The most abundant stromal cells of the tumor microenvironment (TME), cancer-associated fibroblasts (CAFs), inhibit the cytotoxic T cell response in solid tumors. CD39 and CD73 together deplete extracellular ATP in the TME to produce adenosine, which can promote tumor immune evasion. We aimed to investigate the role of CAF-T-cell crosstalk in the adenosine pathway in NSCLC. CD4+ and CD8+ T cells were flow sorted from in vitro culture with or without CAFs, and RNA-Seq was performed using the nCounter platform (NanoString). The expression of cell surface markers involved in adenosine production was assessed using flow cytometry in CAFs and peripheral T cells from healthy donors or early NSCLC patients following in vitro co-culture. Purinergic synthesis of AMP and adenosine was measured by HPLC. TCGA data was used to investigate the translational relevance of adenosine signaling in NSCLC, and NanoString Geomx was performed to investigate differences in the transcriptomics of tumor stromas with a high versus low adenosine signature. CD4+ and CD8+ T cells isolated from in vitro co-culture with CAFs show upregulated expression of CD39 and CD73, which results in functionally relevant production of AMP and adenosine. TCGA data illustrates that adenosine signaling is predictive of poor outcome in lung squamous cell carcinoma. Spatial transcriptomics (GeoMx) of the tumor stroma of early untreated NSCLC patients shows a downregulation of immune-related genes in lung squamous-cell carcinoma. CAF T cell crosstalk promotes the expression of CD39 and CD73 on CAFs and T cells, resulting in an increased synthesis of AMP and adenosine in vitro.

Bladder cancer is a long-standing clinical issue, with frequent recurrence and continuously disappointing results in patients, so that therapeutic development is primarily reliant on delineating the original molecular defects. Increasing interest has turned to the Kinesin Superfamily Proteins (KIFs), basic molecular motors that move along microtubule rails, and are now emerging as important key oncogenic derivers in bladder cancer pathogenesis. This review synthesizes available evidence indicating that several KIFs, specifically KIF4A, KIF14, KIF20A, and KIFC1, function as key oncogenic regulators and represent important prognostic biomarkers and therapeutic targets in bladder cancer. When KIF expression or activity is disrupted, it provides mechanical and signaling support for all the cancer hallmarks, facilitating cellular proliferation, invasion, metastasis, and resistance to highly effective cell death. Its oncogenic activity is generally facilitated by the activation of principal signaling pathways. A remarkable proportion of certain KIF isoforms are commonly overexpressed in cancer, and the scale of such overexpression increases with the severity of adverse clinical predictors, such as increasing disease stage, and patient survival worsens. This nuanced molecular image renders KIFs so highly promising targets for therapeutic intervention and prognostic stratification, and initial exploration of kinesin inhibitors is encouraging to abate chemoresistance, aside from optimizing the efficacy of current immunotherapies. Uncovering modalities that exploit the aggressive bladder cancer cell dependence on KIF motor activity is a highly promising path to clinical application.

The chemotherapy resistance genes in breast cancer are closely related to prognosis. This study is aimed at exploring the key genes that may be involved in chemotherapy resistance of breast cancer and establishing a prognostic model.

Multiple myeloma (MM) is a heterogeneous hematological malignancy characterized by the clonal proliferation of plasma cells in the bone marrow, with distinct subtypes including smoldering MM (SMM), newly diagnosed MM (NDMM), and relapsed/refractory MM (RRMM). Despite therapeutic advances, outcomes remain unsatisfactory, especially for RRMM, due to unclear heterogeneity, progression mechanisms, and crosstalk between tumor cells and the bone marrow microenvironment (BMME) via direct interactions or extracellular vesicles (EVs).

This study aimed to evaluate the first-line treatment patterns and prognostic factors associated with survival in patients with driver gene-negative non-small cell lung cancer (NSCLC) and liver metastases, in order to identify the optimal treatment strategy.

