Multimodal profiling of different molecular layers from the same single cell enables more comprehensive characterization of cellular heterogeneity compared with conventional single-modality approaches. A key example is co-detection of chromatin accessibility and gene expression that offers the opportunity to investigate cell type-resolved gene regulatory mechanisms. Here we describe a sensitive and robust protocol for in situ sequencing hetero RNA–DNA-hybrid after assay for transposase-accessible chromatin using sequencing (ISSAAC-seq) for the concurrent measurement of chromatin accessibility and gene expression from the same single nucleus. The method begins with dual Tn5 tagging of open chromatin regions and the RNA–cDNA hybrid produced by reverse transcription that take place in bulk nuclei. Then, various single-nucleus isolation strategies, including plate and droplet barcoding-based approaches, can be used based on the experimental purpose of the user. The protocol is highly modular with a flexible throughput ranging from several hundreds to tens of thousands of nuclei. The generated data are of high quality in both modalities. The entire workflow can be finished within 1 or 2 days, and the procedures work on multiple different single-nucleus isolation and barcoding platforms. This protocol describes a flexible workflow for joint profiling of chromatin accessibility and transcriptomes in single nuclei, compatible with either plate or droplet single-cell isolation platforms.

BCL-xL inhibition does not change mitochondrial fusion and fission related proteins.

BACKGROUND:The current treatment of triple-negative breast cancer (TNBC) remains challenging; however, regulating ferroptosis through miRNAs offers new insights for TNBC treatment strategies. METHODS:Bioinformatics methods were used to screen ferroptosis-related differentially expressed genes (FRDEGs) in TNBC, and ferroptosis-related miRNAs were screened by combining gene-miRNA interaction network, miRNA survival analysis, and expression validation in clinical specimens. A nomogram was constructed to evaluate the prognostic impact of miR-301a-3p in TNBC. Cell proliferation and migration capabilities were assessed using the CCK-8 assay, colony formation assay, and wound healing assay, respectively. The intracellular protein expression of GPX4 was measured by Western blot, and fluorescent probes were used to detect intracellular ROS and Fe2+ levels. RESULTS:This study used bioinformatics methods to screen five FRDEGs in TNBC, thereby identifying six core miRNAs that can regulate these genes. Among these, miR-301a-3p expression was significantly upregulated in tumor tissues compared to adjacent normal tissues and was associated with poor patient prognosis. Subsequently, an excellent prediction model was established using miR-301a-3p expression information and patient clinicopathological information. Functional analyses revealed that miR-301a-3p promoted TNBC cell proliferation and migration. In addition, the inhibition of cell proliferation activity by miR-301a-3p inhibitor could be reversed by Ferrostatin-1, and miR-301a-3p inhibitor could inhibit the expression of GPX4 and promote the accumulation of intracellular ROS and Fe2+. The promotion of cell proliferation activity by miR-301a-3p mimic could be reversed by Erastin, and miR-301a-3p mimic could promote the expression of GPX4 and inhibit the accumulation of intracellular ROS and Fe2+. CONCLUSION:In conclusion, this study provides evidence that inhibition of miR-301a-3p expression promotes ferroptosis in TNBC cells and produces a synergistic anti-cancer effect with Erastin, providing a new target for future TNBC ferroptosis treatment strategies.

