A pan-cancer landscape of LILRB4 identifies it as a context-dependent marker of the myeloid and antigen-presentation axis.

Deciphering spatial-temporal mechanisms of PD-1 blockade resistance via biologically informed machine learning.

High frequency of RB1 mutations p16 positive early stage oropharyngeal carcinoma: A genomic and transcriptomic analysis.

SFTPB: A signature gene for lung adenocarcinoma development.

A palmitoylation signature for prognosis immune infiltration and drug sensitivity in esophageal carcinoma.

Objective: To investigate the clinicopathological and molecular genetic characteristics of SMARCB1-deficient sinonasal adenocarcinoma. Methods: A retrospective analysis was performed on 51 cases of poorly differentiated adenocarcinoma, yolk sac tumor, and SMARCB1-deficient carcinoma, diagnosed in the Eye, Ear, Nose and Throat Hospital of Fudan University between January 2016 and December 2024. Four cases of SMARCB1-deficient sinonasal adenocarcinoma were identified. The histological features, immunophenotypes and molecular characteristics were analyzed, and relevant literatures were reviewed. Results: Among the 4 patients, 2 were male and 2 female, with age of 75, 52, 47 and 59 years, respectively. The clinical manifestations included nasal obstruction, epistaxis, and specific symptoms associated with the affected sites. Imaging studies revealed a mass lesion in the nasal cavity and ethmoid sinus, with invasion into surrounding structures. Histologically, the tumor demonstrated glandular, nested, trabecular, and cribriform patterns. The tumor cells displayed moderate to abundant eosinophilic cytoplasm with epithelioid or plasmacytoid features, while a few showed basaloid characteristics. Three cases showed a yolk sac tumor-like differentiation, including case 1 with Schiller-Duval body, case 4 characterized by a cribriform structure, and case 2 consisting of areas of basaloid cells and reticular/microcystic yolk sac tumor-like component. SMARCB1 protein was absent in all cases. SMARCA2 was detected in 3 cases, of which 2 cases (cases 1 and 4) were loss of expression. SMARCA4, ARID1A, and ARID1B proteins were retained. CK7 and CK19 immunoreactivity was variable. CDX2, SALL4 and Glypican-3 were predominantly present in the yolk sac tumor-like region, but not limited to this area. Only case 1 demonstrated focally positive for CK20, whereas S-100 and SOX-10 were negative in all cases. The Ki-67 index was 30% to 50%. Three cases (cases 1, 3 and 4) underwent FISH and next-generation sequencing analyses. Two cases demonstrated SMARCB1 deletion, whereas case 3 was negative. Tumor mutation burden ranged from 0.2 to 3.2 Muts/Mb. Follow-up data were available for 3 cases (excluding case 1), with durations of 29, 20, and 7 months, respectively. Case 2 died, and case 3 and case 4 were alive. Conclusions: SMARCB1-deficient sinonasal adenocarcinoma is a rare tumor, characterized by various degree of glandular differentiation and/or yolk sac tumor-like structures. It should be differentiated from other tumors with similar morphology, particularly intestinal-type and non-intestinal adenocarcinomas as well as yolk sac tumors. To avoid misdiagnosis, SMARCB1 immunohistochemistry should be routinely applied in the diagnosis and differential diagnosis of high-grade sinonasal malignant tumors.

Tumor mutational burden (TMB) is a predictive biomarker for immune checkpoint inhibitors (ICIs). Its clinical utility in head and neck squamous cell carcinoma (HNSCC) is limited by differences in detection approaches and inconsistent cut-off values. In this meta-analysis, we systematically reviewed multiple high-quality studies to assess the predictive value of tissue-based TMB (tTMB) and blood-based TMB (bTMB) for treatment response of ICIs. This study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We systematically searched PubMed, Web of Science, Scopus, and SpringerLink for studies published through January 2026. Eligible studies included HNSCC patients treated with ICIs, with outcomes stratified by TMB status. The primary endpoint was objective response rate (ORR), and the secondary endpoints were overall survival (OS) and progression-free survival (PFS). In addition, subgroup analyses were conducted to further explore between-study differences according to different TMB detection approaches. We included 17 independent high-quality cohorts comprising 1472 patients. High TMB was evaluated using two approaches: tTMB and bTMB, and this two-modality framework was consistently applied to survival outcomes. Overall, high TMB showed prognostic utility across both tissue and blood measurements. Specifically, high TMB was associated with improved ORR (odds ratio [OR] = 2.80; 95% CI, 2.14-3.65; p < 0.001) with negligible heterogeneity (I2 = 0%). Similarly, superior outcomes were observed for OS (hazard ratio [HR] = 0.58; 95% CI, 0.51-0.67; p < 0.001) and PFS (HR = 0.66; 95% CI, 0.57-0.77; p < 0.001). Subgroup analysis of platform-specific patterns revealed distinct cut-off tendencies: tissue-based targeted panels often clustered around a threshold of 10 mut/Mb, whereas blood-based assays required higher cut-offs (≥ 16 mut/Mb) to show predictive signals. TMB shows promise as a predictive biomarker for objective response and survival in HNSCC patients receiving immunotherapy. In our analysis, both tTMB and bTMB were associated with improved objective response, although evidence for bTMB remains limited. Differences between tTMB and bTMB may contribute to variability in commonly used cut-off values, which should be considered when interpreting results across studies and platforms.

