Search Results (1,074)

Background/Objectives: Immune exclusion in head and neck squamous cell carcinoma (HNSCC) limits immunotherapy efficacy, yet the molecular determinants of stromal-immune organization remain incompletely characterized. The desmosomal cadherin DSG2 is highly expressed in squamous epithelium; its role in shaping the tumor microenvironment (TME) is unknown. Methods: We integrated bulk RNA-seq from 836 HNSCC patients (TCGA-HNSC n = 566, GSE65858 n = 270), single-cell RNA-seq (GSE139324, n = 26 patients, 133,308 cells), spatial transcriptomics (GSE208253, n = 12), proteomics (CPTAC-HNSCC, n = 108), and external validation cohorts (GSE41613, n = 97). CellChat ligand-receptor analysis, mediation analysis, Mendelian randomization (MR), LASSO-penalized Cox regression, HPV-stratified sensitivity analysis, and transcription factor (TF) correlation analysis were employed. Results: DSG2 exhibited epithelial-specific expression and showed consistent positive correlation with CXCL8 (IL-8; TCGA ρ = 0.228, p = 4.4 × 10⁻⁸) and myCAF activation across independent cohorts. Single-cell analysis revealed that 99.5% of CXCL8-producing cells have zero DSG2 expression, establishing the bulk correlation as compositional rather than cell-intrinsic. CellChat identified CXCL8-CXCR2 as the strongest tumor-stroma interaction in DSG2-high regions (probability = 0.821, 1.80-fold enrichment). Mediation analysis demonstrated 43.6% (95% CI [34.3–53.6%]) of DSG2’s tissue-level association with myCAF activation is mediated through CXCL8 (compositional mediation). Multi-instrument MR (IVW: Beta = −0.028, p = 0.028; I² = 0.0%) corroborated the compositional model. Protein-level validation in CPTAC-HNSCC confirmed DSG2-CD8A inverse correlation (Spearman ρ = −0.35, p = 2.2 × 10⁻⁴). Pan-squamous meta-analysis confirmed negative DSG2-cytolytic activity correlations (pooled ρ = −0.213, 95% CI [−0.296, −0.128], I² = 58.6%, 4 cohorts). DSG2 correlated with TIDE score (ρ = 0.176) and TGF-β exclusion subscore (ρ = 0.428). DepMap analysis identified CXCR2 inhibitor collateral sensitivity (ρ = −0.408, p < 0.0001). An eight-gene co-expression module was validated in two independent cohorts (GSE41613: HR = 3.09, p = 0.003; GSE65858: HR = 1.57, p = 0.032). Conclusions: DSG2 marks a stromal-immune organizational state characterized by CXCL8-CXCR2 paracrine signaling, myCAF activation, and immune exclusion, conserved across squamous malignancies. DSG2-high/PD-L1-high tumors (30.4% prevalence) exhibit the worst predicted ICI response and represent a candidate population for biomarker-selected CXCR2 inhibitor trials in combination with anti-PD-1 therapy. Full article

