB2 (CB2-/- or CB2fl/flCD4Cre) exhibit worsened colitis, with an increased IFN-γ+ and IL-17+ cells, mirroring the Nrnfl/flCD4Cre phenotype. T cell-specific Nrn knockin (NrnKI/KICD4Cre) or exogenous NRN administration ameliorated disease severity in multiple autoimmune models, including DSS-induced colitis, IMQ-induced psoriasis, and collagen-induced arthritis, by promoting Treg expansion and suppressing IFN-γ+ and IL-17+ pro-inflammatory cells. However, these protective effects of NRN were abolished in CB2-deficient mice. Overall, NRN is an immunosuppressive molecule with therapeutic potential in autoimmune and inflammatory diseases.

Lung squamous cell carcinoma (LUSC) exhibits poor prognosis and a highly complex tumor immune microenvironment (TIME), creating an urgent clinical need for novel biomarkers to guide personalized treatment. Although kinase-related genes (KRGs) play a central role in signal transduction and malignant progression across multiple tumors, large-scale systematic exploration of KRGs’ regulatory functions in LUSC survival prognosis and microenvironmental remodeling remains scarce. This study aims to investigate the impact of KRGs on LUSC development, construct a promising predictive model, and provide theoretical support for personalized treatment strategies. This study integrated transcriptomic and clinical data from the TCGA-LUSC cohort to identify differentially expressed and prognosis-related KRGs. Unsupervised consensus clustering identified kinase-related intrinsic subtypes in LUSC. Subsequently, LASSO-Cox regression analysis was employed to determine key KRGs and construct a risk prediction model, which was validated across two independent GEO external datasets (GSE157010 and GSE73403). Furthermore, this study combined ESTIMATE and CIBERSORT algorithms to assess immune infiltration patterns. Using single-cell RNA sequencing data (GSE127465 and GSE162498), it characterized the expression distribution patterns of key KRGs within the tumor microenvironment. By integrating gene transcriptomics data, it predicted chemotherapy drug sensitivity across different risk subgroups. The study identified 21 differentially expressed KRGs associated with prognosis, which were used to classify LUSC patients into molecular subtypes (C1-C2 and CA-CB) exhibiting significant survival differences and distinct immune landscapes. Four key KRGs (LATS2, CHEK2, TRIB1, and ROS1) were selected via machine learning, enabling the construction of a kinase-associated risk prediction model. Its area under the curve (AUC) for predicting 1-, 3-, and 5-year overall survival in the TCGA-LUSC training cohort was 0.585, 0.637, and 0.605, respectively. This predictive model was further developed and validated in two external cohorts, where the 1-year, 3-year, and 5-year AUC values hovered around 0.60, confirming its moderate and relatively stable predictive performance. Immunological analysis revealed that high-risk features were closely associated with reduced CD8 + T cell infiltration and abnormal enrichment of neutrophils and resting immune cells, collectively shaping a highly immunosuppressive microenvironment. Drug sensitivity analysis further indicated that the high-risk group exhibited stronger intrinsic resistance to multiple traditional first-line chemotherapy drugs but potentially demonstrated high sensitivity to specific agents such as topoisomerase I inhibitors. A risk model comprising four key KRGs can relatively effectively predict survival outcomes in LUSC patients and accurately reflect the highly immunosuppressive and exhausted characteristics of the tumor microenvironment. This study comprehensively and systematically reveals the multidimensional synergistic network of kinase features driving malignant progression in LUSC, providing potential insights and theoretical basis for overcoming conventional chemotherapy resistance and developing personalized drug strategies.

Allergic rhinitis (AR) imposes an escalating health burden on Chinese children, with prevalence surges linked to rapid urbanisation and distinctive environmental exposures. To estimate the pooled prevalence of AR and synthesise observational evidence on factors associated with AR among Chinese children aged 0–18 years. We conducted a comprehensive literature search across Embase, PubMed, Web of Science, Cochrane, Chinese Biomedical Literature Database, China National Knowledge Infrastructure (CNKI), VIP Database for Chinese Technical Periodicals, and Wanfang databases. We selected literature published from January 2014-June 2024, and the types of literature included cohort studies, cross-sectional studies, and case–control studies. Study quality was evaluated using the Newcastle–Ottawa Scale (NOS) and JBI criteria, Meta-analysis was performed using random-effects or fixed-effect models, and heterogeneity, publication bias, and sensitivity were assessed. The search identified 7,403 records, of which 226 underwent full-text assessment; 42 studies involving 1,405,844 participants were included. The pooled prevalence was 16.1