Since the introduction of the hallmarks of cancer framework over 25 years ago, treatment approaches have evolved into personalized medicine, offering benefits to select patient populations. However, three major components of heterotypic interactions in cancer-mutational evolution of cancer stem cells, epithelial-mesenchymal plasticity (EMP), and cancer-remodeled extracellular matrix (ECM)-remain critical barriers to therapy, particularly in patients who have failed treatment. EMP encompasses a spectrum of to-and-fro transitions between mesenchymal and epithelial states, yielding hybrid phenotypes of evolutionary heterogeneity. These are embedded in the vascular, metabolic, mutational, and immune-suppressive reprogramming of the tumor microenvironment (TME), induced and advanced by the hypoxia-reactive oxygen species (ROS)-hypoxia-inducible factor-1α (HIF-1α)-transforming growth factor-β (TGF-β) signaling axis. This review systematically examines the molecular mechanisms underlying EMP, tumor heterogeneity, and the hallmarks of cancer. It explores pharmacological strategies to target tumor burden, epigenetically revert transitional states, and restore immune-editing functions. Based on this analysis, we propose a phased anti-hallmark Combinations, Timing, and Sequencing (CTS) protocol. The methodology integrates vascular normalization, epigenetic modifiers, trimodal radiotherapy or stereotactic body radiotherapy (SBRT), chemotherapy (CT), and immunotherapy optimization, aiming to improve outcomes while minimizing toxicities. Also, mechanistically, by reverting mesenchymal phenotypes and normalizing the vasculature, the CTS protocol is designed to rescue the immune-suppressive tumor microenvironment-curtailing the recruitment of myeloid-derived suppressor cells (MDSCs) and regulatory T (Treg) cells. This restores cytotoxic T-cell homing, thereby converting immunologically "cold" tumors into "hot," immunotherapy-responsive lesions.

Clear cell renal cell carcinoma (ccRCC) is a kidney cancer in which immune activity is closely intertwined with von Hippel-Lindau (VHL) loss, hypoxia-inducible factor (HIF) signaling, angiogenesis, hypoxia, and metabolic adaptation. Although immune checkpoint inhibitor (ICI)-based regimens have changed the treatment landscape of advanced ccRCC, only a subset of patients achieve durable benefit. Commonly used biomarkers, such as programmed death-ligand 1 (PD-L1) expression, tumor mutation burden (TMB), and broad inflammatory gene signatures, have not been sufficient to explain this variation or to guide routine treatment selection. One reason is that immune infiltration in ccRCC is not synonymous with effective antitumor immunity. A tumor rich in CD8+ T cells may still be resistant if these cells are exhausted, metabolically restricted, spatially separated from tumor nests, or surrounded by suppressive myeloid, stromal, and vascular programs. Therefore, the key issue is not simply whether a tumor is immunologically "hot" or "cold," but which part of the antitumor response has failed. In this Mini Review, we discuss ccRCC immunotherapy response from an immune-ecological perspective. We focus on several treatment-relevant immune states, including T-cell-inflamed but dysfunctional tumors, myeloid-dominant suppressive tumors, angiogenesis- and hypoxia-skewed tumors, and immune-excluded tumors. We also consider how bulk transcriptomics, single-cell and spatial profiling, T-cell receptor sequencing, proteomics, metabolomics, and longitudinal liquid biopsy may help define these ecotypes and capture treatment-induced remodeling. This perspective may support more refined patient stratification and more mechanism-matched immunotherapy strategies in ccRCC.

To investigate the mechanisms underlying benzo[a]pyrene-induced esophageal cancer (EC), and to screen and identify the key targets and biomarkers associated with benzo[a]pyrene-related EC.

Glioblastoma (GBM) is a highly malignant tumor with poor prognosis and limited effective treatment options. Emerging studies have suggested that gut microbiota may influence glioma progression through the gut-brain axis, though the precise mechanisms remain largely unclear. In this study, we employed a comprehensive multi-omics approach-encompassing single-cell transcriptomics, spatial transcriptomics, metagenomics, metabolomics, and m6A-seq-to investigate how antibiotic-induced gut microbiota disruption impacts glioma progression in a mouse model. Gene expression analysis revealed significant alterations in antibiotics-treated mice (ABX-treated mice), including reduced expression of Epha6 and upregulated expression of Tead1, key genes associated with glioma progression and immune modulation. Spatial transcriptomics and metabolomic profiling identified reduced methionine levels in gliomas of ABX-treated mice, linking gut-derived metabolite changes to epigenetic regulation via m6A methylation. Single-cell RNA sequencing further demonstrated an increased proportion of AC-like cells, disrupted intercellular communication, and aberrations in the EPHA and NRXN signaling pathways. These findings highlight the interplay between gut microbiota, immune signaling, and epigenetic modifications in shaping the glioma microenvironment. This study advances our understanding of the gut-brain axis in glioma biology and proposes the EPHA pathway as a promising biomarker for the immune-mediated modulation of tumor progression, thereby providing new insights into the role of the gut-brain axis in glioma regulation.