Background: Immune checkpoint inhibitors (ICIs) have transformed the treatment of advanced melanoma, but the comparative cardiac safety of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)-containing regimens versus programmed cell death protein 1 (PD-1)-only regimens in real-world populations remains poorly characterized. We compared cardiac outcomes between melanoma patients exposed to CTLA-4 blockade (ipilimumab) and those treated with anti-PD-1 therapy alone (nivolumab or pembrolizumab) using a large multicenter electronic health record database. Methods: This retrospective cohort study used de-identified data from the TriNetX Research Network (111 US healthcare organizations). Adults with melanoma (ICD-10-CM C43) who received ipilimumab (CTLA-4 exposed) were compared with those who received nivolumab or pembrolizumab without ipilimumab (anti–PD-1 only); both groups were therefore treated with immune checkpoint inhibitors, isolating the effect of CTLA-4 exposure. Propensity score matching (1:1) balanced demographics, cardiovascular comorbidities, and baseline antiarrhythmic use. The primary outcome was a cardiac conduction disorder composite; outcomes were assessed at 1 and 3 years. Results: Of 7313 CTLA-4-exposed and 11,481 anti-PD-1-only patients, 6841 matched pairs were analyzed (all standardized mean differences <0.03). CTLA-4 exposure was associated with a significantly higher incidence of cardiac conduction disorders that was already present at 1 year (3.8% vs. 2.1%; RR 1.82; 95% CI 1.48–2.24; p < 0.001) and persisted at 3 years (5.1% vs. 3.7%; RR 1.36; 95% CI 1.16–1.60; p < 0.001). Atrioventricular block was higher at both 1 year (RR 2.10; 95% CI 1.59–2.78) and 3 years (RR 1.49; 95% CI 1.20–1.85), and complete heart block was markedly increased at 3 years (0.5% vs. 0.2%; RR 3.28; 95% CI 1.67–6.43; p < 0.001). Heart failure was modestly higher with CTLA-4 exposure at both timepoints (1-year RR 1.35; 3-year RR 1.17). Conclusions: Among melanoma patients treated with immune checkpoint inhibitors, CTLA-4-containing therapy is associated with a higher burden of cardiac conduction disorders, including a roughly three-fold excess of complete heart block, that is evident within the first year and sustained thereafter. Because the CTLA-4-exposed cohort comprised both ipilimumab monotherapy and nivolumab plus ipilimumab and the subgroup analyses localized the excess risk to the combination regimen, this association reflects CTLA-4-containing (predominantly combination) therapy rather than ipilimumab monotherapy in isolation. These findings support electrocardiographic surveillance beginning during, not only after, treatment for patients receiving CTLA-4-containing immunotherapy. Full article

Immune checkpoint inhibitors (ICIs) have significantly changed the treatment landscape of several gastrointestinal (GI) malignancies, particularly microsatellite instability-high (MSI-H) and mismatch repair-deficient (dMMR) tumors. However, most GI cancers remain resistant to current PD-1/PD-L1-based immunotherapy because of complex and highly suppressive tumor microenvironments characterized by immune stromal exclusion, myeloid-driven immune suppression, defective antigen presentation, and adaptive immune resistance mechanisms. Emerging evidence suggests that alternative inhibitory pathways, including lymphocyte activation gene-3 (LAG-3), T-cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT), T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), and V-domain Ig suppressor of T-cell activation (VISTA), contribute substantially to persistent T-cell dysfunction and resistance to checkpoint blockade. This review summarizes the immune landscape of GI malignancies and discusses the biological mechanisms underlying resistance to current ICIs. We highlight the evolving role of next-generation immune checkpoints, ongoing clinical development of novel inhibitors, and emerging combination strategies involving chemotherapy, anti-angiogenic therapy, radiation, bispecific antibodies, and tumor microenvironment modulation. In addition, we discuss current limitations in biomarker development and the growing role of circulating tumor DNA, spatial immune profiling, and multi-omics approaches in patient selection. Finally, we explore future directions aimed at improving precision immunotherapy and expanding durable responses across GI cancers. Full article

Background: Glioblastoma (GBM) carries a median overall survival below 15 months despite aggressive multimodal therapy. Treatment resistance reflects the interplay of genomic instability, dysregulated DNA damage repair (DDR), and an immunosuppressive tumor microenvironment (TME). The shelterin complex maintains telomere integrity, yet its broader role in coordinating DDR, TME remodeling, and clinical outcomes in GBM remains unclear. Methods: We integrated transcriptomic and clinical data from four public cohorts (TCGA, CGGA1, CGGA2, and REMBRANDT, n = 583) and an institutional cohort (CSUXY, n = 65). A composite shelterin score was computed by ssGSEA and correlated with DDR activity, immune infiltration, and checkpoint expression. Ten machine-learning algorithms generated 101 candidate model configurations; the final shelterin-related signature (SRS) was trained in TCGA and evaluated in external public cohorts and the institutional cohort. EFEMP2, the top-weighted gene in the SRS, was further examined using public transcriptomic datasets, an exploratory anti-PD-1 cohort, immunohistochemistry, and in vitro assays. Results: Higher shelterin scores were associated with enhanced DDR pathway activity, greater immune and stromal infiltration, and elevated checkpoint expression. The SRS achieved moderate discrimination, with a mean C-index of 0.60, and stratified patients into prognostically distinct risk groups across cohorts. EFEMP2 was consistently associated with inferior overall survival. High EFEMP2 correlated with an immunosuppressive TME enriched for MDSCs and exhausted T cells alongside reduced enrichment of several DDR pathways. Silencing EFEMP2 suppressed proliferation, migration, and invasion while inducing DNA double-strand break markers. In the small anti-PD-1 cohort, high EFEMP2 showed non-significant trends toward longer OS and PFS, which should be interpreted as hypothesis-generating. Conclusion: This study provides a biologically interpretable prognostic framework that was externally evaluated across multiple independent cohorts and links shelterin-related biology to GBM outcomes. EFEMP2 may connect genomic stress and immune suppression, but its mechanistic and immunotherapy-predictive roles require further validation. Full article