Interpreting genetic risk variants within their relevant cellular contexts remains a central challenge in esophageal squamous cell carcinoma (ESCC), a malignancy with a substantial inherited component. We integrate single-cell RNA sequencing with genotype data to generate a cell-type-resolved expression quantitative trait loci (sc-eQTL) map spanning epithelial, immune, and stromal compartments in ESCC tissues. Most regulatory effects are highly cell-type-specific and largely undetectable in bulk transcriptomic analyses. Integration with ESCC genome-wide association studies reveals significant enrichment of risk variants in defined cellular populations, most prominently within invasive epithelial cells. Cell-type-specific transcriptome-wide association, Mendelian randomization, and colocalization analyses prioritize RPS3A as a susceptibility gene whose genetically regulated expression colocalizes with ESCC risk variants and increases during malignant progression. Fine-mapping identifies cooperative enhancer-promoter variants influencing RPS3A expression, and integrative functional analyses implicate RPS3A in alternative splicing programs. These results establish a cell-type-resolved regulatory framework for interpreting inherited susceptibility in ESCC.

Most colorectal cancers are resistant to immune checkpoint inhibitors due to an immunosuppressive tumor microenvironment. LINC00673, previously classified as a long non-coding RNA, has been implicated in tumor progression, but its role in antitumor immunity remains poorly understood. We used single-cell RNA sequencing, flow cytometry, and functional assays in Linc00673 knockout and wild-type mouse models treated with programmed death 1 (PD-1) blockade to dissect changes in immune landscape and tumor cell behavior. Linc00673 deletion enhanced the efficacy of PD-1 therapy, reducing tumor burden and prolonging survival. KO tumors showed increased infiltration of cytotoxic CD8⁺ T cells, reduced exhaustion, and improved antigen presentation. The tumor microenvironment shifted toward a pro-inflammatory state, with elevated dendritic cell function, reduced immunosuppressive macrophages, and improved T cell–tumor interactions. Linc00673 also promoted tumor cell migration and immune evasion independently of immune cells, suggesting dual tumor-intrinsic and -extrinsic roles. LINC00673 suppresses antitumor immunity and promotes tumor aggressiveness. Its deletion synergizes with PD-1 blockade, revealing a promising therapeutic target to overcome immune resistance in colorectal cancer.

The intricate relationship between the microbiota and cancer has recently emerged as a pivotal area of research, highlighting their critical roles in carcinogenesis, progression, and prognosis. With the increasing recognition of the therapeutic potential of the microbiota in cancer, there is an urgent need to understand the diverse impacts of different microbiota on tumors and explore innovative strategies to harness their benefits. For the first time, this review traces the historical evolution of microbiota–cancer studies, from early observations of microbial presence in cancers to landmark discoveries linking specific microorganisms to carcinogenesis. Furthermore, this study delves into the molecular mechanisms underlying microbiota-mediated cancer progression to elucidate the modulatory roles of oncogenic pathways, immune responses, and tumor metabolism. We also discuss the dual roles of the microbiota in promoting and inhibiting cancer, highlighting its potential as both a facilitator of tumor growth and a target for therapeutic intervention. In addition, this review highlights the mechanism by which the microbiota mediates the response to anticancer immunotherapy, chemotherapy, and radiotherapy. Simultaneously, emerging anticancer strategies targeting microbiota (e.g., probiotics, antibiotics, and fecal microbiota transplantation) have been explored alongside U.S. Food and Drug Administration-approved drugs and ongoing clinical trials. Finally, this review outlines future directions in this field, emphasizing the need for personalized approaches to harness the anticancer potential of the microbiota. The interpretations in this review are expected to establish a stereoscopic, comprehensive framework for advancing research and clinical applications in microbiota-targeted oncology.

