The tumor microenvironment (TME) is a highly dynamic and heterogeneous system composed of tumor cells, stromal cells and non-cellular components that collectively govern tumor initiation, progression, and metastasis. Beyond host-derived components, accumulating evidence has established that microorganisms are integral constituents of the TME. These tumor-associated microbes not only affect tumor cells directly but also reshape the TME. Importantly, microbial-driven remodeling of the TME is accompanied by changes in its biomechanical properties. These alterations introduce a biophysical dimension of the TME that operates alongside biochemical signaling. Studies have shown that certain microorganisms reshape mechanotransduction pathways within tumor cells. Such biomechanical alterations enhance tumor cell adaptability to shear stress, promote survival in circulation, and facilitate invasion and colonization at distant sites. Although direct evidence linking microbes to specific biomechanical changes in tumors remains limited, these preliminary insights point to a largely unexplored yet highly promising frontier. This review explores the physical properties of the TME and delineates the association between microorganisms and the dynamics of these physical signals. It then examines strategies for leveraging microorganisms in tumor therapy. Understanding these interactions may reveal novel therapeutic targets to harness microbial influences and inhibit tumor progression.

The efficacy and safety of anti-HER2 therapy and immune checkpoint inhibitors combined with chemotherapy to treat HER2-positive advanced breast cancer that has failed standard HER2-directed therapies is unknown. This study evaluated the efficacy and safety of a novel, fully China-developed combination therapy—comprising inetetamab (an anti-HER2 monoclonal antibody), camrelizumab (an anti-PD-1 antibody), and utidelone (a microtubule inhibitor)—in this treatment-refractory population. The ICU study (NCT04681287) was a single-arm, multicentre, phase 2 trial conducted at five centres in China. Patients with HER2-positive MBC who had experienced progression on prior trastuzumab and TKIs were enrolled. The primary endpoint was the 3-month progression-free survival (PFS) rate in the per-protocol population. A total of 48 patients with a median of three previous systemic therapies for advanced disease (range, 1–4) were enrolled (median follow-up duration 43.0 months). The 3-month PFS rate in 46 patients was 71.67

Human epidermal growth factor receptor 2 (HER2) is a key biomarker and therapeutic target in several malignancies, including breast, gastric, and other solid tumors. Recent advancements in cancer molecular profiling and the Food and Drug Administration's approval of trastuzumab deruxtecan for HER2u2010positive panu2010tumor indications have highlighted the broader relevance of HER2 alterations across diverse cancers. However, the lack of standardized guidelines for HER2 testing in a panu2010tumor context creates variability in clinical practice, hindering the optimal implementation of HER2u2010targeted therapies beyond traditional indications. To address this gap, a multidisciplinary panel of Chinese experts has developed a consensus providing comprehensive recommendations on diagnostic strategies, testing methodologies, and clinical applications of HER2 overexpression detection. By establishing a unified framework for HER2 overexpression assessment, this consensus aims to enhance the precision of HER2 testing, optimize patient selection for targeted therapies, and improve clinical outcomes across a wide spectrum of HER2 overexpression malignancies.

The biological and clinical heterogeneity of younger patients with microsatellite stable (MSS)/proficient mismatch repair (pMMR) colorectal cancer (CRC) is largely unexplored. This retrospective study compared the clinicopathological factors, prognosis, and molecular characteristics of MSS/pMMR CRC in patients younger and older than 30 years. Overall, 191 younger (≤ 30 years old) and 892 older (> 30 years old) CRC patients were enrolled. Statistically significant differences between the groups were determined using the χ2 or Fisher’s exact test. Progression-free survival (PFS) was assessed by Kaplan–Meier analysis and compared using log-rank test. Univariate and multivariate Cox regression analyses were used to identify independent prognostic factors. Younger patients with MSS/pMMR CRC exhibited significantly more aggressive features, including higher rates of mucinous adenocarcinoma, poor differentiation, deeper tumour invasion and advanced tumour–node–metastasis (TNM) stage than older patients. Among all CRC patients, molecular analysis revealed a higher microsatellite instability-high incidence but lower KRAS mutation frequency in younger patients compared with in older individuals. Comprehensive genetic profiling of 1021 genes revealed no additional significant variations between the two MSS/pMMR CRC groups. Survival analysis showed that younger patients with MSS/pMMR CRC had significantly shorter PFS than older patients (log-rank P < 0.001), although multivariate analysis indicated that age was not an independent prognostic factor. Younger patients with CRC exhibit unique biological behaviour. Therefore, unravelling the mechanisms of its aggressiveness through integrated multi-omics technologies should be a key focus in future research.