Background: Metronomic chemotherapy (MCT), understood as continuous, low-dose cytotoxic administration without prolonged drug-free intervals, has become an established strategy in several solid tumors, acting primarily through antiangiogenic, immunomodulatory, and direct cytostatic mechanisms rather than replication-dependent cytotoxicity. Despite an expanding evidence base, including positive randomized trials, validated predictive biomarkers of response remain unavailable. Methods: We searched PubMed/MEDLINE, Embase, and ClinicalTrials.gov (January 2000 to July 2026) for phase II/III randomized trials, prospective cohorts, and selected retrospective analyses of MCT in breast cancer, head and neck squamous cell carcinoma, NSCLC, and mCRC, and extracted biomarker data from embedded translational substudies of eligible trials. Results: In breast cancer, phase III SYSUCC-001 (adjuvant metronomic capecitabine, improved DFS in TNBC) and MECCA (metronomic capecitabine plus aromatase inhibitor in HR+/HER2− disease) provide the strongest evidence, supported by randomized phase II data for the VEX regimen (METEORA-II) and MCT-anti-PD-1 combinations. TEMPO LUNG established metronomic vinorelbine as effective in platinum-unfit NSCLC, while CAIRO3 confirmed metronomic capecitabine–bevacizumab as an effective mCRC maintenance therapy. Most recently, the phase III TMC-I trial extended positive randomized evidence to head and neck cancer. Candidate biomarkers span angiogenic, immune, tumor proliferative, molecular, pharmacodynamic cytokine, on-treatment clinical (adverse-event-based), and gut–microbiome domains, with FOXC1, circulating endothelial cell kinetics, VEGF pathway markers, and regulatory T-cell dynamics among the most promising; however, none has been prospectively validated in a dedicated confirmatory trial. Conclusions: MCT has moved from empirical use to an evidence-based strategy across multiple tumor types, but the lack of validated predictive biomarkers limits informed patient selection. Future trials should incorporate biomarker-driven designs, particularly FOXC1, endothelial cell kinetics, and immune profiling as co-primary objectives. Defining an MCT-sensitive biological phenotype remains the key translational challenge for the field. Full article

Background: Immune checkpoint inhibitors and adoptive T-cell therapies have substantially improved cancer treatment outcomes, but their use is often limited by immune-related toxicities, including cytokine release syndrome. The role of interleukin (IL)-17A in tumor immunity remains controversial, hindering its therapeutic applications in cancer. A concern is that application of IL-17 blocking agents to release cytokine storms caused by tumor immunotherapy reverses anti-tumor immunity. Methods: In this study, we evaluated the effect of IL-17A blockade alone and in combination with anti–PD (programmed cell death)-1 therapy or tumor-specific CD8⁺ T cells in melanoma, colon, and lung tumors, and in UVB-induced skin carcinogenesis. Results: Our results showed that blocking IL-17A inhibited tumor development, and did not impair the efficacy of tumor immunotherapies with checkpoint inhibitors or tumor-specific T cells. Combined treatment with anti-IL-17A and anti-PD-1 antibodies significantly enhanced tumor suppression compared to single-agent therapies in all tested tumor models. Moreover, IL-17A blockade improved the efficacy of adoptive CD8⁺ T-cell therapy. Mechanistic analyses revealed that the combination therapy increased infiltration of activated antigen-specific CD8⁺ T cells in tumors. In none of the tested tumor models did IL-17A blockade negatively affect the efficacy of tumor immunotherapy with checkpoint inhibitors or T-cell therapy. Conclusions: These findings suggest that the combined application of anti-IL-17A blocking agents with current tumor immunotherapy at the same time is a promising strategy to enhance the efficacy and potentially diminish immune-related adverse effects. Full article