Oral squamous cell carcinoma (OSCC) represents a significant global health burden with heterogeneous clinical outcomes. Understanding the molecular and cellular complexity of OSCC is crucial for developing precision therapeutic strategies. We performed comprehensive integrative analysis combining single-cell RNA sequencing (scRNA-seq) and bulk transcriptomics to characterize the cellular landscape of OSCC. Samples from HPV-positive, HPV-negative, recurrent, and non-recurrent cases were analyzed using advanced computational approaches including dimensionality reduction, trajectory inference, cell-cell communication analysis, and spatial transcriptomics. Survival analysis was performed using Kaplan-Meier methods, and pathway enrichment was assessed using GSEA. Immunotherapy response predictors were evaluated based on PD-L1 expression, tumor mutational burden, and immune cell infiltration patterns. Our analysis identified distinct molecular subtypes of OSCC with differential survival outcomes (p < 0.001). Single-cell profiling revealed significant cellular heterogeneity with 6-8 major cell clusters including cancer epithelial cells, cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), T cells, and B cells. Epithelial-mesenchymal transition (EMT) pathway showed significant enrichment (NES = 2.5, pFDR = 0.001) in aggressive tumor subtypes. Trajectory analysis identified branching developmental paths from pre-malignant states through dysplasia to invasive carcinoma and recurrent disease. Cell-cell communication networks revealed extensive interactions between immune cells, fibroblasts, and cancer cells through key ligand-receptor pairs including VEGF-VEGFR2, EGF-EGFR, and Collagen-CD44 (p = 0.00001). Spatial transcriptomics analysis demonstrated distinct tumor microenvironmental niches with specific cellular compositions. Methylation analysis revealed strong negative correlation with gene expression (R = -0.70, p < 0.001), indicating epigenetic regulation. A six-gene prognostic signature effectively stratified patients into high-risk and low-risk groups. Immunotherapy response prediction identified PD-L1 expression (likelihood score 0.75) and tumor mutational burden as key biomarkers. Cell type proportions significantly correlated with recurrence rates (R² = 0.65, p < 0.001). This comprehensive multi-omics analysis provides unprecedented insights into OSCC cellular heterogeneity, tumor microenvironment dynamics, and disease progression mechanisms. Our findings identify novel prognostic biomarkers and therapeutic targets, particularly highlighting the potential of immunotherapy in specific patient subsets. The integrated single-cell and spatial transcriptomics approach offers a framework for precision medicine in oral cancer management.

Immunotherapy advancements in high-grade serous ovarian cancer: From promise to practice.

Thyroid cancer exhibits substantial heterogeneity in its tumor immune microenvironment (TIME), which critically shapes disease progression and therapeutic responsiveness. While most differentiated thyroid cancers (DTCs) remain indolent, a subset evolves into radioiodine-refractory disease or progresses to poorly differentiated (PDTC) and anaplastic thyroid carcinoma (ATC), characterized by aggressive behavior and limited treatment options. Emerging evidence suggests that this transition is accompanied by dynamic immune reprogramming rather than static immune evasion. In this review, we propose a stepwise model of immune evolution in thyroid cancer, spanning from autoimmune-driven inflammation in chronic lymphocytic thyroiditis (CLT) to immune-exhausted states in advanced tumors. We systematically characterize immune cell composition, functional states, and regulatory networks across disease stages, highlighting key shifts in antigen presentation, T-cell functionality, and myeloid cell polarization. Building on this framework, we integrate tumor immune phenotypes (“hot”, “altered”, and “cold”) with actionable biomarkers, including PD-L1 expression, tumor mutational burden, IFN-γ signatures, M2 macrophage-related signature, and tertiary lymphoid structures. We further map these immune contexts to rational therapeutic strategies, encompassing immune checkpoint blockade, combination regimens with tyrosine kinase inhibitors or radiotherapy, and emerging approaches such as innate immune activation and adoptive cell therapies. By linking immune evolution with therapeutic vulnerabilities, this review provides a translationally relevant framework for precision immunotherapy in thyroid cancer and highlights future directions for overcoming resistance in advanced disease.