Background: Ibrutinib, a first-line Bruton's tyrosine kinase (BTK) inhibitor, has revolutionized the treatment of chronic lymphocytic leukemia (CLL). However, the integrated transcriptional and signaling mechanisms linking BTK dysregulation, glycolytic metabolism, and mutation-mediated resistance remain poorly defined in CLL. Methods: Single-cell RNA sequencing (scRNA-seq) derived from the GEO dataset GSE111014 was used to characterize heterogeneous B cell subpopulations and glycolytic features. Clinical CLL PBMC samples and the MEC-1 cell line were used for in vitro functional verification. Molecular docking, molecular dynamics simulation, isothermal titration calorimetry (ITC), and surface plasmon resonance (SPR) assays were performed to evaluate the binding affinity of ibrutinib to wild-type and mutant BTK proteins. Lentiviral-mediated gene knockdown/overexpression, qRT-PCR, WB, ELISA, flow cytometry, and Seahorse glycolytic flux analysis were applied to dissect regulatory signaling axes. A CLL xenograft mouse model was constructed to verify in vivo tumor progression and drug therapeutic effects. Results: Transcription factor SPIB activated BTK transcription to initiate glycolytic reprogramming in CLL cells. Mechanistically, an intracellular BTK-LDHA-lactate-RELA positive feedback loop sustained glycolytic hyperactivation. Extracellularly, MIF secreted by BTKhigh B cells bound to CD74 on BTKlow CD74high B cells, triggering AKT/mTOR/RELA signaling to convert drug-sensitive cells into the resistant BTKhigh CD74high phenotype. Notably, BTK mutations conferred dual pro-resistance phenotypes: the ARG525→GLY (R525G) and LEU408→ARG (L408R) variants not only diminished the binding affinity of ibrutinib for BTK but also potentiated RELA-driven glycolytic reprogramming to reinforce drug resistance in CLL cells. In vivo experiments verified that BTK overexpression and mutations accelerated leukemic cell expansion and tissue infiltration, and BTK-mutant CLL showed marked ibrutinib resistance. Conclusion: This study establishes a novel SPIB-BTK-glycolysis-RELA regulatory network coupled with MIF/CD74 paracrine signaling in CLL. BTK mutations drive ibrutinib resistance through dual mechanisms of drug binding defect and metabolic hyperactivation. The identified signaling axis provides novel therapeutic targets for overcoming acquired ibrutinib resistance in CLL.

Glucocorticoids are potent immune regulators, yet how cortisol controls human CD8 T cell function remains poorly defined. Here, we show that cortisol reshapes the transcriptional landscape of human CD8 T cells through cooperation between the glucocorticoid receptor (GR) and RUNX transcription factors. Integrative RNA sequencing (RNA-seq) and chromatin immunoprecipitation followed by sequencing (ChIP-seq) analyses identified genome-wide cortisol-responsive immunoregulatory genes, and NR3C1 deletion confirmed GR dependency. GR chromatin occupancy was enriched at RUNX motifs rather than canonical glucocorticoid response elements, and co-immunoprecipitation confirmed a ligand-dependent interaction between GR and RUNX3, requiring the N-terminal activation function-1 (AF1) domain of GR and the C-terminal region of RUNX3. Single-cell transcriptomic analyses across multiple solid tumors revealed consistent enrichment of GR-RUNX co-regulated genes in tumor-infiltrating CD8 T cells, predominantly within the predysfunctional state. These findings identify RUNX3 as a critical non-canonical GR partner and uncover a therapeutically actionable mechanism by which endogenous glucocorticoids drive CD8 T cell dysfunction in human cancer.

Pituitary adenomas constitute 10 to 25% of intracranial tumors, rendering them one of the most prevalent types of brain tumors. While the majority of pituitary adenomas are benign, ~35% exhibit invasive behavior. Compared with their non-invasive counterparts, invasive pituitary adenomas are more challenging to manage, highlighting the need to elucidate their underlying pathogenesis. However, the molecular mechanisms driving the invasive behavior of these tumors remain incompletely understood. Thus, the present study employed an integrated proteomic and metabolomic approach to investigate the molecular features associated with tumor invasiveness in pituitary adenomas. The investigation was performed at the First Affiliated Hospital of Xiamen University (Xiamen, China). Fresh-frozen tumor specimens were collected from 16 patients diagnosed with clinically non-functioning pituitary adenomas. These samples were divided into two groups based on invasiveness: Invasive tumors (n=8; Knosp grade ≥2) and non-invasive tumors (n=8; Knosp grade <2). Using data-independent acquisition mass spectrometry (MS) in conjunction with liquid chromatography-MS/MS metabolomics analysis, differentially expressed proteins (DEPs) and differentially expressed metabolites (DEMs) were identified. Comparative analysis identified 614 DEPs, including 286 proteins that were upregulated and 328 that were downregulated in invasive tumors relative to non-invasive tumors. Additionally, 74 DEMs were found, comprising 42 increased and 32 decreased metabolites. Enrichment analysis of pathways revealed notable involvement of the cyclic adenosine monophosphate (cAMP) signaling cascade, pathways related to pathogenic Escherichia coli (E. coli) infection and the synaptic vesicle cycle. Integration of the proteomic and metabolomic data underscored consistent changes within these biological pathways. The present investigation represents a comprehensive effort to combine proteomic and metabolomic approaches to characterize the invasive phenotype of pituitary adenomas. The identification of enriched pathways associated with cAMP signaling, E. coli infection and synaptic vesicle cycling provides new mechanistic understanding and offers potential biomarkers or therapeutic targets for differentiating tumor aggressiveness.

