Paclitaxel, a natural diterpenoid compound derived from Taxus species, is one of the most successful plant-based anticancer drugs and has been widely applied in the treatment of various solid tumors. In recent years, emerging evidence has suggested its potential efficacy in refractory or advanced colorectal cancer (CRC), particularly in patients resistant to standard first-line chemotherapy such as 5-fluorouracil (5-FU). However, responses to paclitaxel in CRC are heterogeneous. This study aimed to elucidate the metabolic determinants underlying the heterogeneous response of CRC to paclitaxel and to identify serum metabolites associated with therapeutic response.

Integrated serum metabolomic profiling was performed in patient-derived tumor organoid (PDTOs, n=18), combined with drug sensitivity assays and in vivo validation using mouse xenograft models. An analysis was conducted to sensitivity of paclitaxel, followed by targeted metabolomic quantification and pathway enrichment to identify key metabolites influencing paclitaxel efficacy.

Linoleic acid (LA) was identified as a serum metabolite significantly correlated with reduced paclitaxel sensitivity. Elevated LA levels attenuated paclitaxel-induced G₂/M cell cycle arrest and reduced cytotoxicity by altering microtubule dynamics. Functional validation in CRC cell lines and animal models further confirmed that LA diminished the antitumor effect of paclitaxel, supporting a metabolism-mediated mechanism of chemoresistance.

This study identifies serum linoleic acid as a metabolism-related candidate biomarker associated with paclitaxel resistance in CRC. These findings highlight the potential clinical relevance of metabolic factors in modulating chemotherapy response and suggest that LA may have potential relevance for patient stratification in future studies of paclitaxel response in CRC.

Paraneoplastic lesions such as intraductal papillary mucinous neoplasms (IPMNs) are uncommonly observed in the graft of recipients of pancreas transplants, despite the well-established association between immunosuppression and malignancy development. Typically, allograft pancreatectomy is performed due to complications such as acute rejection or vascular thrombosis. We report a rare case of a patient who developed histologically confirmed IPMN occurring 8 years after pancreas transplantation. As the detection of paraneoplastic lesions increases with advancing imaging techniques and pancreas allograft survival continues to improve, these findings may gain greater clinical relevance. This case underscores important considerations for transplant surgeons, particularly regarding posttransplant surveillance strategies, management approaches, and long-term follow-up.

Chylous ascites is an uncommon condition characterized by the accumulation of triglyceride-rich, milky fluid in the peritoneal cavity due to lymphatic disruption or obstruction. Although lymphoma is a leading cause of malignant chylous ascites, its occurrence as an initial presentation remains rare.

A 69-year-old woman presented with a three-month history of postprandial abdominal pain, weight loss, anorexia, and dyspnea. Imaging revealed extensive abdominal and pelvic lymphadenopathy with bilateral pleural effusions. Diagnostic laparoscopy demonstrated milky peritoneal fluid, and fluid analysis confirmed chylous ascites (triglycerides, 1361 mg/dL). Lymph node biopsy demonstrated high-grade B-cell lymphoma with morphological features favoring follicular lymphoma. Immunohistochemistry revealed a markedly elevated Ki-67 proliferative index (> 90%), and genomic profiling identified pathogenic EZH2 and TET2 mutations with a high tumor mutational burden. According to the fifth edition of the WHO Classification of Haematolymphoid Tumours (2022), these findings are most consistent with follicular lymphoma, a mature B-cell neoplasm with high-grade features. Given the high-output drainage and recent surgery, cytotoxic chemotherapy was deferred, and rituximab monotherapy was initiated. Rapid clinical improvement and decreased drain output allowed safe transition to standard R-CHOP therapy, achieving a complete metabolic response (Deauville score 2) after six cycles.

This case highlights chylous ascites as a rare but important presenting feature of lymphoma. Its recognition should prompt early histopathologic evaluation and multidisciplinary management. In selected postoperative or frail patients, rituximab monotherapy can serve as an effective bridge to full chemotherapy, facilitating recovery and improving outcomes. Early diagnosis and targeted treatment remain essential to prevent complications from lymphatic loss and to optimize prognosis in lymphoma-associated chylous ascites.

Somatic mutations in protein-coding genes and noncoding regulatory regions are the major drivers of cancer. Only a relatively small number of somatic noncoding mutations that are likely drivers have been described to date, including those in the promoters of the TERT, FOXA1, and TP53 genes. The impact of these alterations can be profound by initiating, increasing, or abolishing gene expression. Promoter mutations in particular have been difficult to identify even from whole tumor genomes due to their high content of G and C nucleotides, which leads to loss of sequencing coverage in these regions. Therefore, the landscape of somatic drivers in gene promoters remains incomplete. Here, we present a hybrid capture assay optimized for >3000 promoters of cancer genes. We show that this assay allows for deep sequencing of challenging GC-rich promoter regions, enabling discovery of reliable point mutations, short insertions and deletions, copy number variants, and mutational signatures in cell line models as well as formalin-fixed, paraffin-embedded archival tissue samples. Our assay nominated candidate noncoding driver mutations in CDK4, SMAD3, and GATA3 in breast cancer for future functional follow-up.

