Tongmei Zhang

Chronic intestinal inflammation is a major driver of colorectal cancer (CRC). As the mucosal barrier's frontline sentinel, the intestinal epithelium initiates the inflammation‐to‐cancer transition. However, the early cell‐intrinsic events that convert inflammatory responses into a sustained pro‐tumorigenic program remain unclear. In this study, we identify MAGI3 as an intestinal epithelial guardian progressively lost during inflammation‐associated colorectal tumorigenesis. Low MAGI3 correlates with heightened inflammatory activity and poor prognosis. Inflammation‐induced epithelial MAGI3 downregulation drives STAT3 hyperactivation, CCL2 upregulation, and recruitment of M2‐like tumor‐associated macrophages (TAMs), thereby promoting an immunosuppressive microenvironment and tumor progression. By contrast, single‐cell RNA sequencing (scRNA‐seq) demonstrated that MAGI3 overexpression reshapes the composition of TAMs and limits M2‐like TAM infiltration. Mechanistically, the PDZ1 domain of MAGI3 binds directly to the C‐terminus of STAT3, blocking the SH2 pocket, impairing the interaction between STAT3 and IL‐6R/JAK2, and ultimately inhibiting STAT3 phosphorylation at Tyr705. Clinically, the MAGI3‐STAT3 axis offers a new therapeutic strategy for chemotherapy‐resistant CRC, with low MAGI3 expression predicting enhanced sensitivity to STAT3 inhibitors. Collectively, these findings establish MAGI3 as a gatekeeper of the intestinal epithelium in inflammation‐associated CRC, with the MAGI3‐STAT3 axis regulating TAM recruitment. Targeting the MAGI3‐STAT3 axis could offer an early intervention to reverse inflammation‐to‐cancer transition.

Background: Given the widespread prevalence of epithelial ovarian cancer as a global malignant tumor, there is an urgent need to deeply explore its risk determinants. This study used cluster analysis to summarize the association patterns of different histological subtypes of epithelial ovarian cancer, and employed the two-sample Mendelian randomization method to evaluate the potential causal association between genetic prediction of IgA nephropathy susceptibility and the risk of epithelial ovarian cancer. This method, under the condition of satisfying the correlation, independence, and exclusion of restrictive assumptions of instrumental variables, helps to reduce the influence of traditional confounding and reverse causation. Methods: Genome-wide association data from 15,587 European IgA nephropathy patients served as the primary exposure, with GWAS data from epithelial ovarian cancer subtypes. Three Mendelian randomization(MR) methods including inverse variance weighting MR-Egger regression and weighted median were adopted for causal inference. Sensitivity analyses included Cochran’s Q test, MR-Egger intercept, MR-PRESSO, and Leave-one-out analysis. Six subtype-specific UVMR analyses were conducted, and the results were reported separately. Because the subtype outcome datasets were overlapping or nested, no formal meta-analysis or pooled estimate was performed. Results: In the subtype-specific UVMR analyses, the effect estimates were generally below the null value, suggesting a directionally concordant pattern towards a lower risk of epithelial ovarian cancer. The association was statistically significant for high-grade serous ovarian cancer (OR =0.81, 95% CI: 0.75- 0.87, P <0.05). The estimates for clear cell ovarian cancer and the remaining evaluated histological subtypes were not statistically significant, although some showed similar inverse directions. Because the subtype-specific outcome datasets were overlapping or nested and shared the same IgA nephropathy exposure GWAS, no formal pooled estimate was calculated. Sensitivity analyses [including MR-Egger intercept, MR-PRESSO, leave-one-out analysis, and Steiger directionality testing] yielded results consistent with the primary subtype-specific analyses. Conclusion: Genetically predicted liability to IgA nephropathy may be associated with a lower risk of epithelial ovarian cancer, particularly high-grade serous ovarian cancer, although this finding requires validation in independent and sex-matched datasets.

The extracellular matrix (ECM) stiffening in the tumor microenvironment (TME) is an important physical characteristic of solid tumors and can serve as an active signaling hub that regulates the biological behavior of tumors. Abnormal deposition, cross-linking, and remodeling of collagen not only alter the mechanical properties and structure of tissues but also convert mechanical stimuli into intracellular signals through mechanosensitive ion channels such as integrin-FAK, Hippo-YAP/TAZ, Piezo1/2, and Transient receptor potential vanilloid subtype 4 (TRPV4), thereby reprogramming tumor cell metabolism, including enhancing the Warburg effect, lipid synthesis, and glutamine catabolism, forming a malignant cycle of “matrix stiffening - metabolic reprogramming” that promotes tumor progression and treatment tolerance. Mechanical signals can also create an immunosuppressive TME by restricting CD8 ⁺ T-cell infiltration and promoting tumor-associated macrophage polarization toward an M2-like state. Metabolites generated by reprogrammed cells, including lactate, can further remodel and stiffen the ECM, creating a positive-feedback loop. Genetic and epigenetic heterogeneity, hypoxia, nutrient availability, and oncogenic signaling may uncouple mechanical regulation from metabolic output and complicate therapeutic targeting. Non-coding RNAs (ncRNAs) add a regulatory layer that may connect mechanotransduction with metabolic plasticity and immune remodeling, although their effects remain context dependent. This review integrates the existing evidence on the regulation of tumor metabolism and immune microenvironment by ECM mechanical signals, focuses on summarizing the key mechanical sensing pathways, feedback mechanisms, and therapeutic targets, and proposes research directions for precisely identifying key regulatory nodes of the mechanical-metabolic axis by combining spatial omics, metabolic flux analysis, and mechanical imaging techniques, providing a conceptual framework for developing novel therapeutic strategies targeting the biomechanical processes of tumors.