Background:Definitive chemoradiotherapy is the standard treatment for inoperable locally advanced esophageal squamous cell carcinoma (ESCC). However, the prognosis for these patients remains poor. This study aimed to evaluate iparomlimab and tuvonralimab (QL1706), a novel PD-1/CTLA-4 dual inhibitor, combined with definitive chemoradiotherapy in patients with unresectable stage III-IVA ESCC. Methods:This single-arm, open-label phase 2 trial was conducted at a single center in China between August 2022 and September 2023. 39 patients with unresectable stage III-IVA ESCC were included. QL1706 is composed of iparomlimab (anti-PD-1 IgG4) and tuvonralimab (anti-CTLA-4 IgG1) in a fixed 2:1 ratio. Patients received radiotherapy (50.4 Gy/28 in fractions on 5 days per week), concurrent chemotherapy (paclitaxel 135 mg/m2 d1+ cisplatin 25 mg/m2 d1-3, q3w, 2 cycles), and QL1706 (5 mg/kg q3w for up to 1 year [total of 18 cycles]). The primary endpoint was progression-free survival (PFS). This study is registered with ClinicalTrials.gov (NCT05490719). Findings:20 patients (51.3%) completed the full cycles of QL-1706. Reasons for the premature cessation of QL1706 were disease progression (n = 7), COVID-19 infection (n = 2), pneumonia (n = 2), allergic reaction (n = 2), patient refusal (n = 4), rash (n = 1), and esophageal hemorrhage (n = 1). With a median follow-up of 21.1 months, the median progression-free survival (PFS) was 14.8 (95% CI: 11.2-NA) months. The median overall survival (OS) was immature. The 1-year PFS and OS rates were 58.6% (95% CI: 44.9-76.4) and 84.6% (95% CI: 74.0-96.7). The objective response rate and median duration of response were 84.6% (95% CI: 69.5-94.1) and 12.7 months (95% CI: 8.9-NA). Exploratory biomarker analyses identified several potential predictive biomarkers: 1) immunochemistry staining revealed that PD-L1 combined positive score ≥1 correlated with prolonged PFS (HR 0.37, p = 0.036); 2) Whole-exome sequencing detected high tumor mutation burden associated with better PFS (HR 0.24, p = 0.0066), while the mutated group (TNRC18/CAMSAP3/CARMIL2/ZFHX4 gene alterations) correlated with poor PFS (HR 6.40, p = 0.0002) and OS (HR 6.45, p = 0.0020); and 3) Olink plasma proteomics identified baseline levels of TWEAK and FASLG were both positively associated with PFS and OS (p < 0.05 for all). Grade ≥3 adverse events occurred in 89.7% (35/39) of the patients, predominantly lymphopenia (31/39, 79.5%). Interpretation:QL1706 combined with chemoradiotherapy demonstrated potential antitumor activity and manageable toxicity, supporting further investigation. Funding:National Natural Science Foundation of China, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Key Medical Discipline Construction Project, and Tianjin Key Medical Discipline (Specialty) Construction Project.

Aberrant lysine 2-hydroxyisobutyrylation (Khib) is a novel post-translational modification implicated in tumor progression, but its role in intrahepatic cholangiocarcinoma (ICC) remains poorly defined. Here, we identify a specific Khib modification at lysine 97 (K97) of the oncogenic transcription factor ETV4, which is significantly upregulated in ICC and strongly associated with tumor metastasis and poor patient outcomes. Functional assays demonstrate that ETV4 K97-Khib enhances ICC cell proliferation, invasion, and distant metastasis by promoting ferroptosis resistance. Mechanistically, ETV4 K97-Khib represses transcription of the ferroptosis inducer TXNIP and simultaneously facilitates its post-translational degradation through upregulation of the SUMO E3 ligase ZBED1, leading to increased SUMOylation of TXNIP. This dual mechanism reduces TXNIP levels and potently suppresses ferroptosis. KAT2A and HDAC1 were identified as the acyltransferase and deacylase controlling ETV4 Khib dynamics, respectively. Notably, the small-molecule compound thiostrepton significantly inhibits ETV4 K97-Khib, thereby promoting ferroptosis and suppressing ICC cell migration, invasion, and lung metastasis. Together, our study reveals a novel ETV4 Khib-driven mechanism underlying ferroptosis suppression and malignant progression in ICC, and highlights ETV4 Khib as a potential therapeutic target in cholangiocarcinoma.