Ki-67 is routinely used in clinical practice to quantify proliferative activity, yet proliferation has not been incorporated into current molecular classification systems for urothelial carcinoma (UC). This work studies the tumor microenvironment (TME), therapeutic vulnerabilities, and clinical implications of the proliferative ecotype in UC. The authors assembled a multi-cohort data set of 1431 UC patients from four institutional cohorts and five publicly available data sets with comprehensive clinicopathological annotations. Through an integrated multi-omics framework coupled with experimental validation, they assessed how proliferative status shapelineage differentiation, clinical outcomes, treatment response, and TME architecture. High Ki-67 expression identified a proliferative ecotype associated with markedly worse prognosis but enhanced sensitivity to platinum-based chemotherapy and PD-1/PD-L1 blockade. This ecotype displayed elevated tumor purity and tumor mutation burden, with characteristic genomic alterations including enrichment of TP53, ERCC2, and ATM/RB1/FANCC mutations and reduced 9p21.3 loss. The proliferative ecotype orchestrated an immune-enriched TME dominated by CD8+ T cells and B cells. Functional analyses revealed that CD8+ T cells preferentially differentiated toward an exhausted state, and mechanistic interrogation identified a GDF-15-TGFBR2 signaling axis through which epithelial cells modulate CD8+ T-cell dysfunction. This study identifies a proliferative ecotype of UC that is orthogonal to classical luminal/basal ecotypes. Despite its adverse prognosis, this ecotype confers superior responsiveness to chemotherapy and immunotherapy and features a distinct genomic and immune ecosystem. These findings position proliferative status as a clinically actionable axis that may refine molecular classification and guide precision therapy in UC.

Hyalinizing clear cell carcinoma (HCCC) of the lung is an exceedingly rare salivary gland-type neoplasm with limited cytomorphologic description. We report a case highlighting these features. A 3 mm incidental left-airway lesion enlarged to 7 mm over 5 months, prompting radial endobronchial ultrasound (EBUS)-guided transbronchial biopsy. Touch preparations revealed abundant bland tumor cells with small round to oval nuclei, smooth nuclear membranes, and scant slightly dense cytoplasm. Scattered cells showed clear or mucinous cytoplasm. The cells displayed round, columnar, or polygonal shapes and were arranged in nests, sheets, cohesive three-dimensional clusters, and acinar or tubular structures within a homogeneous paucicellular fibrotic stroma. Histology demonstrated tumor cells in trabeculae, nests, and cords with occasional glands and mucinous microcysts set in hyalinized stroma. Most tumors cells had eosinophilic cytoplasm with scattered clear and mucinous cells. Immunohistochemically, tumor cells were positive for p40, DOG1, CK AE1/AE3, CAM5.2, CK5/6, CK7, EMA, and p63, and negative for TTF1; stromal cells were positive for SMA. Mucinous cells were mucicarmine-positive, and the Ki-67 index was very low (~2%). Molecular analysis identified an EWSR1::ATF1 fusion and SUZ12 and WRN mutations. The tumor mutational burden was 5.4 mutations per megabase. Segmentectomy confirmed HCCC with no nodal metastasis (stations 5, 9, 10, 11). Recognition of the cytomorphology, immunohistochemical profile, and characteristic EWSR1::ATF1 or EWSR1::CREM fusions is essential for accurate diagnosis of primary pulmonary HCCC.

Comparison of protein-based and genetic prognostic markers in a large cohort of primary pulmonary and extrapulmonary small cell neuroendocrine carcinoma.