Pseudomonas aeruginosa is an important opportunistic pathogen associated with diverse healthcare-associated infections and increasing antimicrobial resistance. This systematic review evaluated antimicrobial treatment regimens, clinical outcomes, and pharmacokinetic/pharmacodynamic (PK/PD) considerations in P. aeruginosa infections. A systematic review was conducted according to PRISMA guidelines. PubMed/MEDLINE and the Cochrane Library were searched for studies published between January 2000 and March 2026. Data on antimicrobial therapies, clinical and microbiological outcomes, and PK/PD parameters were extracted. Study quality was assessed using the NHLBI quality assessment tool. Narrative synthesis was performed for all eligible studies, and a quantitative meta-analysis was conducted for studies with standardized outcome data. Of the 982 records identified, 249 studies met the inclusion criteria, and 34 were included in the quantitative meta-analysis. The evidence base was highly heterogeneous regarding study design, patient populations, infection types, and treatment regimens. Respiratory infections, particularly in cystic fibrosis patients, accounted for most studies. Quantitative synthesis showed no consistent superiority of any antimicrobial regimen (or combination of them), while treatment outcomes were influenced by infection characteristics, antimicrobial resistance patterns, and PK/PD factors. No universally superior antimicrobial regimen was identified for Pseudomonas aeruginosa infections. Some novel and promising treatment options have been identified, such as anti-Pseudomonas aeruginosa LPS monoclonal antibody panobacumab and inhaled Clostridium butyricum delivered via oxygen-driven nebulization. Two novel treatment modalities did not yield a clinically relevant effect, namely, the bispecific monoclonal antibody MEDI3902 (gremubamab) and the IC43 Pseudomonas aeruginosa vaccine. Treatment effectiveness appears to depend on clinical context, antimicrobial susceptibility, and PK/PD considerations, highlighting the need for further standardized research. Full article

Introduction: Cutaneous squamous cell carcinoma (cSCC) is one of the most common skin cancers, with a subset progressing to locally advanced (laSCC) or metastatic (mSCC) stages. The introduction of anti-PD1 immunotherapy has transformed treatment, but real-world data remain limited, particularly in immunosuppressed patients. Methods: This single-centre, retrospective study included 189 patients with advanced cSCC treated between 2012 and 2022. Demographic, clinical, and treatment data were analyzed to assess clinical management and outcomes before and after the introduction of anti-PD1. Results: Among the 189 patients, 72.5% were male, with a median age of 79 years. Overall, 86 patients presented with laSCC and 103 with mSCC. In 100 patients, a preceding primary cSCC was documented, and its complete resection (R0) was associated with significantly better overall survival (OS) after diagnosis of advanced disease (p < 0.001). Immunosuppressed patients, including organ transplant recipients and those with chronic lymphocytic leukemia (CLL), had significantly reduced OS (p = 0.017 and p = 0.0059, respectively). First-line treatment prior to 2018 predominantly involved surgery and radiotherapy. Following the introduction of anti-PD1 therapy, its use increased rapidly in both first- and second-line settings. From 2018 onward, the number of advanced cSCC cases discussed at the multidisciplinary tumorboard increased approximately threefold. Median OS was significantly longer for mSCC patients treated in the post-2018 era (p = 0.025), while the survival disadvantage of CLL patients compared to non-CLL patients widened, suggesting limited benefit from advances in systemic therapy in this subgroup. Best overall response to first-line anti-PD1 correlated significantly with OS, with complete responders achieving a 1-year progression-free survival of 83.3%. Conclusions: The introduction of anti-PD1 has demonstrated improved survival outcomes in advanced cSCC, though significant challenges remain for immunosuppressed patients, particularly those with CLL and solid organ transplant recipients. Future research should focus on optimizing treatment for these high-risk groups, therapeutic sequencing, and the role of perioperative (neoadjuvant and adjuvant) immunotherapy strategies. Full article