BACKGROUND:Adenoid hypertrophy (AH) is a common condition in children that can lead to various complications and significantly affect their growth and development. However, the underlying pathogenesis is not fully understood. This study aims to investigate Th2-M2 polarization in the pathogenesis of AH, focusing on a predominant type 2 inflammatory pattern. METHODS:We recruited control participants without AH and patients with AH combined with allergic rhinitis (AR), and investigated the predominant inflammatory type in AH with concomitant AR by measuring the Th cell sub-populations and the expression of their key transcription factors, and the levels of type 2 inflammatory factors IL-4 and IL-13 in the adenoid tissue. Additionally, the distribution and quantity of M2 macrophages (M2) in the adenoid tissue were detected to determine their involvement in the pathogenesis of type 2 inflammation-predominant AH. Finally, differentially expressed genes were identified through transcriptome RNA sequencing, followed by their functional validation. A co-culture system of CD68+ macrophages and CD4+ T cells was established, with IL-4 and dermatophagoides farinae intervention used to explore the role of Th2-M2 polarization in the pathogenesis of type 2 inflammatory predominant AH. RESULTS:We found that the predominant inflammatory subtypes in AH with concomitant AR were type 2 inflammation and Th17-type inflammation. Further investigation revealed that M2 is involved in the pathogenesis of type 2 inflammation- predominant AH. Transcriptome RNA sequencing identified differentially expressed genes CHI3L2, SOCS1, and STAT6. Functional validation revealed that the Th2-M2 polarization crosstalk promote M2 polarization and may participate in the pathogenesis of AH through the STAT6/SOCS1 pathway. Furthermore, CHI3L2 was found to be highly expressed in the adenoid tissue with a predominant type 2 inflammatory profile. The co-culture of CD68+ macrophages and CD4+ T cells along with IL-4 and dermatophagoides farina intervention further validated the sequencing results. CONCLUSION:The Th2-M2 polarization may be involved in the pathogenesis of type 2 inflammatory predominant AH, possibly through the STAT6/SOCS1 pathway, which promotes the polarization of M2 macrophages, increases cellular proliferation in the adenoid tissue, and drives the disease process. CHI3L2 was highly expressed in type 2 inflammation-predominant AH and may serve as a promising biomarker candidate for this inflammatory subtype. Further studies are required to determine whether CHI3L2 functionally contributes to adenoid hypertrophy or immune-cell proliferation, which could serve as a therapeutic target.

Serum bile acids (BAs) emerge as risk factors for cancer, but their roles in colorectal cancer (CRC) remain unclear. We show that glycocholic acid (GCA), a primary BA, is elevated in the serum of CRC patients. In a mouse CRC model, GCA promotes tumor programmed death-ligand 1 (PD-L1) expression in tumors, suppressing CD8⁺ T cell-mediated antitumor immunity and facilitating tumor growth. Mechanistically, GCA inhibits the BA receptor farnesoid X receptor (FXR), a transcriptional repressor for SRY-box transcription factor 14 (SOX14). Loss of FXR repression upregulates SOX14-mediated expression of zinc finger DHHC-type palmitoyl transferase 9 (DHHC9), thereby reducing PD-L1 palmitoylation and stabilization. Silencing SOX14 or DHHC9, or activating FXR, synergizes with anti-PD-1 therapy, reducing tumor growth in GCA-treated mice. These findings uncover a mechanism that GCA remodels the tumor microenvironment to mediate CRC resistance to immunotherapy, highlighting therapeutic opportunities targeting the FXR-PD-L1 axis in CRC patients with elevated serum GCA.

Epidemiological studies indicate a rising prevalence of allergic diseases, now recognized as a major global public health concern. In children, the progression of these diseases often follows the "atopic march," beginning with eczema, followed by food allergies, allergic rhinitis, and asthma. Recent research has linked gut microbiota dysbiosis to the development of allergic diseases in children. The gut microbiota, a crucial component of human health, plays a vital role in maintaining overall well-being, highlighting its potential in preventing and modifying the course of allergic diseases. This review examines the relationship between childhood allergic diseases and gut microbiota, drawing on the latest evidence. We first elaborated the concepts of allergic diseases and gut microbiota, followed by a discussion of the developmental trajectory of the gut microbiota in healthy children. This review further explored the richness, diversity, and composition of the gut microbiota, as well as specific microbial taxa associated with allergic disease. Lastly, we discussed the current status and future potential of probiotic interventions in managing pediatric allergic diseases.