Multiple primary lung cancer (MPLC) is an increasingly recognized subtype characterized by distinct lesions with independent origins. While recent studies have profiled the immune landscape of MPLC, its tumor-intrinsic metabolic features and immunoregulatory interactions remain largely unexplored.

Pituitary tumors (PT) constitute the second most frequent intracranial tumor. A subset of PT can behave aggressively despite multimodal treatment. Hallmarks such as cellular senescence, epithelial-mesenchymal transition (EMT), and stemness have been implicated in tumor progression, but their role in PT pathogenesis remains is unclear.

Patient-derived organoids (PDOs) have emerged as physiologically relevant cancer models that preserve key genetic, histological, and functional features of the tumors from which they are derived. In parallel, CRISPR-based perturbation technologies have transformed functional genomics by enabling scalable interrogation of gene function. Their integration provides a powerful framework for identifying cancer dependencies, modeling oncogenic evolution, and investigating mechanisms of drug response and resistance in patient-relevant settings. This review examines how CRISPR knockout, CRISPR interference/activation, and precision editing approaches have been applied in PDO systems to uncover context-specific vulnerabilities, reconstruct mutational trajectories, and study tumor heterogeneity. We further compare pooled and arrayed screening formats and discuss what is uniquely enabled by performing CRISPR screens in organoids rather than conventional 2D models. Particular emphasis is placed on the technical and analytical constraints of organoid-based screening, including variable editing efficiency, clonal bottlenecks, biological heterogeneity, and limited scalability. We argue that the major value of organoid-based CRISPR screening lies in its ability to identify functionally actionable cancer vulnerabilities in a patient-contextualized model, while also introducing methodological challenges that must be addressed for robust clinical translation.

Circulating tumor DNA (ctDNA) monitoring may detect resistance to KRASG12C inhibitors earlier than conventional imaging. However, in the specific context of KRASG12C inhibitors, the temporal relationship between molecular, radiologic, and clinical progression remains poorly characterized. A 66-year-old woman with KRASG12C/STK11/KEAP1-mutant lung adenocarcinoma received second-line adagrasib after progression on chemo-immunotherapy. Serial ctDNA monitoring by droplet digital PCR and targeted next-generation sequencing was performed. Baseline KRASG12C ctDNA (6205.3 copies/mL) declined to 3.2 copies/mL after 7 weeks, indicating initial response. However, ctDNA levels rose to 21.1 copies/mL at month 4 and 315.2 copies/mL at month 6. Concurrent NGS revealed three emergent KRAS mutations (G12D, G13D, Q61H), confirming polyclonal resistance. Notably, CT and MRI imaging remained stable by RECIST criteria throughout this period. Significant clinical deterioration, requiring prolonged hospitalization, occurred approximately 8 weeks after initial ctDNA rise. The patient died 2 months after detection of resistance mutations. In this case, NGS ctDNA detected three acquired KRAS resistance mutations in addition to the original G12C, during a prolonged period of radiographic stability, illustrating polyclonal evolution under adagrasib pressure. These findings suggest that longitudinal liquid biopsy monitoring may provide early detection of resistance in KRASG12C-mutant NSCLC.

BACKGROUND Thoracic SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 4 (SMARCA4)-deficient undifferentiated tumor (SMARCA4-UT) is a rare and highly aggressive thoracic malignancy. It predominantly affects male smokers and typically arises in the mediastinum, where rapid tumor growth and early metastasis contribute to a poor prognosis. Recent evidence suggests that this tumor exhibits biological heterogeneity and variable responses to therapy, underscoring the need for further clinical characterization. CASE REPORT A 67-year-old man presented with dyspnea and superior vena cava syndrome. Computed tomography revealed a 7-cm mass in the anterior and superior mediastinum with suspected lymph node and bone metastases. Histological examination demonstrated a sheet-like proliferation of large atypical cells with rhabdoid features and necrosis. Immunohistochemical analysis showed loss of SMARCA4 (Brahma-related gene 1 [BRG1]) expression, positivity for cluster of differentiation 34 (CD34) and sex-determining region Y-box 2 (SOX2), weak epithelial membrane antigen expression, preserved integrase interactor 1 (INI1) expression, and negativity for other epithelial markers, fulfilling the diagnostic criteria for SMARCA4-UT. Despite palliative radiotherapy and combination immunotherapy with nivolumab and ipilimumab, the tumor rapidly progressed. The patient developed grade 4 drug-induced pneumonitis; transient stabilization was achieved, but his condition deteriorated. He died 6 months after disease onset. Autopsy revealed widespread metastases with minimal therapeutic effect, highlighting the aggressive clinical course and treatment resistance. CONCLUSIONS SMARCA4-UT is a highly aggressive tumor requiring comprehensive immunohistochemical evaluation for accurate diagnosis. This case highlights the limited efficacy of immune checkpoint inhibitors in a PD-L1-negative setting and underscores the need for more effective therapeutic strategies.