Multiple myeloma (MM) typically evolves from monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). Its progression is accompanied by significant tumor heterogeneity and immune microenvironment remodeling, and MM remains largely incurable despite therapeutic advances. Elucidating cellular heterogeneity and regulatory mechanisms involved in disease progression is critical for understanding MM pathogenesis.

Single-cell RNA sequencing (scRNA-seq) provides important support for systematically elucidating the molecular mechanisms and immune regulatory pathways associated with the progression of MM. The scRNA-seq datasets from healthy donors (HD), MGUS, SMM, and MM patients were obtained from the GEO database to analyze plasma cell transcriptional heterogeneity within the bone marrow microenvironment. Plasma cell differentiation trajectories were inferred using pseudotime analysis, and intercellular communication and transcription factor regulatory networks were predicted using CellChat and SCENIC analyses. In addition, functional validation of ELK3 was performed in vitro using MM cell lines RPMI 8226 and U266.

In this work, we used scRNA-seq to thoroughly evaluate the heterogeneity of MM. We identified a tumor-associated plasma cell subtype, C4 TTN+ plasma cell subtype, which was predominant in SMM and MM and was significantly enriched throughout the intermediate and final phases of differentiation. We hypothesized that C4 TTN+ plasma cell subtype may be associated with the progression of MM. We also found that the TGFb signaling pathway played a key role in the interaction between C4 TTN+ plasma cell subtype and various cell types within the TME. Furthermore, in vitro experiments validated the positive regulatory effects of ELK3 on plasma cell proliferation, migration, and cell viability in MM.

In summary, this study, based on scRNA-seq analysis, identified a C4 TTN+ plasma cell subtype potentially associated with ELK3. This subtype may be associated with progression and immune evasion in MM, thereby providing a potential new direction for targeted immunotherapeutic strategies in MM.

Lung cancer remains a leading cause of global cancer-related mortality, with most patients diagnosed at advanced stages. The emergence of immune checkpoint inhibitors (ICIs), specifically targeting PD-1/PD-L1 and CTLA-4 pathways, has revolutionized the treatment landscape by restoring anti-tumor immune responses. Currently, ICIs are integrated into clinical practice across all stages of lung cancer, administered either as monotherapy or in combination with chemotherapy, radiotherapy, and anti-angiogenic agents. Despite significant survival benefits, several critical challenges persist. First, primary and acquired resistance, driven by tumor microenvironment (TME) immunosuppression, impaired antigen presentation, and aberrant signaling, limits long-term efficacy. Second, existing biomarkers like PD-L1 expression and tumor mutational burden (TMB) face limitations due to insufficient standardization and spatiotemporal heterogeneity. Furthermore, immune-related adverse events (irAEs) across multiple organ systems necessitate vigilant clinical management and occasionally treatment discontinuation. This review systematically evaluates the research progress and clinical applications of ICI therapy in lung cancer. We highlight the therapeutic heterogeneity observed across different histological types, including non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), with a specific focus on the management of brain metastases (BMs). Additionally, the article discusses varying response patterns within specific patient subgroups, such as geriatric patients and individuals with differing smoking or performance statuses. By synthesizing data on both favorable therapeutic outcomes and the spectrum of irAEs, we emphasize the necessity of personalized immunotherapy. Ultimately, this review looks forward to future advancements aimed at enhancing the precision and safety of lung cancer treatment, providing a roadmap for more tailored clinical interventions.

Tumor cell heterogeneity is a fundamental driver of breast cancer aggressiveness, underlying recurrence, metastasis, and therapy resistance. Understanding the biological characteristics and functions of specific tumor cell clusters in the tumor microenvironment is crucial for advancing precision oncology.

We delineated breast cancer tumor cell heterogeneity by integrating single-cell transcriptomics, spatial transcriptomics, bulk transcriptomics, genomic and radiomic data. The oncogenic functions of the candidate gene TMSB10 were rigorously validated in vitro. To advance individualized patient management, we employed machine learning to develop a non-invasive MRI radiomic model for estimating tumor cluster abundance and a robust prognostic signature for risk stratification.