BACKGROUND:Colorectal cancer (CRC) remains a leading cause of cancer-related mortality, primarily due to its immunosuppressive microenvironment that facilitates immune evasion and resistance to therapy. Although the traditional Chinese medicine Trametes robiniophila Murr (Huaier) has been shown to exert anti-tumor effects, its immunomodulatory potential in CRC and mechanistic interaction with immune checkpoints have not been investigated. RESULTS:Treatment with Huaier significantly improved overall survival in CRC patients (HR=0.682, 95 % CI=0.576-0.809) and reduced tumor burden in both AOM/DSS-induced colitis-associated cancer and subcutaneous models. Notably, Huaier restored intestinal barrier integrity and reprogramed the tumor immune landscape by upregulating the expression of major histocompatibility complex class I (MHC I), which enhanced CD8+ T cell infiltration and cytolytic activity while depleting regulatory T cells. Mechanistically, Huaier activated the STAT1-MHC I pathway, leading to the upregulation of MHC I antigen presentation components, which facilitates the effective recognition of neoantigens by cytotoxic T cells. Crucially, in patient-derived organoids, Huaier synergized with anti-PD-1 therapy, enhancing T cell cytotoxicity. A subcutaneous tumor model was also developed to assess the synergistic effects of Huaier and anti-PD-1, demonstrating that combination therapy exhibited superior efficacy compared to monotherapy. CONCLUSIONS:Our findings establish Huaier as a multifaceted immunoadjuvant that bridges innate and adaptive immunity in CRC. This natural agent offers a translatable strategy to enhance the therapeutic efficacy of existing immunotherapies of CRC patients.

Inflammatory bowel disease (IBD) encompasses two main conditions: Crohn's disease and ulcerative colitis. The role of foodborne pathogens, often transmitted through contaminated food, is a subject of ongoing research regarding their potential involvement in IBD. The most common foodborne pathogens S. typhimurium usually causes intestinal inflammation in the intestines of both humans and cattle, known as enterocolitis. Phage therapy shows promise in treating Salmonella-induced colitis due to its highly specific targeting of bacteria. Here, we demonstrated the efficacy of phage therapy in a murine model of Salmonella-induced colitis. In mice, Salmonella administration exacerbated colitis severity, as evidenced by reduced colon length and elevated production of inflammatory cytokines. Comprehensive metabolomic investigations demonstrated that treatment with a Salmonella-specific novel phage FPSP6 effectively mitigated colitis induced by Salmonella. This therapeutic approach effectively reduced intestinal inflammation, increased CD4+ T-cell levels and decreased cytokine expression, demonstrating its potential efficacy and safety for treating Salmonella-induced colitis. This study, the first to verify the effectiveness and immunomodulatory mechanism of FPSP6, indicates that phage therapy targeting the gut microbiota is a viable alternative to antibiotics, connecting phage therapy, immune regulation, and microbial dynamics in the context of intestinal inflammation caused by foodborne pathogens.

This study aimed to investigate the impact of molecular subtype on the accuracy of intraoperative touch imprint cytology (ITPC) for sentinel lymph node (SLN) evaluation in clinically axillary node-positive (cN +) breast cancer patients treated with neoadjuvant chemotherapy (NAC). We conducted a retrospective cohort study of 232 cN + breast cancer patients undergoing NAC followed by SLN biopsy with ITPC. Diagnostic performance values (sensitivity, specificity, NPV, false-negative rate, etc.) were calculated against final histopathological diagnosis, and stratified by molecular subtypes. ITPC identified 53 positive cases (23 false-negatives) across 917 SLNs, demonstrating 69.74