Synergistic cell death induction by MCL-1 inhibitor, AZD5991 and BCL-xL inhibitor, A1155463, in DM cell lines and PDC.

Pancreatic cancer remains one of the most aggressive malignancies, characterized by early metastatic spread and intrinsic resistance to chemotherapy, which ultimately results in poor treatment outcomes. While the Cell Division Cycle 6 (CDC6) protein has been extensively characterized across multiple cancer types, its functional role in the pathogenesis of pancreatic cancer remains poorly understood. In this study, we performed bioinformatics analysis using RNA-seq data from The Cancer Genome Atlas (TCGA) pancreatic adenocarcinoma cohort, and identified differentially expressed genes through microarray profiling. We conducted a comprehensive functional characterization of CDC6 using CCK-8, colony formation, wound healing, Transwell assays, and flow cytometry, and assessed cellular glycolysis levels based on measurements of ATP production, lactic acid generation, and glucose content. Subcutaneous xenograft mouse models were established to evaluate the impact of CDC6 on tumor growth in vivo, while mechanistic investigations were carried out using co-immunoprecipitation, chromatin immunoprecipitation, dual-luciferase reporter assays, and nucleocytoplasmic fractionation. Our results revealed that CDC6 expression is upregulated in pancreatic cancer, and its elevated expression is significantly correlated with unfavorable patient prognosis. Functional experiments demonstrated that CDC6 promotes the proliferation, migration, and invasion of pancreatic cancer cells. Thrombospondin 1 (THBS1) was identified to be positively correlated with CDC6 expression, and differentially expressed genes were notably enriched in the glucose metabolism pathway. Mechanistically, CDC6 cooperates with E2F1 to facilitate the transcription of THBS1, and the AKT signaling pathway is activated via the CDC6/THBS1 interaction. Overexpression of CDC6 significantly promoted glycolysis and tumor progression in pancreatic cancer, whereas these pro-tumor effects were markedly abrogated by THBS1 knockdown. Collectively, our findings demonstrate that CDC6/THBS1/AKT signaling drives glycolysis and accelerates pancreatic cancer progression, suggesting that the CDC6/THBS1/AKT axis may serve as a promising therapeutic target for pancreatic cancer.

N-acetyltransferase 10 (NAT10) mediated N4-acetylcytidine (ac4C) modification has been implicated in tumor progression; however, the precise role and underlying mechanism of NAT10 in breast cancer progression remain largely undefined. The expression and prognostic significance of NAT10 in breast cancer were evaluated using clinical tissue samples and public databases. Functional assays were performed in vitro and in vivo to assess the effects of NAT10 on tumor growth and immune evasion. Mechanistic studies, including RNA immunoprecipitation (RIP), ac4C RNA immunoprecipitation (acRIP), and co-immunoprecipitation (Co-IP), were conducted to elucidate the interaction between NAT10 and histone deacetylase 4 (HDAC4) and their roles in regulating NF-κB signaling and programmed death-ligand 1 (PD-L1) expression. NAT10 expression was significantly upregulated in breast cancer and correlated with poor patient prognosis. NAT10 mediated ac4C modification enhanced the stability of HDAC4 mRNA, thereby promoting HDAC4 expression. Conversely, HDAC4 stabilized NAT10 protein through post-transcriptional deacetylation, forming a self-reinforcing regulatory loop. Elevated HDAC4 activated the NF-κB signaling pathway, resulting in increased PD-L1 transcription and enhanced immune evasion of breast cancer cells. Inhibition of the NAT10/HDAC4/NF-κB axis markedly reduced PD-L1 expression and restored antitumor immune responses. Our findings identify a self-reinforcing NAT10/HDAC4 signaling circuit that drives breast cancer progression and immune evasion. Targeting NAT10 represents a promising therapeutic strategy to overcome immunosuppression and improve patient outcomes in breast cancer.