This phase II trial investigated perioperative camrelizumab plus neoadjuvant chemotherapy for patients with stage IIB–IIIB lung squamous cell carcinoma (LUSC) and explored predictive biomarkers of treatment response. Patients received neoadjuvant camrelizumab (200 mg, Day 1) in combination with nab‐paclitaxel (130 mg/m ² , Days 1 and 8) and carboplatin (area under the curve = 5, Day 1) every 3 weeks for two cycles, followed by surgery and adjuvant camrelizumab for 1 year. The primary endpoint was major pathological response (MPR) rate. Forty‐five patients were treated, of whom 41 underwent surgery. Twenty‐seven of 45 patients (60.0%) achieved MPR and 20 (44.4%) achieved pathological complete response (pCR). With a median follow‐up of 37.5 months, the 3‐year disease‐free survival and overall survival rates were 65.9% and 68.7%, respectively. Among eight patients with stage IIIB disease, three (37.5%) achieved pCR. Baseline neutrophil percentage and smoking history were associated with MPR. T‐cell receptor (TCR) sequencing revealed that three V‐J gene pairs in TCR beta clones differed between the pCR and non‐pCR groups. This study supports the application of perioperative immunotherapy combined with neoadjuvant chemotherapy in patients with resectable locally advanced LUSC. The identification of blood biomarkers for precise patient selection warrants further in‐depth investigation.

Background: Understanding of the possible vasoactive toxicities associated with platinum‑containing chemotherapeutic drugs for solid tumors remains limited. Objectives: This study comprehensively identifies the vessel-threatening effects of cisplatin (CDDP), carboplatin (CBP), and oxaliplatin (OXA) and aims to compile an analytical model. Design: A retrospective pharmacovigilance study was combined with network pharmacology analysis and in vitro experimental validation. Methods: Disproportionality analyses, including reporting odds ratio, proportional reporting ratio, empirical Bayesian geometric mean, and Bayesian confidence propagation neural network, were conducted to identify vascular adverse events (VAEs) related to the three drugs using data from the FDA Adverse Event Reporting System (FAERS) database from 2004 to 2024. Network pharmacology was used to identify potential molecular targets and pathways. Human umbilical vein endothelial cells were treated with cisplatin, carboplatin, or oxaliplatin to evaluate cell viability (CCK-8 assay), apoptosis (flow cytometry), and gene expression by reverse transcription quantitative polymerase chain reaction (RT-qPCR) including Nrf2, ICAM1, VCAM1, NOS3, and HIF1A. Results: Among the 10,536 VAEs identified, all three drugs showed strong correlations with vascular events. Oxaliplatin had a correlation coefficient of 2.05 (95% confidence interval (CI): 1.99–2.11). Early failure characteristics (Weibull β ⩽ 1) were observed for all three drugs. The most frequently reported VAEs were hypotension, flushing, hypertension, and thrombosis. Network analysis highlighted the HIF-1, EGFR, and oxidative stress pathways. In vitro, oxaliplatin significantly reduced Nrf2 expression and cell viability, while cisplatin upregulated ICAM1 expression. Conclusion: Platinum compounds induce a short‑term vasoconstrictive effect, with oxaliplatin showing a relatively lower association. The results suggest activation of the oxidative stress pathway through Nrf2 inhibition and increased ICAM1 levels, alongside pathway‑specific alterations such as reduced HIF1A and NOS3 expression and decreased VCAM1 levels. Early cardiovascular monitoring and Nrf2‑targeted therapy warrant further investigation.