Homologous recombination deficiency (HRD), a genomic instability phenotype resulting from impaired DNA repair, has been associated with increased tumor immunogenicity in several solid tumors. However, its clinical relevance in metastatic gastric cancer (mGC), particularly in the context of immunotherapy-containing regimens, remains unclear. This study included 139 GC patients with nivolumab plus chemotherapy as first line between May 2022 and May 2024 and underwent tissue-based NGS (n = 116); a smaller subset additionally underwent ctDNA-based NGS (n = 24). HRD was defined by the presence of pathogenic or likely pathogenic variants in predefined homologous recombination repair (HRR) genes. Treatment outcomes, and molecular characteristics were compared according to HRD status based on tissue- and/or circulating tumor DNA (ctDNA) NGS results. Among 116 patients who underwent tissue-based NGS, HRD-positive tumors (14.7%) were significantly associated with longer progression-free survival (PFS; median 23.1 vs. 9.6months; p = 0.032) to immune checkpoint inhibitor (ICI) plus chemotherapy and overall survival (OS; median not reached vs. 17.9months; p = 0.027). HRD positivity remained an independent favorable prognostic factor for OS in multivariate analysis (HR: 0.247; 95% CI 0.071-0.859; p = 0.028). HRD-positive tumors showed higher frequencies of high tumor mutational burden (TMB) and microsatellite instability (MSI)-high tumors. However, exploratory analysis of ctDNA-based HRD in a small subset did not demonstrate a statistically significant association with survival outcomes. Tissue-based HRD positivity was associated with favorable survival outcomes and may provide complementary prognostic information in mGC patients with nivolumab plus chemotherapy as first line.

CCT7 is a chaperonin containing tailless complex polypeptide 1 subunit. The study focused on investigating its prognostic significance for lung adenocarcinoma (LUAD). CCT7 expression in LUAD and matched non-carcinoma lung samples was examined via TCGA database. Besides, we utilized the GEO database and RT-qPCR for validating differential CCT7 expression. The relation with clinical factors and its functions in diagnosis and prognosis prediction were determined. GO, KEGG, along with GSEA were conducted for exploring CCT7's functions. We also performed CIBERSORT, ssGSEA, and ESTIMATE for examining the LUAD immune microenvironment. By analyzing tumor mutational burden (TMB) and immune checkpoints, the relationship between CCT7 and immunotherapy was explored. CCT7 expression significantly increased within LUAD relative to matched non-carcinoma lung samples. As revealed by GO, KEGG, as well as GSEA results, CCT7 was mostly related to cell movement and regulation of multiple biological processes. Furthermore, CCT7 expression varied significantly among different immune cells, and those having increased CCT7 expression showed greater TMB. An increase in CCT7 expression carries significant implications for diagnosing and predicting LUAD prognosis.

Deep penetrating nevus (DPN)-like melanomas are believed to arise through sequential activation of the mitogen-activated protein kinase (MAPK) and Wnt/β-catenin signaling pathways, followed by additional mutations. Due to their rarity and lack of standardized diagnostic criteria, their molecular landscape and clinical behavior remain still poorly understood. Here, we report the largest cohort to date of 14 DPN-like melanomas. These tumors predominantly affected middle-aged adults (median, 46y), with the head and neck skin as the most common site. One rare case involved a mucosal site (epiglottis). DPN-like melanomas exhibited infiltrative growth, prominent vertical growth phase, severe nuclear atypia with occasional multinucleation, and increased mitotic activity (median, 3.5/mm 2 ). The median Breslow thickness was 3.3mm (range: 1.2 to 9.2mm), with all cases showing microscopic satellitosis, sentinel lymph node positivity, or synchronous metastasis. Most cases (93%) harbored MAPK pathway-activating mutations, predominantly in BRAF (77%), followed by NRAS and EGFR (an upstream regulator of the MAPK pathway). In addition, 79% of cases had mutations activating the canonical Wnt/β-catenin signaling pathway, mainly in CTNNB1 and APC . Two CTNNB1 / APC wild-type cases exhibited alternative mutations in genes indirectly modulating this pathway, such as ARID1A , EZH2 , FAT1 , and SETD2 , along with other mutations, including TERT promoter mutations (TPMs). TPMs were present in 56%, and the median tumor mutational burden was 30 mutations/Mb. After a median follow-up of 33.5 months, 36% of patients developed distant metastases, and 2 patients died of disease 8 and 32 months, respectively, after initial diagnosis. These findings expand the molecular diversity of DPN-like melanomas and provide valuable insights into their clinical outcomes.