Neoadjuvant immunochemotherapy (NICT), mainly anti-PD-1/PD-L1 therapy combined with cytotoxic chemotherapy, significantly improved perioperative outcomes for resectable solid tumors such as lung cancer and breast cancer. But a large number of patients still had residual lesions and eventually relapsed. Residual tumor cells are not simply unremoved cellular debris, but represent a therapy-selected and therapy-amplified subset of a pre-existing heterogeneous and plastic tumor ecosystem. To avoid implying that therapy generates a new form of tumor plasticity de novo, we use the term “plasticity of non-apoptotic residual tumor cells” to describe the plastic behavior of viable malignant cells that survive treatment-induced cytotoxicity rather than entering apoptosis. In this review, we define the plasticity of non-apoptotic residual tumor cells as the capacity of residual malignant cells to preserve, switch, or re-enter phenotypic states such as dormancy, hybrid EMT, stem-like regeneration, and immune evasion under the combined influence of intrinsic tumor heterogeneity, systemic therapy pressure, and microenvironmental protection. Before the NICT-specific discussion, we outline general theoretical frameworks including therapeutic stress response, apoptosis-induced regeneration, genetic and non-genetic heterogeneity, as well as spatial heterogeneity of involved lymph nodes, so as to provide a more robust interpretation of residual lesion biology under NICT. Also, this review proposes that residual disease may be reconceptualized as a treatment-shaped plastic niche, whose biological behavior is jointly shaped by clonal selection, reversible phenotypic transformation, and microenvironmental ecological protection. We summarize several key states of residual tumor cells: persistent-like/resting state, hybrid EMT/invasive plasticity state, stem-like/regenerative state, and immune escape state, and elucidate the underlying epigenetic basis, including DNA methylation, histone modification, chromatin remodeling, and non-coding RNA network reprogramming. Meanwhile, niche factors such as immune stress, CAF/TAM enrichment, fibrotic matrix, hypoxia, and metabolic stress can further stabilize these states and promote the survival of relapse seeds. Based on this, we propose that future postoperative assessments should be upgraded from residual volume to a stratified residual state, and dynamically identified by combining single-cell omics, spatial pathology, and ctDNA/MRD monitoring. Furthermore, treatment strategies should shift from simply shrinking tumors to plasticity-locking therapy, that is, identifying, classifying, and blocking the plasticity escape pathways of residual lesions before they evolve into recurrence. Full article

Background: The highly heterogeneous and dynamically evolving tumor microenvironment leads to the development of drug resistance and recurrence in traditional therapies. Although immunotherapy demonstrates unique advantages, its clinical utility remains constrained by the suboptimal immunogenicity and the limited effect of monotherapy. Herein, a hybrid drug delivery system based on a spatiotemporal hierarchical controlled-release strategy was proposed to achieve dual immunotherapy with immune checkpoint blockade (ICB) and immunogenic cell death (ICD) to promote synergistic anti-tumor therapy. Methods: A liposome–micelle hybrid drug delivery system (RUT-RPP-LP) was constructed using a lipid bilayer composed of dioleoyl phosphatidylethanolamine/hemisuccinyl cholesterol to encapsulate rutin (RUT) and to form an inner cavity-encapsulated resveratrol micelle (RPP). RUT-RPP-LP was characterized, and its pH sensitivity and release behavior were investigated. Subsequently, a colon cancer tumor-bearing mouse model was constructed to evaluate the in vivo targeted anti-tumor effect and biological safety. On this basis, the combined mechanism of ICB and ICD was preliminarily explored. Results: RUT-RPP-LP possessed excellent formulation characteristics, stability, and biocompatibility, achieving graded controlled release of drugs via responding to the TME and lysosomal acidity, respectively. Obviously, RUT-RPP-LP could specifically target the tumor site, induce the occurrence of ICD, and simultaneously block the PD-1/PD-L1 immune checkpoint signaling pathway, thereby enhancing the function of T cells and inducing apoptosis of tumor cells. Conclusions: The RUT-RPP-LP based on the hierarchical controlled-release strategy exerted a spatiotemporally coordinated enhancement of anti-tumor immunity, and may provide a novel combinatorial approach to overcome the low response of immunotherapy in solid tumors. Full article