609 Background: Novel treatment options are needed to improve long-term outcome of high-risk early HR+/HER2− breast cancer. Evidence shows a programmed death 1 inhibitor combined with chemotherapy increases pCR rates in this subtype. We aimed to evaluate the efficacy and safety of serplulimab combined with nab-paclitaxel and epirubicin in high-risk, early HR+/HER2− breast cancer. Methods: This multicentre, single-arm, phase 2 trial was conducted in China at 6 hospitals. Patients were eligible if they were 18 years or older, with previously untreated early HR+/HER2- breast cancer, and Ki-67 greater than or equal to 20%, and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1. Participants were allocated to intravenous nab-paclitaxel (260 mg/m 2 ) and intravenous epirubicin (75 mg/m 2 ) on the first day and intravenous serplulimab (4.5mg/kg) on the third day of the treatment cycle. 6 cycles of neoadjuvant treatment were administered. The primary outcome was pCR (defined as ypN0 or ypT0/is), assessed in the full analysis set, which included all patients who had started the trial treatment. We estimated that with enrollment of 109 participants, this trial would have 80% power to detect a true difference in the percentage of patients with a pCR of 10% at a one-sided alpha level of 0.025, with a dropout rate of 10%. This study is registered with ClinicalTrials.gov (NCT06394661). Results: Between Apr 28, 2024, and May 24, 2025, 136 patients were assessed for eligibility; 27 were ineligible and 109 participants were enrolled in this study, of whom 101 participants started trial treatment. Median age of the participants was 49 [range, 30 to 72] years at the time of enrolment, and 45 (44.6%) were PD-L1 positive (CPS ≥1). pCR was achieved in 23 patients (22.8%, 95%CI 15.3%-32.4%). PCR rate was numerically higher in patients with PD-L1 positive tumors (44.4%, 95%CI 30.0%-59.9%). During the neoadjuvant phase, 30 (29.7%) patients experienced grade 3 or higher treatment-related adverse events. The most common grade 3–4 adverse events were increased alanine aminotransferase (ALT; six [5.9%]), increased aspartate aminotransferase (AST; five [5.0%]), and diarrhea (four [4.0%]), There were no treatment-related deaths. Conclusions: Delayed serplulimab combined with nab-paclitaxel and epirubicin showed promising anti-tumour activity and manageable safety in patients with HR+/HER2− breast cancer; the pCR rate was higher in PD-L1 expression tumor. These findings support further evaluation of this regimen in randomized controlled trials. Clinical trial information: NCT06394661 .

To investigate the added diagnostic value of contrast-enhanced MRI (CE-MRI) to T2-weighted imaging (T2WI) and diffusion-weighted imaging (DWI) for evaluating vaginal fornix invasion (VFI) in cervical carcinoma (CC). We retrospectively enrolled 149 consecutive CC patients (training cohort) and 37 external patients (validation cohort) who underwent radical hysterectomy and preoperative MRI (T2WI, DWI, and CE-MRI). Two radiologists independently assessed VFI first using T2WI + DWI, then T2WI + DWI + CE-MRI, with histopathology as reference. Diagnostic metrics were compared with the McNemar test; interobserver agreement was evaluated via the kappa statistic. Subgroup analyses and multivariate logistic regression were performed to validate CE-MRI’s added value. Histopathology confirmed VFI in 68/149 patients (45.6