We discovered a poor-prognosis tumor cell cluster (C1 cluster). C1 cluster exhibited a late evolutionary state, metabolic reprogramming (OXPHOS/glycolysis), and active crosstalk with cancer-associated fibroblasts and endothelial cells. High abundance of C1 cluster was associated with poor survival, specific somatic mutations, and predicted superior response to immune checkpoint blockade, but not to chemo/radiotherapy. The radiomic model based on MRI images was exploratively established for estimating the abundance of C1, and the prognostic model based on C1-derived genetic features significantly stratified the survival risk of breast cancer in multiple cohorts. In vitro experiments confirmed that TMSB10, a C1 core gene, promotes proliferation, migration, invasion.

This study revealed C1 cluster as a key driver of breast cancer progression and its application for predicting immunotherapy response. Additionally, TMSB10 was identified as a functional effector of C1 cluster, providing a new and applicable clinical tool for non-invasive detection and prognostic stratification for breast cancer.

Cancer-associated fibroblasts (CAFs) contribute to the metastatic progression of high-grade serous ovarian cancer (HGSOC), partly through the transfer of regulatory RNAs via exosomes. Here, we identify a circRNA, circMPP6 as a key pro-metastatic factor enriched in CAF-derived exosomes. circMPP6 is upregulated in metastatic HGSOC tissues and is associated with poor prognosis. In HGSOC cells, nuclear circMPP6 interacts with SFPQ and NONO to stabilize ADAM22 mRNA, whereas cytoplasmic circMPP6 binds EEF1A2 to enhance ADAM22 protein expression. Elevated ADAM22 levels activate TGF-β/Smad2/3 signaling via binding to ITGB1, promoting proliferation, migration, and invasion in vitro and metastasis in vivo. Silencing circMPP6 or disrupting the ADAM22 axis attenuates these oncogenic phenotypes. In CAFs, its loading into exosomes is mediated by hnRNPA2B1, enabling its transfer to adjacent tumor cells. These findings reveal a dual regulatory mechanism by which CAFs-derived exosomal circMPP6 enhances ADAM22 expression and activates pro-metastatic TGF-β signaling in HGSOC. Our study highlights circMPP6 as a potential therapeutic target and critical mediator of stromal-tumor communication in ovarian cancer metastasis.

Solid tumors create an acidic tumor microenvironment (TME) that drives cancer progression, therapy resistance, and immune evasion. Bicarbonate is crucial for maintaining acid-base balance, however, its role in non-small cell lung cancer (NSCLC) remains unclear. Through the analysis of single-cell RNA sequencing data and the TCGA and CPTAC databases, we identified solute carrier family 4 member 7 (SLC4A7) as the predominantly expressed bicarbonate transporter in NSCLC. Functionally, SLC4A7 knockdown impaired bicarbonate uptake, resulting in intracellular acidification and extracellular alkalinization. This phenomenon led to a decrease in glycolysis and subsequently suppressed the growth and metastasis of NSCLC. Both in vivo and in vitro data demonstrate that the alkalinization of the TME induced by Slc4a7 knockout enhances the infiltration and function of cytotoxic T cells, significantly inhibiting tumor growth. Additionally, Slc4a7 knockout exhibits synergistic antitumor efficacy in combination with PD-1/PD-L1 immune checkpoint inhibitors. Mechanistically, integrative analysis of RNA-seq and ATAC-seq data identified CTCF as a transcription factor regulating SLC4A7 expression. In summary, our study demonstrates that SLC4A7-mediated bicarbonate transport is crucial for maintaining acid-base homeostasis in NSCLC and represents a promising therapeutic target for this disease.

During metastasis, circulating tumor cells (CTCs) are subjected to fluidic shear stress (SS), which eliminates many of them but paradoxically enhances malignancy and metastatic success. Meanwhile, given the critical roles of reactive oxygen species (ROS) in stress response and cancer, we engineer a circulation-mimicking microfluidic system which generates pulsatile SS to investigate the interplay among SS, ROS and metastasis. A 3-hour SS treatment rapidly elevates ROS levels, boosting metastatic abilities in triple-negative breast cancer (TNBC) cells in vitro and in vivo. RNA-sequencing and subsequent investigation identify activator protein-1 (AP-1) transcription factor members FOS, ATF3 and FOSB, which undergo dramatic ROS-dependent increase and nuclear localization upon SS stimulation. All three genes exhibit metastasis-promoting potential, while FOS displays the strongest ability to trigger distant lung metastasis in an orthotopic tumor model and correlates with worse clinical outcomes. Mechanistically, calcium channel acts as the mechano-sensor to initiate the SS-ROS cascade, with calcium channel blockers Mibefradil and Nifedipine effectively weakening SS-ROS-induced invasiveness. Following ROS elevation, the downstream activation of p38-ELK1-cFOS and JNK-cJUN pathways subsequently increase the expression of malignancy-related genes. This metastasis-promoting SS-calcium channel-ROS-FOS axis provides new insights for combating metastatic progression in breast cancer.