Objectives: Novel agents such as brentuximab vedotin and anti-PD-1 antibodies, together with PET-adapted intensified strategies, have improved outcomes in advanced-stage classical Hodgkin lymphoma (cHL). However, their applicability remains limited in many middle-income countries because of restricted drug availability, reimbursement barriers, and toxicity concerns. Therefore, real-world data on the effectiveness of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) remains essential. Methods: We conducted a retrospective two-center study including 95 patients with newly diagnosed cHL treated with first-line ABVD. Baseline characteristics, treatment response, progression-free survival (PFS), overall survival (OS), and mortality were compared between early-stage (I–II, n = 33) and advanced-stage (III–IV, n = 62) disease. Results: The median age was 38 years (range, 18–73), and 69.5% were male; 65% had advanced-stage. Complete response rates were high in both early-stage (97%) and advanced-stage (95.2%) patients. Median PFS (21 vs. 23 months; p = 0.994) and OS (23 vs. 25 months; p = 0.848) were similar. Five-year OS was 84.3% for early-stage and 98% for advanced-stage patients (p = 0.292), while five-year PFS was 55.3% and 29.6% (p = 0.526). Mortality rates were comparable. Conclusions: In this real-world cohort, first-line ABVD achieved high response rates and favorable long-term survival in advanced-stage cHL, supporting its continued use as a frontline treatment option, particularly in settings where access to novel therapies may be limited. Full article

Background/Objectives: Interleukin-15 (IL-15) is a promising immunotherapeutic cytokine, but its short half-life limits clinical utility. We developed a stable PEGylated receptor-linker IL-15 agonist (PEG-RLI) to improve pharmacokinetic properties while preserving biological activity and antitumor efficacy. Methods: PEG-RLI was synthesized by site-specific N-terminal conjugation of a 40 kDa methoxy polyethylene glycol (MeOPEG) to RLI. The conjugate was characterized for purity and receptor agonism. Pharmacokinetics were evaluated in mice, and pharmacodynamic effects on NK cells and CD8+ T cell subsets were assessed. Antitumor activity was tested in CT26 tumor-bearing mice alone and in combination with anti-PD-1 therapy. Results: PEGylation preserved RLI agonistic activity and extended its mouse half-life from approximately 3 h to approximately 15 h. PEG-RLI induced robust expansion of NK cells and CD8⁺ T cells, with preferential enrichment of CD8⁺ T cells and CD44^hiCD8⁺ T cells. In CT26 solid tumors, PEG-RLI enhanced the antitumor efficacy of anti-PD-1 treatment. Conclusions: Stable PEGylation improved the pharmacokinetic profile of RLI while maintaining potent immunostimulatory activity. PEG-RLI preferentially expanded CD8⁺ T cells and showed promising efficacy with immune checkpoint blockade, supporting further development as a differentiated IL-15-based immunotherapeutic. Full article

Background: Immune checkpoint blockade (ICB) targeting the PD-1/PD-L1 axis has improved outcomes in non-small cell lung cancer (NSCLC), although reliable biomarkers for predicting benefit are still limited. Methods: In this exploratory study, we conducted a longitudinal analysis of the peripheral T-cell receptor (TCR) β repertoire in 28 patients with unresectable stage IIIb non-small cell lung cancer (NSCLC) who received anti-PD-L1 immunotherapy following chemoradiotherapy. Blood samples were collected at baseline and three months after treatment initiation. Results: At the cohort level, global TCR repertoire features such as diversity and richness did not change significantly over time. However, when looking at individual patients, more specific patterns became evident. Patients could be broadly separated based on changes in clonotype richness, with reductions generally accompanied by lower diversity and decreased convergent TCR frequency. We also observed differences in TRBV gene usage in relation to clinical outcome, with higher TRBV20-1 and lower TRBV28 frequencies tending to associate with improved survival and delayed disease progression. Interestingly, the disappearance of dominant clonotypes from the peripheral blood during treatment was linked to longer progression-free survival (PFS). In addition, patients with higher baseline blood plasma tumor mutational burden (bTMB) showed greater clonotype richness and were more likely to exhibit this clonotype loss. The combination of high bTMB and clonotype disappearance identified a subgroup of patients with particularly favorable outcomes. Conclusions: Overall, these results suggest that early responses to PD-L1 blockade may be reflected less in global TCR repertoire shifts, including clonality and diversity measures, and more in subtle changes in clonotype composition and dynamics, since the frequencies of certain TRBV genes and the disappearance of dominant clonotypes following ICB were associated with clinical outcomes integrating TCR profiling with bTMB and could therefore help refine patient stratification and improve the understanding of immune responses in NSCLC. Nevertheless, due to the small number of recruited patients, our study is exploratory and hypothesis-generating, and further validation in larger patient cohorts is warranted. Full article