Whole Slide Images (WSIs) are essential for the intelligent-assisted diagnosis of diseases such as cancer. However, the high resolution and complex pathological features of WSIs limit traditional manual analysis due to its time-consuming nature and subjectivity. Multiple-Instance Learning (MIL) offers a viable solution to this challenge, but conventional MIL methods disproportionately rely on salient instances, thereby underutilizing the diverse pathological information present in all positive instances and restricting the model’s comprehensive utilization of complex pathological features. To address this, we propose a novel weakly supervised MIL model, PFS-MIL (Pathological Feature Stratification-based MIL). This framework combines feature stratification with teacher–student learning to guide the model learning robust patterns from instances with different saliency levels. The core innovation of PFS-MIL is the pathological feature stratification mechanism, which uses a teacher model to categorize instances in WSIs into three groups based on the prominence of their pathological features: significant, latent, and trivial. Based on the stratification strategy, pseudo-labeling and feature shuffling techniques are introduced to support the dual-level learning of the student model. Our experiments compared PFS-MIL with ten advanced MIL methods across three public lung cancer datasets. Results show that PFS-MIL significantly outperforms other methods, validating the effectiveness of pathological feature stratification in lung cancer pathological image classification.

Neoadjuvant chemotherapy (NACT), a key strategy for various cancers, markedly improves patient prognosis and 5-year survival rates. However, numerous patients develop resistance to NACT and thus fail to benefit from it. Therefore, identifying reliable biomarkers to predict patient responsiveness to NACT remains a critical challenge. Here, we demonstrate that elevated expression of INCENP and CDCA8 contributes to poor NACT responsiveness across multiple cancers. Mechanistically, the 5'UTR (GGACT at position 113) of INCENP and the 3'UTR (GGACT at position 1041) of CDCA8 undergo m⁶A methylation and are recognized by YTHDF3, which facilitates their translation through interaction with eIF3A, ultimately driving poor response to NACT. Moreover, inhibition of INCENP and CDCA8 enhances NACT sensitivity by promoting multipolar spindle formation. Collectively, our findings establish that INCENP and CDCA8 serve as crucial biomarkers for predicting NACT responsiveness and as potential therapeutic targets for combination therapy with NACT to improve patient survival.

Human epidermal growth factor receptor 2 (HER2) is a key biomarker and therapeutic target in several malignancies, including breast, gastric, and other solid tumors. Recent advancements in cancer molecular profiling and the Food and Drug Administration's approval of trastuzumab deruxtecan for HER2-positive pan-tumor indications have highlighted the broader relevance of HER2 alterations across diverse cancers. However, the lack of standardized guidelines for HER2 testing in a pan-tumor context creates variability in clinical practice, hindering the optimal implementation of HER2-targeted therapies beyond traditional indications. To address this gap, a multidisciplinary panel of Chinese experts has developed a consensus providing comprehensive recommendations on diagnostic strategies, testing methodologies, and clinical applications of HER2 overexpression detection. By establishing a unified framework for HER2 overexpression assessment, this consensus aims to enhance the precision of HER2 testing, optimize patient selection for targeted therapies, and improve clinical outcomes across a wide spectrum of HER2 overexpression malignancies.

The impact of neoadjuvant combined chemotherapy, immunotherapy, and targeted therapy on pathologic responses and survival outcomes in HER2-positive locally advanced gastric cancer remains unclear. In this single-arm, phase 2 trial, patients with HER2-positive resectable cT4 and/or N + M0 gastric or gastroesophageal junction (G/GEJ) adenocarcinoma received four cycles of neoadjuvant camrelizumab plus trastuzumab and CapOx, followed by D2 gastrectomy and four cycles of CapOx. The primary endpoint was pathological complete response (pCR, ypT0N0) rate. Twenty-five patients were enrolled and received neoadjuvant combination treatment. Of these patients, 11 (44