Immune checkpoint blockade (ICB) has transformed cancer therapy; however, its efficacy remains limited in immunologically “cold” tumors such as breast cancer. These tumors are typically characterized by low T-cell infiltration and an immunosuppressive tumor microenvironment (TME), which restrict the effectiveness of current immunotherapies. Therefore, strategies that enhance antigen presentation and promote coordinated activation of innate and adaptive immunity are needed to improve therapeutic outcomes. We developed a lipid nanoparticle platform (IC-LNP) for the co-delivery of interleukin-33 (IL-33) messenger RNA (mRNA) and the stimulator of interferon genes (STING) agonist cyclic di-adenosine monophosphate (c-di-AMP). This formulation enabled sustained intratumoral IL-33 expression and was associated with enhanced dendritic cell maturation and antigen cross-presentation, accompanied by activation of nuclear factor kappa B (NF-κB) signaling. In parallel, c-di-AMP activated the STING pathway, induced type I interferon responses, and enhanced cytotoxic T-cell activity. Consistent with these immunostimulatory effects, IC-LNP increased immune cell infiltration, reduced immunosuppressive cell populations, and shifted the tumor microenvironment toward a more immune-active state. In vivo, IC-LNP improved tumor control and potentiated the therapeutic efficacy of programmed death-ligand 1 (PD-L1) blockade, together with enhanced systemic antitumor immune responses. By enabling the coordinated delivery of IL-33 mRNA and a STING agonist, IC-LNP offers a dual-component immunotherapeutic strategy to enhance innate and adaptive antitumor immunity. These findings provide a basis for further development of combination immunotherapy strategies for poorly immunogenic breast cancer, including strategies to improve responses to checkpoint blockade.

Abstract Glioma remains a highly aggressive malignancy with frequent recurrence and resistance to radiotherapy and chemotherapy. BTN3A2 is a multifunctional regulatory protein originally implicated in γδ T-cell–mediated immune responses, yet its tumor-intrinsic role and mechanistic relevance in glioma are poorly defined. Here, BTN3A2 expression and prognostic associations were assessed in TCGA and CGGA cohorts and further validated by immunohistochemistry on tissue microarrays. Functional studies using lentivirus-mediated BTN3A2 knockdown demonstrated that BTN3A2 promotes glioma cell proliferation, migration, and invasion, and its depletion increases TMZ sensitivity in vitro and in vivo. Mechanistically, integrated RNA-seq, CUT&Tag, and promoter luciferase assays identified BTN3A2 as a hypoxia-responsive gene directly transcriptionally activated by HIF-1α. BTN3A2 subsequently enhanced DNA damage repair capacity through activation of the AKT/SP1/RAD51 axis, thereby contributing to TMZ resistance. Collectively, these findings establish BTN3A2 as a hypoxia-driven, cell-intrinsic mediator of glioma progression and chemoresistance, highlighting its potential value as a prognostic biomarker and therapeutic vulnerability.

Triple-negative breast cancer (TNBC) is a highly invasive subtype characterized by high recurrence rates and the absence of specific therapeutic targets, resulting in limited treatment efficacy and immune insensitivity. Nanoparticle-based photothermal therapy holds promise due to its selective tumor heating and minimal invasiveness; however, its effectiveness is constrained by limited biocompatibility and localized heat transfer. To address these challenges, a multifunctional therapy utilizing CaO@C@PTX@TG nanoparticles was developed for TNBC treatment. This platform combines multiple mechanisms, with the CaO@C core enabling photothermal and chemothermal conversion while simultaneously releasing calcium ions. In parallel, paclitaxel (PTX) enhances chemotherapy synergy. The TG modification improves nanoparticle biocompatibility and supports efficient drug release within target cells. Under light activation, the platform induces calcium-overload, generating synergistic effects with photothermal therapy, promoting apoptosis and enhancing the antitumor immune response through immunogenic cell death (ICD). In vivo and in vitro experiments demonstrated that the CaO@C@PTX@TG system effectively inhibited tumor growth and metastasis. This approach integrates thermotherapy, photothermal therapy, chemotherapy, calcium-overload and immune activation, presenting an effective treatment strategy for TNBC.

