Abstract Non-apoptotic cell death modalities shape the tumor immune microenvironment and treatment outcomes in hepatobiliary cancers. Ferroptosis could directly kill cancer cells and enhance antitumor immunity and immunotherapy efficacy, but it may also promote immunosuppression in some contexts. Cuproptosis could eliminate tumor cells, activate antitumor immune responses, and sensitize tumors to immunotherapy. Pyroptosis could induce immunogenic cell death, amplify antitumor immunity, and synergize with immune checkpoint inhibitors. Necroptosis may foster an immunologically active microenvironment and has therapeutic potential, although its clinical relevance requires further study. Disulfidptosis was a newly recognized vulnerability that may elicit antitumor immune responses. Simultaneous engagement of multiple cell death pathways may cooperatively reshape the tumor microenvironment and help overcome therapeutic resistance. Combining two or more cell death modalities may therefore kill hepatobiliary cancer cells directly while establishing an antitumor immune microenvironment.
Abstract Objectives This study aimed to evaluate programmed death-ligand 1 (PD-L1) expression and mismatch repair (MMR) protein status in laryngeal squamous cell carcinoma (LSCC) and to investigate their associations with clinicopathological parameters and overall survival. Methods A total of 100 patients diagnosed with LSCC between 2017 and 2024 were retrospectively enrolled in this study. PD-L1 expression was evaluated using both the Tumor Proportion Score (TPS) and Combined Positive Score (CPS) scoring systems. The expression of mismatch repair (MMR) proteins, including MLH1, MSH2, MSH6, and PMS2, was assessed by immunohistochemistry. Associations between biomarker expression and clinicopathological variables were analyzed using univariate and multivariate logistic regression analyses. Overall survival was estimated using the Kaplan–Meier method, and independent prognostic factors were identified using multivariate Cox proportional hazards regression analysis. Results PD-L1 expression assessed by CPS was positive (CPS ≥1) in 64 % of cases, while high PD-L1 expression (CPS ≥20) was observed in 16 % of the entire cohort (16/100), corresponding to 25 % of CPS-positive cases (16/64). Using TPS, 48 % of tumors were PD-L1-positive (TPS ≥1 %). All tumors retained MLH1, MSH2, MSH6, and PMS2 expression, indicating proficient MMR. During follow-up, 40 deaths occurred; median overall survival was 74 months, with an estimated mean of 90.97 months (95 % CI: 75.07–106.87). Presenting symptoms were the only independent factor associated with PD-L1 expression (OR=0.214, 95 % CI: 0.067–0.679; p=0.009) and overall survival (HR=2.898, 95 % CI: 1.203–6.977; p=0.018). PD-L1 expression was not independently associated with survival. Conclusions PD-L1 expression in LSCC shows limited association with clinicopathological features and does not independently predict survival. MMR deficiency appears to be rare in this tumor type. These findings suggest that PD-L1 and MMR status alone are insufficient as standalone biomarkers, supporting the need for integrated molecular and immune profiling approaches.
Abstract Objectives Immune checkpoint inhibitor-related myocarditis (ICI-M) is rare in patients with gastrointestinal (GI) cancers, yet it may be life-threatening. Rapid and cost-effective risk stratification biomarkers remain lacking. This study sought to assess the prognostic utility of six ratio-based biomarkers in this patient group. Methods This retrospective study involved 88 GI cancer patients with clinically diagnosed ICI-M at the Fourth Hospital of Hebei Medical University from June 2021 to June 2026, with a 1-year follow-up period. Patients were stratified by Common Terminology Criteria for Adverse Events (CTCAE) grade (≤2 low-grade, n=59; ≥3 high-grade, n=29). Ratio biomarkers were calculated from complete blood counts and high-density lipoprotein cholesterol (HDL-C). 7-day major adverse cardiovascular events (MACEs) and 1-year all-cause mortality were the primary clinical endpoints. Receiver operating characteristic (ROC) analyses and univariate logistic regression (LR) for 7-day MACEs, and time-dependent ROC analysis, univariate/multivariate Cox regression, and calibration curve analysis for 1-year overall survival (OS) were performed. Restricted cubic spline (RCS) curves and Kaplan–Meier analyses further demonstrated the prognostic performance of ratio biomarkers. Results Pan-Immune-Inflammation Value (PIV) demonstrated prognostic value for 7-day MACEs [AUC=0.786; OR=8.81, 95 % confidence interval (CI):2.24–34.64]. Neutrophil-to-HDL-C ratio (NHR) emerged as the prognostic risk factor for 1-year OS in the univariate (HR=1.26, 95 % CI: 1.14–1.40, p=0.001) and multivariate (HR=1.27, 95 % CI: 1.15–1.41, p<0.001) Cox regression, with an optimal threshold of 5.70 effectively stratifying low- and high-risk patients (log-rank p<0.05). Both PIV and NHR showed significant positive correlations with cardiac biomarkers (cTnI and NT-proBNP: both R>0, both p<0.05) and were higher in the high-grade ICI-M group (both p<0.01). The combination of PIV with cTnI significantly improved the prediction of 7-day MACEs compared with cTnI alone (p=0.0307), while the combination of NHR with cTnI improved the prediction of 1-year OS at 90 days compared with cTnI alone (p=0.037). Conclusions PIV discriminated 7-day MACEs, whereas NHR served as a stratifier for 1-year OS in GI cancer patients with ICI-M. These easily obtainable ratio biomarkers may support risk-adapted monitoring, though external validation in larger cohorts is still needed.