One of the most abundant cellular components of the normal adjacent tissue surrounding colorectal cancer is colonic epithelial cells (CECs); however, little is known about their interactions with tumor cells. Here we found that peritumoral CECs collaborate with cancer cells to orchestrate a pro-carcinogenic niche. In clinical cohort analyses, we show that growth differentiation factor 15 (GDF15) levels increase in normal adjacent tissue, in particular in CECs, at advanced disease and are inversely correlated with survival. Using mouse models, organoids and in vitro approaches, we link GDF15 upregulation to senescence in peritumoral CECs and identify a CEC-derived GDF15-driven metabolic feedback loop fueling tumor survival. We show that GDF15 secretion upregulates the glycolytic enzyme ENO1 in cancer cells, which triggers extracellular lactate release and subsequent lactylation of H4K8 in CECs, augmenting GDF15 transcription. Our findings establish a mode of intercellular crosstalk mediating collaboration between colorectal cancer cells and peritumoral CECs, providing a potential avenue for targeted intervention in colorectal cancer.

Regulatory T cells (Tregs) and effector T cells play critical roles in tumor immunity, with Tregs suppressing immune responses and contributing to an immunosuppressive tumor microenvironment (TME). Neuritin-1 (Nrn), a neuropeptide, has been identified to enhance Treg expansion. However, its role in T cell biology and tumor development remains unclear. We demonstrated that Nrn is highly expressed in the in-vitro-induced Tregs (iTregs). Functionally, Nrn promoted iTreg differentiation in a dose-dependent manner, while Nrn deletion or anti-Nrn antibody treatment significantly inhibited iTreg differentiation. Additionally, Nrn suppressed IL-2 transcription and secretion in T cells, impairing T cell activation and pro-inflammatory cytokine production. Treg-specific Nrn knockout mice exhibited reduced B16 melanoma tumor growth, decreased Treg infiltration, and increased effector T cell infiltration. Conversely, overexpression of Nrn accelerated B16 melanoma tumor progression by enhancing Treg-mediated suppression. Importantly, we developed the first anti-Nrn antibody, which effectively reduced tumour growth, decreased Treg infiltration, and enhanced effector T-cell activity. Importantly, anti-Nrn synergistically worked with anti-PD1 and improved the anti-PD1 response by reducing Tregs and increasing effector function in tumor-infiltrated T cells, resulting in enhanced tumor regression. Our findings identify Nrn as a critical regulator of Treg differentiation and effector T cell suppression, contributing to tumor progression. Targeting Nrn alone or combined with anti-PD1 therapy represents a promising strategy to enhance anti-tumor immunity.

Keratin 6 A (KRT6A) is a member of the keratin family and can participate in the occurrence and development of some tumors. However, there is still a lack of pan-cancer analysis of KRT6A in humans. We studied the pan-cancer role of KRT6A with the help of a variety of external public databases (mainly including TCGA, GTEx, HPA, TIMER2.0, UALCAN, TISIDB, GEPIA2, Kaplan-Meier Plotter, cBioPortal and TISCH2, etc.). We performed immunohistochemistry detection of KRT6A protein expression in lung adenocarcinoma (LUAD) and its adjacent normal tissues. The results showed that KRT6A mRNA and protein were differentially expressed in most tumors, and its expression and function may be regulated by DNA methylation, RNA methylation and protein phosphorylation, and were related to the prognosis and clinical subtypes of patients with different tumors. KRT6A has multiple genetic and epigenetic characteristics in different cancers, and the main type of its genetic variation is mutation. At the same time, KRT6A is closely related to tumor mutation burden (TMB), microsatellite instability (MSI), tumor stemness score (TSC), immune checkpoints, immunomodulatory genes, and tumor immune microenvironment (TIME) in different human tumors. Secondly, the expression level of KRT6A is associated with immunotherapy and drug sensitivity. In addition, bioinformatics analysis and immunohistochemistry experiments verified that KRT6A mRNA and protein were up-regulated in LUAD, and could promote the development process of LUAD by promoting processes such as epidermis development, intermediate filament cytoskeleton and cornified envelope. This is the first pan-cancer analysis of KRT6A, which provides a comprehensive and systematic understanding of its role in various human tumors, and also reveals that KRT6A is expected to become a potential prognostic biomarker and a new target for cancer immunotherapy.