Avapritinib is a selective tyrosine kinase inhibitor approved for advanced PDGFRA exon 18-mutant gastrointestinal stromal tumors (GIST), including the imatinib-resistant D842V variant. However, its role in the preoperative setting for localized, resectable disease has not been defined.

Transgender and gender diverse (TGD) individuals undergoing gender-affirming mastectomy (GAM) face unique challenges related to breast cancer risk assessment and screening. This study aimed to identify factors that influence healthcare professionals' (HCPs) integration of cancer risk evaluation, including genetic assessment, within the context of GAM and pre-surgical planning.

Herbal medicine has emerged as an important area of investigation in gastrointestinal cancers owing to its multitarget therapeutic potential and growing integration with modern oncology. However, the rapid expansion of the literature has resulted in a fragmented understanding of the field's knowledge structure, research evolution, and emerging directions.

Genetic profiling of a new HPV-negative cervical cancer model identified pathogenic variants in genes implicated in oncogenic signaling, cell cycle regulation, and DNA damage repair pathways, including homologous recombination, non-homologous end-joining, and mismatch repair. Deficiencies in BRCA2, RAD51 and MLH1 were among these actionable targets. The newly described cervical cancer model revealed sensitivity towards the PARP inhibitor olaparib, which was further augmented upon combination with platinum-based chemotherapeutics. In contrast, BRCA1/2-proficient cervical cancer cells exhibited greater resistance to these strategies. This study highlights the potential of in-depth genetic analysis to identify genetic susceptibilities to guide personalized medicine approaches.

Dysregulation of chromatin remodeling is a key driver of malignant progression. The SWI/SNF ATPase subunits SMARCA2 and SMARCA4 are essential for chromatin dynamics, yet the clinicopathological and microenvironmental landscape of SMARCA2/4-deficient esophageal adenocarcinoma (EAC) remains insufficiently defined. We analyzed 722 resected EACs from a large Western cohort. SMARCA2 and SMARCA4 status were assessed by immunohistochemistry, and tumors were classified as SMARCA-intact or SMARCA-deficient (complete loss of nuclear expression in tumor cells with internal controls). Molecular co-alterations were evaluated by immunohistochemistry and fluorescence in situ hybridization, including amplifications of MET, ERBB2 (HER2), EGFR, PIK3CA, MYC, MDM2, TERT, and Y-chromosome loss (LOY). Several markers were available from prior works. Digital pathology workflows quantified CAF markers (SMA, PDGFRβ, FAP, Periostin, Tenascin) and immune infiltrates (including CD4, CD8, FOXP3, CD20, MUM1, mast cell tryptase). Overall survival was examined using Kaplan-Meier estimates and Cox regression models. SMARCA2/4-deficient tumors accounted for 11.2% of the cohort (81/722) and were enriched among patients aged ≥ 65 years. SMARCA-deficient EACs showed a significantly higher frequency of MET amplification (16.9%), particularly after neoadjuvant therapy. Within SMARCA-deficient tumors, PDGFRβ-positive CAFs, increased plasma cell (MUM1+) and mast cell infiltrates correlated with a favorable outcome, whereas loss of Y-chromosome (LOY) identified an adverse-risk subgroup with particularly poor prognosis. This largest-to-date study defines SMARCA-deficient EAC as a distinct subtype characterized by frequent MET amplification and high-risk interaction with LOY, alongside prognostically relevant stromal-immune features, supporting refined biomarker-based risk stratification and therapeutic exploration.