Pathogenic/likely pathogenic variants (P/LPVs) in DNA damage response (DDR) genes are known ovarian cancer (OC) risk factors, but gene-specific risk estimates in Han Chinese remain unclear. To accurately assess the risk associated with DDR genes in the Han Chinese population to facilitate personalized risk management and enhance clinical decision-making. We performed next-generation sequencing of 45 DDR genes in 666 OC patients from Henan, China. Associations between P/LPVs and clinical features were assessed using chi-squared tests. Variant frequencies were compared with population controls (gnomAD and ChinaMAP databases) to estimate gene-specific odds ratios (ORs) using Fisher’s test. In Henan Ovarian Cancer patients, the median disease onset age was 53 years (range: 24–81), with 7.7

ObjectiveTertiary Lymphoid Structures (TLSs) are ectopic lymphoid aggregates that form within the tumor microenvironment (TME) and are increasingly recognized as potential prognostic biomarkers in various cancers. However, the spatial heterogeneity and prognostic value of TLSs in esophageal squamous cell carcinoma (ESCC) remain poorly defined. This study aimed to characterize the spatial distribution patterns of TLSs and tumor-infiltrating lymphocytes (TILs), and to establish a refined prognostic model for ESCC patients in both surgery-only and neoadjuvant therapy cohorts.MethodsThe TLSs were quantified through microscopic evaluation and digital slide analysis and correlated with prognosis by Cox regression and Kaplan-Meier analyses. The heterogeneity and clinical prognostic value of TLSs were explored by analyzing their distribution, density, and maximum diameter in different regions of ESCC patients.ResultsTLSs showed spatial distribution heterogeneity in the tumor area, adjacent area, and marginal area, with consistent differences observed across different paraffin blocks. The distribution of iTIL and sTIL also exhibited certain spatial heterogeneity. In the surgical cohort (n = 117), the median Overall Survival (OS) and Disease-Free Survival (DFS) were 33 months and 15 months, respectively. Univariate analyses showed that TLS presence in tumor (TG), TLS-rich regions (TR), TLS ratio in normal regions (NR), tumor-stroma ratio (TSR), and both iTIL and sTIL levels were significantly associated with OS (p < 0.05). Multivariate analysis confirmed N stage, TG, TR, TLS abundance in adjacent regions (NA), and TLS density in tumor (NT), along with TSR, iTIL, and sTIL, as independent predictors of prognosis (p < 0.05). High TLS presence in tumor regions (TG-high) was associated with significantly improved OS (log-rank p = 0.026).ConclusionThis study demonstrates that TLSs and TILs in ESCC are not only prognostically relevant but also spatially heterogeneous. The refined spatial immune profiling across multiple tumor regions improves prognostic stratification and may inform personalized treatment planning in ESCC.

BACKGROUND:Body composition alterations such as skeletal muscle (SM) loss in cancer patients are associated with poor survival. In turn, immune cell-driven pathways have been linked to muscle wasting. We aimed to investigate the relationship between body composition, tumour-infiltrating lymphocytes and survival in patients with advanced lung cancer. METHODS:We studied 200 patients with advanced lung cancer receiving immunotherapy (n = 81) or non-immunotherapy regimens (n = 119). Body composition including SM index (SMI) at baseline and longitudinal changes were assessed using computed tomography (CT) scans at the third lumbar vertebra. Associations between body composition parameters and overall survival (OS) were evaluated using Cox regression analysis. The median value of SMI, stratified by sex, was used as the cut-off to define groups with high and low baseline SMI. Stable SMI was defined by any increase or < 2% decrease per 100 days; loss of SMI was defined by ≥ 2% decrease per 100 days. Logistic regression analysis was applied to investigate the association between SMI and peripheral circulating immune cells. Tumour-infiltrating lymphocytes were identified by immunohistochemistry, and their relationship with SMI was evaluated. RESULTS:SMI loss was associated with shorter OS (whole cohort: HR = 2.314, 95% CI = 1.388-3.858, p = 0.001; immunotherapy cohort: HR = 3.028, 95% CI = 1.113-8.236, p = 0.03; non-immunotherapy cohort: HR = 2.298, 95% CI = 1.191-4.435, p = 0.013). Low baseline SMI was associated with higher CD3+ T cell abundance (OR = 1.240, 95% CI = 1.080-1.424, p = 0.002) but lower CD3+ CD8+ T cell abundance (OR = 0.862, 95% CI = 0.762-0.974, p = 0.018) in peripheral blood. Subsequent SMI loss during treatment was also significantly associated with higher CD3+ T cell counts (OR = 3.414, 95% CI = 1.301-8.961, p = 0.013) and lower CD3+ CD8+ T cell abundance (OR = 0.666, 95% CI = 0.459-0.968, p = 0.033). Patients with stable SMI had a higher number of CD8+ tumour-infiltrating lymphocytes than patients with SMI loss (15.4% vs. 7.9%, p = 0.036). CONCLUSION:SM loss is an independent predictor for survival in patients with advanced lung cancer and is associated with reduced peripheral and tumour-infiltrating cytotoxic T cell abundance. An inadequate antitumour immune response may contribute to metabolic tissue wasting in cancer.

