OTUB1 (OTU deubiquitinase, ubiquitin aldehyde binding 1) is a deubiquitinating enzyme (DUB) that belongs to the OTU (ovarian tumor) superfamily. The aim of this study was to clarify the role of OTUB1 in colorectal cancer (CRC) and to identify the mechanism underlying its function. Two hundred and sixty CRC samples were subjected to association analysis of OTUB1 expression and clinicopathological variables using immunohistochemical (IHC) staining. Overexpression of OTUB1 was achieved in SW480 and DLD-1 cells, and downregulation of OTUB1 was employed in SW620 cells. Then, migration and invasion assays were performed, and markers of the epithelial-mesenchymal transition (EMT) were analyzed. In addition, hepatic metastasis models in mice were used to validate the function of OTUB1 in vivo. OTUB1 was overexpressed in CRC tissues, and the expression level of OTUB1 was associated with metastasis. A high expression level of OTUB1 was also associated with poor survival, and OTUB1 served as an independent prognostic factor in multivariate analysis. OTUB1 also promoted the metastasis of CRC cell lines in vitro and in vivo by regulating EMT. OTUB1 promotes CRC metastasis by facilitating EMT and acts as a potential distant metastasis marker and prognostic factor in CRC. Targeting OTUB1 may be helpful for the treatment of CRC.

Immune checkpoint inhibitors (ICIs) have been widely applicated in clinical therapy in recent years. Skin-related adverse reaction is one of the most common adverse events for ICIs. Stevens-Johnson syndrome (SJS) is one of the serious cutaneous reactions threatening the life. Here, we reported a case of 76-year-old male patient with poorly differentiated metastatic lung adenocarcinoma, after 9 weeks exposure of sintilimab (3 doses) combined with paclitaxel liposome after concurrent chemotherapy/radiotherapy, experienced Stevens-Johnson syndrome involving limbs, trunk, lip and the oral mucosa. Biopsy of the skin tissue showed infiltration of CD4 and CD8 positive T lymphocytes. We also found PD-L1 expression in the glands and the basal layer of the skin. This finding is distinct from the previously reported expression of PD-L1 on the surface of epidermal keratinocytes in patients with SJS due to immunotherapy.

Background: Caspase-8 (Casp8) acts as an initiator in cell apoptosis signaling. However, the role of Casp8 in tuning the tumor immune microenvironment remains controversial due to the complicated crosstalk between immune-tolerogenic apoptotic cell death and immunogenic cell death cascades. Methods: The Cancer Genome Atlas (TCGA) and publicly accessible immune checkpoint blockade (ICB)-treated cohorts were used to investigate the clinical relevance of Casp8. A tumor-bearing mouse model was used to characterize changes in the tumor microenvironment and to explore the efficacy of ICB treatment under Casp8 knockout conditions. Results: By exploring TCGA datasets, we showed that the expression level of Casp8 was associated with an immuno-hot microenvironment across various solid tumor types. Casp8 deficiency leads to decreased CD8⁺ T cell infiltration and resistance to anti-PD-L1 therapy in a mouse model. Mechanistically, Casp8 deficiency or pharmacological disruption results in impaired ecto-calreticulin transition in tumor cells, which in turn hampers antigen presentation in draining lymph nodes. Furthermore, radiotherapy restored sensitivity to anti-PD-L1 treatment via elevated calreticulin surface expression. Conclusions: Our data revealed a causative role of Casp8 in modulating the immunogenicity of tumor cells and responsiveness to ICB immunotherapies and proposed radiotherapy as a salvage approach to overcome Casp8 deficiency-mediated ICB resistance.

Background: Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality worldwide, and accurate survival prediction is essential for individualized treatment planning. Existing prognostic models often rely on single algorithms with limited capacity to capture the complexity inherent in clinical data. This study aimed to develop, validate, and interpret an attention-gated stacking ensemble model for predicting 1-, 3-, 5-year overall survival (OS) in NSCLC patients. Methods: A retrospective cohort of 67,400 NSCLC patients from the Surveillance, Epidemiology, and End Results (SEER) database (2004–2021) was analyzed. A dual-filtering strategy combining Pearson and Spearman correlation analysis identified 11 prognostic features. An attention-gated stacked ensemble model was constructed, consisting of eleven diverse base learners plus a feature attention-gated mechanism, which ultimately generated survival probability estimate of 1, 3, and 5 years. Model performance was assessed using area under the receiver operating characteristic curve (AUC), confusion matrices, calibration curves with Brier scores, and decision curve analysis (DCA). An independent external validation cohort of 623 patients from Xinqiao Hospital (2015–2023) was used to evaluate generalizability. SHapley Additive exPlanations (SHAP) analysis was employed for model explanation. A web-based tool was developed for clinical application. Results: On the internal test set, the attention-gated stacking ensemble model achieved AUC values of 0.799, 0.799, and 0.778 for 1-, 3-, and 5-year OS prediction, respectively, outperforming all eleven individual base learners and a conventional stacking model without the attention gate. On external validation, AUC values reached 0.817, 0.807, and 0.825, with Brier scores of 0.127, 0.107, and 0.095, demonstrating robust cross-population generalizability. SHAP analysis identified metastasis (M) stage, tumor size, and lymph node (N) stage as the three most influential predictors, and the learned attention gate weights exhibited concordant importance rankings. A publicly accessible web-based calculator was deployed to facilitate personalized survival estimation at the point of care. Conclusions: The proposed attention-gate stacking ensemble model provides accurate and explainable survival predictions for NSCLC patients, outperforming conventional single-algorithm and standard stacking approaches. The integration of a feature-wise attention gate mechanism enhances both predictive performance and clinical transparency, supporting its potential utility in personalized oncological decision-making. The deployed web-based clinical decision support tool further bridges the gap between algorithmic development and bedside application.

Background Caspase-8 play as an initiator caspase of cell apoptosis signaling. However, the role of caspase-8 in tunning tumor immune microenvironment remains controversial due to a complicated crosstalk between immuno-tolerogenic apoptotic cell death and immunogenic cell death (ICD) cascades. Methods TCGA and publicly accessible immune checkpoint blockade (ICB)-treated cohort were introduced to investigate the clinical relevance of caspase-8. Tumor-bearing mouse model was used to characterize the change of tumor microenvironment and explore efficacy to ICB treatment in caspase-8 knockout condition. Results We showed that the expression level of Casp8 was associated with an immuno-hot microenvironment across various solid tumor types by exploring TCGA dataset. Casp8 deficiency led to decreased CD8⁺ T cell infiltration and resistance to αPD-L1 therapy in mouse model. Mechanistically, Casp8 deficiency or pharmacological disruption resulted in impaired ecto-calreticulin (ecto-CRT) transition on tumor cells, which in turn hampered antigen presentation in draining lymph node. Furthermore, radiotherapy restore the sensitivity to αPD-L1 treatment via elevated surface expression of CRT. Conclusions Our data revealed a causative role of Casp8 in modulating immunogenicity of tumor cells and responsiveness to immune checkpoint blockade immunotherapies and proposed that radiotherapy as a salvage approach to overcome Casp8 deficiency-mediated ICB resistance.