Drug resistance remains a significant challenge in the clinical treatment of acute myeloid leukemia (AML). Therefore, there is an urgent need to develop a novel combinatorial therapy strategy, aiming to overcome drug resistance and improve therapeutic outcomes in AML. Herein, we developed a covalent organic framework bispecific nanosystem, namely glucose oxidase-loaded iron porphyrin covalent organic framework coated with bone marrow stromal cell membrane and functionalized with anti-CD3 and anti-PD-L1 antibodies (abbreviated FeC-G@M-C&P). The fabricated FeC-G@M-C&P displayed good cascade catalytic activity. The bone marrow stromal cell membrane endowed the nanosystem with robust targeting ability, which further triggered abundant reactive oxygen species (ROS) production for chemodynamic therapy. Moreover, bone marrow stromal cell membrane component suppressed the migration and adhesion of C1498 cells by interfering with the CXCR4/CXCL12 axis. Meanwhile, anti-CD3 and anti-PD-L1 antibodies improved T cell activation, relieved immune suppression, and jointly enhanced T cell-mediated immune responses against leukemia cells. Experimental results indicated that the FeC-G@M-C&P plus T cells group showed better anti-leukemia effects compared with other groups, which can be attributed to the integration of chemodynamic therapy, CXCR4/CXCL12 axis blockade therapy and immunotherapy. Collectively, the fabricated nanosystem provided a promising approach for the combined treatment of AML. Full article

Background: Overexpression of programmed death-ligand 1 (PD-L1) and programmed cell death protein 1 (PD-1) induces immune evasion by cancer cells. Nivolumab and pembrolizumab (anti-PD-1 antibodies) are used to treat advanced non-small cell lung cancer (NSCLC). However, objective response rates are limited (20–30%), indicating that individual tumor microenvironments may differ according to immune evasion processes. Therefore, the development of biomarkers predictive of responders to immune checkpoint inhibitors is necessary. Activation of the nuclear factor erythroid 2-related factor 2/Kelch-like ECH-associated protein 1 (NRF2/KEAP1) signaling pathway promotes lung cancer cell growth and resistance to chemotherapy, radiotherapy, targeted therapy, and PD-1/PD-L1 inhibition. The present study investigated whether NRF2 expression in NSCLC is associated with clinicopathological factors, the expression levels of intratumoral PD-L1 and CD8, and the efficacy of anti-PD-1 monotherapy. Methods: NRF2, PD-L1, and CD8 expression on tumor cells and tumor-infiltrating lymphocytes were examined by immunohistochemistry in 54 patients with advanced adenocarcinoma (N = 40) and squamous cell carcinoma (N = 14) treated with nivolumab or pembrolizumab. Histological subtypes, tumor stages, and other clinicopathological features were compared with their expression levels. Results: Weak NRF2 staining was significantly correlated with high levels of PD-L1 and CD8+ tumor-infiltrating lymphocytes, and a favorable response to treatment with nivolumab or pembrolizumab in NSCLC. Progression-free survival of patients treated with anti-PD-1 therapy differed according to the different NRF2 levels. Conclusions: NRF2 overexpression in NSCLC is associated with resistance to PD-1 blockade monotherapy. Full article