Abstract Colorectal cancer (CRC) remains a major global health burden, with marked interindividual variability in disease progression and therapeutic response. Emerging evidence suggests that the gut microbiota shapes CRC biology not only through inflammation and metabolism, but also by regulating programmed cell death (PCD) pathways that may influence tumor cell fate and treatment sensitivity. This review summarizes recent advances in microbiota-mediated regulation of major PCD modalities relevant to CRC, including apoptosis, pyroptosis, ferroptosis, autophagy, and emerging forms of regulated cell death. We discuss how microbial species, microbial metabolites, and microbiota-derived signals influence these processes through immune modulation, metabolic reprogramming, epithelial barrier regulation, and canonical signaling pathways. Importantly, the available evidence is predominantly preclinical, consisting largely of in vitro and animal studies, with limited clinical or correlative data. For several mechanisms, CRC-specific evidence remains incomplete, and relevant insights are partly extrapolated from intestinal inflammatory conditions or non-CRC tumor models. We therefore examine the potential, rather than established, translational implications of microbiota–PCD interactions for biomarker development, therapeutic stratification, and microbiome-targeted interventions. We also review microbiota-based strategies, including probiotics, prebiotics, synbiotics, postbiotics, fecal microbiota transplantation, dietary interventions, and other microbiome-targeted approaches, while highlighting challenges related to causality, patient heterogeneity, safety, standardization, and clinical validation. Overall, the microbiota–PCD axis provides a mechanistic framework for future CRC-specific investigation, but its clinical utility requires validation in well-designed prospective studies and interventional trials.
Abstract Objectives The lymphocyte-to-monocyte ratio (LMR) is an inflammatory biomarker that reflects immune dysregulation associated with the growth and survival of multiple myeloma (MM) cells. This study aimed to determine the prognostic significance of LMR in patients with MM after adjustment for the Revised International Staging System (R-ISS) and the Second R-ISS (R2-ISS). Methods There were 117 patients with newly diagnosed MM that were enrolled in an ambidirectional cohort study. Pre-treatment LMR values were obtained before the initiation of chemotherapy. Patients received chemotherapy and were followed to evaluate overall survival (OS) and progression-free survival (PFS). Receiver operating characteristic curve analysis identified an optimal LMR cutoff value of 3.0 for predicting survival outcomes. Results LMR was inversely associated with creatinine, β 2 M levels, ISS, and R2-ISS stages. An LMR ≤3.0 was associated with a poor response to chemotherapy. Patients with an LMR ≤3.0 had significantly shorter OS and PFS than those with an LMR>3.0 (median OS: 20.0 vs. 28.7 months, p=0.005; median PFS: 18.1 vs. 25.0 months, p=0.035). Multivariable Cox proportional hazards analysis, adjusted for R-ISS or R2-ISS, demonstrated that an LMR ≤3.0 was independently associated with OS but not PFS. Conclusions The LMR appears to be an independent predictor of OS in patients with MM. However, its prognostic value for PFS remains inconclusive.