Appendiceal cancer (AC) is a rare malignancy that often presents at advanced stages with significant histological variability influencing clinical outcomes. Precise genomic profiling is essential for accurate diagnosis and personalized patient management. This study interrogated DNA from appendiceal tumor tissue, buffy coat cells, and the cell-free DNA component of plasma using a 523-gene panel for comprehensive genomic profiling (CGP) to identify cancer-related genetic mutations in tumor and blood, evaluate tumor mutation burden, and determine genetic markers associated with histologic grade. A total of 73 patients provided blood samples comprising cell-free DNA (cfDNA) and germline buffy coat cells (bcDNA) for analysis compared with tumor tissues available from 56 of these patients. Concordance of mutations between matched tumor tissue and plasma samples (n = 51) was assessed and tumor-specific and germline variants were classified using OncoKB™ clinical criteria to delineate oncogenic and therapeutically actionable variants [level 1 mutations with U.S. Food and Drug Administration (FDA)-approved therapy]. Additionally, cfDNA concentrations were tested for association with clinical and pathologic features and oncologic outcome including disease-specific (DSS) and progression-free (PFS) survival. Circulating tumor DNA (ctDNA) from plasma cell-free DNA demonstrated high concordance with tumor genomic profiling, reaching 98.4% concordance [median, interquartile range (IQR) 13.5, 21.5] overall and 85.7% (IQR 64.6, 100) for therapeutically actionable level 1 mutations. Prevalent appendiceal tumor-specific mutations included KRAS proto-oncogene, GTPase (KRAS) (41%), GNAS complex locus (GNAS) (30%), tumor protein p53 (TP53) (30%), and SMAD family member 4 (SMAD4) (29%). Tumor-specific TP53, SMAD4, and spectrin alpha, erythrocytic 1 (SPTA1) mutations strongly correlated with intermediate and high-grade histology, whereas GNAS mutations predominated in low-grade tumors. Germline analysis identified coding mutations shared among this patient cohort in notch receptor 4 (NOTCH4) (55%) and BRCA1 associated RING domain 1 (BARD1) (48%) genes, with zinc finger homeobox 3 (ZFHX3) (29%) and adhesion G protein-coupled receptor A2 (ADGRA2), DNA polymerase epsilon (POLE), and transcription factor 3 (TCF3) mutations (all = 23%) specifically enriched in intermediate and high-grade AC. Both histological grade and cfDNA stratified by concentration tertiles independently predicted progression-free and disease-specific survival. Plasma samples exhibited consistently lower variant allele frequencies than solid tumors, limiting sensitivity for discovery of novel mutations exclusively from plasma. This study supports integrating comprehensive ctDNA assays into standard diagnostic and treatment pathways for AC using large gene panels. TP53, SMAD4, SPTA1, and GNAS mutations serve as prospective tumor-specific molecular classifiers for histological grade, while germline variants in NOTCH4 and BARD1 may further influence disease biology, with ZFHX3, ADGRA2, POLE, and TCF3 affecting grade stratification. Overall cfDNA concentration may serve as a potential prognostic biomarker in AC.

Overcoming conditional immune resistance in MSS and pMMR colorectal cancer: A sequential gating framework for immunotherapy.

While immune checkpoint inhibitors (ICIs) have failed to improve outcomes in unselected ovarian cancer populations, objective responses are observed in a minority of ovarian clear cell carcinoma (OCCC) cases, implying biological heterogeneity and a yet-undefined immunologically responsive subset within this histotype. We performed immunohistochemical profiling of tumor-infiltrating immune cells and analyzed transcriptomic data from human OCCC cohorts. Functional studies were conducted using an immunocompetent syngeneic OCCC mouse model to assess the effects of IL-17 on tumor cell inflammatory signaling, immune microenvironment remodeling, and responsiveness to immune checkpoint blockade, including single-cell RNA sequencing of tumor-infiltrating T cells. OCCC exhibited an immune-sparse tumor microenvironment with relative enrichment of CD4⁺ T cells. RORC expression was elevated in OCCC but showed intertumoral heterogeneity. In the transcriptome data (n = 180), an IL17Ahigh subset (5%), enriched within the RORChigh fraction, exhibited a T cell-inflamed gene expression profile independent of microsatellite instability and tumor mutational burden, yet was not associated with survival. Mechanistically, IL-17 directly activated NF-κB-dependent inflammatory programs in OCCC tumor cells, inducing cytokines and chemokines involved in T-cell recruitment and activation. In the syngeneic model, IL-17 exposure increased intratumoral CD4⁺ and CD8⁺ T-cell infiltration and activation. Single-cell profiling further revealed expansion of Th17/Tfh-like CD4⁺ T cells and cytotoxic, non-terminally exhausted CD8⁺ T cells. Consistent with these changes, anti-PD-L1 therapy improved survival in Th17-biased partial chimera mice. IL-17-responsive, tumor cell-intrinsic inflammatory programming remodels the tumor immune microenvironment toward an immunotherapy-permissive state. These findings establish IL-17-responsive tumor cell inflammatory programming as a mechanistic axis shaping immune checkpoint sensitivity and provide a rationale for biomarker-guided immunotherapy strategies.

APOBEC mutational signatures predict immune checkpoint inhibitor benefit in TMB-low metastatic NSCLC independent of PD-L1 status.