Optimal first-line treatment for epidermal growth factor receptor (EGFR) mutant NSCLC with brain metastases (BMs) has not been fully defined. We aimed to compare different first-line tyrosine kinase inhibitor (TKI) combination therapies and monotherapy for these patients in a real-world setting, especially in the era of 3rd generation TKIs. Patients with EGFR-mutant NSCLC and BMs receiving first-line EGFR-TKIs from 2019 to 2023 were retrospectively reviewed (n = 150): TKI alone (n = 73), TKI plus brain radiation (TKI + BRT, n = 25), TKI plus bevacizumab (TKI + BEV, n = 38) and TKI plus chemotherapy (TKI + CT, n = 14). Intracranial progression-free survival (iPFS), PFS, overall survival (OS), responses and adverse events of each group were compared and survival beneficial population were explored. Among enrolled patients, majority (70.7%) received 3rd generation EGFR-TKIs and 29.3% received 1st /2nd generation drugs. The median iPFS of TKI alone group was significantly inferior than those in TKI + BRT, TKI + BEV and TKI + CT groups (22.1 vs. 32.9 months vs. not reached [NR] vs. NR, p = 0.001). The median PFS and OS were 11.1 and 40.1 months, 18.9 and 67.1 months, 16.5 and 38.8 months, 39.8 and 79.8 months, respectively, with TKI alone, TKI + BRT, TKI + BEV and TKI + CT (PFS, p = 0.014; OS, p = 0.015). The combination therapies brought iPFS and PFS benefits over TKI alone regardless of TKI generations. A linear correlation was demonstrated between iPFS and OS (R² = 0.508, p < 0.001). Multivariate analysis revealed that the addition of BRT (HR = 0.375, 95%CI, 0.176-0.802, p = 0.011) or bevacizumab (HR = 0.294, 95%CI, 0.141-0.611, p = 0.001) significantly reduced intracranial progression risk. Whereas, the combinations of TKI and RT (HR = 0.326, 95%CI, 0.128-0.834, p = 0.019) or chemotherapy (HR = 0.083, 95%CI, 0.010-0.666, p = 0.019) were independent factors for favorable OS. No significant difference on survival or toxicity was observed among the three combination therapies. EGFR-TKI combination therapies improved iPFS, PFS and OS than TKI monotherapy for patients with EGFR-mutant NSCLC and BMs irrespective of TKI generation or combination strategy.

Non-small cell lung cancer is among the most prevalent cancers worldwide, with its high metastatic potential driving poor prognosis and mortality. Advances in molecular testing and high-throughput sequencing have highlighted the roles of driver genes (EGFR, ALK, KRAS) and key non-driver genes (TP53, STK11, KEAP1) in NSCLC metastasis. These mutations influence tumor invasiveness, drug resistance, and organ-specific metastatic patterns—EGFR and ALK mutations favor brain metastasis, KRAS mutations are linked to bone, liver, and multiple lung metastases, while TP53, STK11, and KEAP1 mutations increase multi-organ metastatic risk. This review summarizes the associations between genetic mutations and metastatic sites, explores underlying molecular mechanisms, and discusses mutation-based risk prediction and personalized therapeutic strategies. With multi-omics integration and further clinical research, genetic profiling may become a key tool for guiding metastasis prevention, early intervention, and treatment optimization in NSCLC.

Objectives: C1QBP is a multi-compartmental protein implicated in diverse cellular processes. However, its clinical predictive value, particularly its association with immune cell infiltration, in lung adenocarcinoma (LUAD) remains unelucidated. Thus, the present study aimed to comprehensively evaluate C1QBP expression patterns, prognostic significance, and its correlation with the tumor immune microenvironment (TIME) in LUAD. Methods: We first assessed C1QBP expression levels and prognostic relevance in LUAD using multiple bioinformatics platforms. Subsequently, we analyzed the associations of C1QBP expression with immune cell infiltration and immunotherapeutic response, and identified signaling pathways linked to C1QBP expression via Gene Set Enrichment Analysis (GSEA). Finally, enzyme-linked immunosorbent assay (ELISA) was employed to validate the correlation between serum C1QBP concentration and prognosis in non-small cell lung cancer (NSCLC) patients receiving immunotherapy. Results: C1QBP was highly expressed in LUAD tissues, and this high expression was significantly associated with advanced tumor stage. Moreover, high C1QBP expression emerged as an independent risk factor for overall survival (OS) in LUAD patients. Bioinformatics analyses revealed that C1QBP expression was negatively correlated with the infiltration levels of multiple immune cell subsets (including T cells, B cells, and dendritic cells) in LUAD, while patients with low C1QBP expression exhibited higher Immunophenoscore (IPS). GSEA further demonstrated that high C1QBP expression was positively correlated with pathways regulating the tumor cell cycle, but negatively correlated with immune-related signaling pathways. Finally, in NSCLC patients treated with immune checkpoint inhibitors (ICIs), those with higher serum C1QBP concentrations had significantly shorter OS and progression-free survival (PFS). Conclusions: Our study identifies C1QBP as a potential oncogene that is closely associated with the TIME in LUAD. Collectively, these findings suggest that C1QBP holds promise as a novel indicator of poor prognosis in LUAD patients.

This case underscores the critical importance of retesting for resistant mechanisms, such as EML4‐ALK fusion, in patients with EGFR‐mutant lung adenocarcinoma who experience rapid progression on EGFR‐tyrosine kinase inhibitor (TKI) therapy. Early identification of such co‐alterations and an immediate switch to alectinib can lead to rapid and sustained clinical improvement.