Glycosylation, a common post-translational modification of proteins, plays a role in numerous biological processes. However, the role of glycosylation in colorectal cancer (CRC) remains incompletely understood. In this study, we identified that CAFs exhibited the highest glycosylation levels in CRC. We classified 6 CAFs subgroups with distinct glycosylation profiles, revealing notable heterogeneity in functional activities, communication pathways, developmental trajectories, and metabolic states. Furthermore, we developed and validated a robust prognostic model capable of predicting CRC patient survival outcomes using 101 machine learning algorithms. The model stratified patients into high-risk and low-risk groups, where genetic and epigenetic alterations, immune infiltration patterns and responses to various therapeutic drugs varied significantly between the groups. In vitro experiments demonstrated that the key gene CCDC85B in the model influences the glycosylation levels of CRC and CD8 + T cell infiltration, underscoring its potential as an essential therapeutic target. These findings underscore the functional complexity within CAFs subgroups and highlight potential therapeutic targets for CRC treatment. These findings deepen our understanding of glycosylation and offer tools for prognosis, drug selection, and targeted therapy in CRC patients.

Background: To optimize precision immunotherapy for advanced NSCLC, comprehensive tumor immune microenvironment (TIME) characterization is crucial for efficacy prediction. Methods: Pretreatment tumor samples from 46 advanced NSCLC patients treated with PD-1/PD-L1 inhibitors were analyzed. The subregional abundance and spatial proximity scores of TIME cell subpopulations in 27 samples were assessed via multiplex immunohistochemistry (mIHC) targeting pan-CK, CD163, CD8, FoxP3, PD-1, and PD-L1. Correlations between the TIME features, clinicopathologic factors, treatment response, and prognosis were evaluated. Results: CD8+FoxP3+ cells were identified in NSCLC tissues, predominantly expressing PD-1/PD-L1. The PD-L1 TPS subgroups showed significant immune cell density/proximity differences, but CD8+FoxP3+PD-1+ infiltration was PD-L1 TPS-independent. Responders had higher CD8+FoxP3+PD-1high density (p = 0.0497) and proximity scores (p = 0.0099) than non-responders. The CD8+FoxP3+PD-1+ presence and tumor proximity were essential for favorable outcomes. In low-PD-L1 TPS patients, the CD8+FoxP3+PD-1+ abundance and proximity scores strongly predicted the response (AUC: 0.79 and 0.75 vs. PD-L1 TPS AUC = 0.58). A survival analysis linked the presence and proximity score of CD8+FoxP3+PD-1+ cells to prolonged overall survival (OS) and progression-free survival (PFS). Notably, a low proximity score of CD8+FoxP3+PD-1+ cells emerged as an independent risk factor for a shorter PFS (HR = 6.16, 95% CI: 2.12–17.93, p = 0.001). Conclusion: The CD8+FoxP3+PD-1+ spatial proximity to tumor cells robustly predicts improved immunotherapy outcomes in advanced NSCLC.

BACKGROUND:Ferroptosis and disulfidptosis are newly discovered forms of regulated cell death that play critical roles in cancer progression, metabolism, and immune evasion. However, their interplay and combined influence on colorectal cancer (CRC) progression remain insufficiently understood. METHODS:We developed a ferroptosis-disulfidptosis-related gene (FDRG) score using machine-learning algorithms to analyze gene modifications associated with these pathways in CRC, utilizing data from the TCGA and GEO databases. The model was externally validated, and associations with clinical outcomes, immune infiltration, mutational landscapes, immunotherapy responses, and drug sensitivity were explored. Key genes were further investigated through bioinformatics and in vitro experiments. RESULTS:We constructed an 8-gene risk model with strong prognostic value, stratifying CRC patients into high- and low-risk groups with significant differences in clinical characteristics, immune cell infiltration, and therapeutic responses. Among these genes, CHMP6 was identified as a previously uncharacterized tumor suppressor in CRC. Beyond its inhibitory effect on tumor cell proliferation, migration, and invasion, CHMP6 was found to play a critical role in modulating anti-tumor immunity. Our findings established CHMP6 as a dual-function tumor suppressor that not only restrains tumor progression but also enhances immune-mediated tumor control. CONCLUSIONS:The FDRG score is a robust tool for predicting CRC prognosis, tumor microenvironment dynamics, and response to immunotherapy. CHMP6 emerged as a promising tumor suppressor and potential therapeutic target, offering new insights into CRC treatment strategies.