B-cell translocation gene 3 (BTG3), a tumor suppressor, is reduced in expression in several malignancies, including ovarian cancer, colorectal cancer, and gastric cancer, but its role in oral squamous cell carcinoma (OSCC) is unknown. This study aimed to investigate the expression of BTG3 in OSCC, as well as explore its impact on the biological behavior of OSCC and the potential regulatory mechanisms. BTG3 expression levels in OSCC and normal tissues were examined using the GEO database and the Kaplan-Meier Plotter database was used for survival analysis. Western blotting and quantitative real-time PCR were used to assess BTG3 expression levels in OSCC tissues and neighboring normal tissues, as well as in oral epithelial cells (HOEC) and OSCC cell lines (CAL27 and SCC15). We found the expression level of BTG3 was lower in OSCC tissues than in surrounding normal tissues, with higher expression indicating a better prognosis. In vitro assay demonstrated that overexpression of BTG3 inhibited OSCC cell proliferation, migration, and invasion, resulting in cell cycle arrest at the G1 phase, as well as negatively regulating the PI3K/AKT signaling pathway and inhibiting EMT progression; knockdown had the opposite effect. BTG3 represents a potential therapeutic target in OSCC treatment.

Characterization of DM patient derived cell lines (PDC) and in vitro growth features.

The local cell-extrinsic and cell-intrinsic roles of endogenous interleukin-33 (IL-33) in tumor progression and metastasis have been controversial, which has delayed scrutiny of the systemic application of IL-33 in tumor immunoprevention and immunotherapy. A prominent concern regards its capacity in stabilizing the immunosuppressive phenotype of regulatory T (Treg) cells. Here, we report that systemic IL-33 treatment potently promotes the effects of prophylactic tumor vaccines and inhibits the progression of mouse solid tumors. Mechanistically, systemic IL-33 treatment reshapes the tumor immune microenvironment, including the increase in suppressor of tumorigenicity 2+ (ST2+) Treg cells. Unexpectedly, systemic IL-33 treatment constrains tumor growth in a Treg ST2-dependent manner, although the endogenous IL-33/ST2 axis in Treg cells promotes tumor growth. Indeed, IL-33 reprograms Treg cells toward a cytotoxic and inflammatory phenotype. Lastly, we fail to show that endogenous IL-33 promotes tumor growth. Thus, our findings elucidate a Treg ST2-dependent mechanism of the anti-tumor effect of systemic IL-33 application and support the use of IL-33 for cancer immunoprevention and immunotherapy.

BACKGROUND:Colorectal cancer (CRC) exhibits substantial prognostic heterogeneity, and immune checkpoint inhibitors benefit only approximately 10%-15% of patients with mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) status. Therefore, there is an urgent need for risk stratification tools that are both biologically interpretable and clinically applicable. METHODS:We integrated transcriptomic and clinical data from the TCGA-COAD/READ and GEO-GSE39582 cohorts, comprising 1209 cases, and identified 25 interleukin-related genes (IRGs). Using consensus clustering, we defined two distinct molecular subtypes. In the training cohort, LASSO-Cox regression identified 12 IRGs for constructing a prognostic risk score model, which was subsequently validated in both an independent cohort and the combined dataset. The immune-stromal microenvironment was characterized using CIBERSORT, Single-sample Gene Set Enrichment Analysis (ssGSEA), and the ESTIMATE algorithm. IL20RB expression was assessed via Quantitative PCR (qPCR) and Immunohistochemistry (IHC), and its functional role was evaluated through small interfering RNA (siRNA)-mediated knockdown assays. RESULTS:The risk model achieved AUC values of 0.683, 0.684, and 0.629 for 1-, 3-, and 5-year OS, respectively, in the combined cohort. After adjustment for TNM stage and age, the risk score remained an independent prognostic factor. The high-risk group exhibited an "immune-cold, stroma-rich" phenotype, characterized by enrichment of M2 macrophages and neutrophils. In contrast, the low-risk group displayed an "immune-inflamed" phenotype, with increased infiltration of CD8⁺ T cells and NK cells. IL20RB was significantly overexpressed in CRC tissues and cell lines, and its knockdown suppressed cell proliferation, migration, and invasion. CONCLUSION:A new prognostic model based on IRG was established and validated in CRC, demonstrating its ability to forecast OS and to effectively differentiate between immune-inflamed ("hot") and non-inflamed ("cold") tumor microenvironments. The overexpression and functional relevance of IL20RB suggest its involvement in the immune-cold, stroma-rich phenotype, providing experimental evidence and a foundation for further investigation into IL-related signaling pathways in CRC progression and targeted therapy.

Co-targeting MCL-1 and BCL-xL synergistically increase cell death through the intrinsic mitochondrial apoptotic pathway in PDC.