Metaplastic breast carcinoma comprises a heterogeneous group of morphologic variants characterized by markedly aggressive pathological behavior and diverse histological subtypes. Accurate diagnosis of metaplastic breast carcinoma is essential for implementing effective and individualized treatment approaches; however, its differentiation from similar tumors may occasionally be challenging. We report two cases of breast tumors diagnosed using comprehensive tumor genome analysis.

PURPOSE:This study investigated the effects of taxane-cisplatin combinations on pathologic complete response (pCR) rates and survival outcomes in triple-negative breast cancer (TNBC). PATIENTS AND METHODS:The HELEN-001 trial enrolled patients ages 18 to 70 years with stage II-III TNBC, randomly assigning them to receive either docetaxel (75 mg/m2) plus cisplatin (75 mg/m2; TP) or docetaxel (75 mg/m2), doxorubicin (50 mg/m2), and cyclophosphamide (500 mg/m2; TAC). Treatments were administered every 3 weeks for six cycles, with the primary endpoint being pCR (ypT0/isN0) and secondary endpoints being event-free survival (EFS), overall response rate, breast-conserving surgery rate, and toxicity. RESULTS:From November 2018 to June 2022, 212 Asian female patients were enrolled across six hospitals in China, with 106 patients in each group. The pCR rate was significantly higher for TP (51.9%) than for TAC (35.8%; P = 0.028). After a median follow-up of 40 months, EFS was 86.1% in the TP group and 80.0% in the TAC group (HR, 0.639; P = 0.196). In germline BRCA1/2 mutation carriers, EFS was significantly higher with TP than with TAC (100% vs. 53.8%; P = 0.008). Grade 3 or higher adverse events occurred in 54% of patients in the TP group and 48% in the TAC group. CONCLUSIONS:The TP regimen demonstrated significantly improved pCR rates with a manageable toxicity profile, suggesting the potential benefit of taxane plus platinum regimens in patients with TNBC.

Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL) is a highly aggressive malignancy with inferior outcomes after treatment, which might be largely attributed to the immune escape induced by EBV via modulation of the immune checkpoint programmed cell death 1 (PD-1)/PD-ligand 1 (PD-L1). This study aimed to explore the role that EBV-encoded latent membrane protein 2A (LMP2A) played in the mechanisms of immune escape of EBV+ DLBCL cells. Ten cases each of EBV+ DLBCL with and without immunohistochemical expression of LMP2A were submitted for evaluation of PD-L1, p65/NF-κB, phosphorylated SYK (pSYK), and p-p65 expression by immunohistochemistry. To observe the relationship between LMP2A expression and the tumor immune microenvironment, tumor-infiltrating CD4+ and CD8+ T-cell levels were also evaluated by immunofluorescence assay. Compared with LMP2A-negative cases, LMP2A+ cases exhibited more pronounced biologic aggressiveness, and featured significantly higher level of pSYK, p-p65 and PD-L1 and increased CD4+/CD8+ ratio. In vitro experiments were conducted to ascertain the effects of SYK, p65/NF-kB signaling on PD-L1 expression in the OCI-LY8 cells. After transfection with LMP2A, the expression levels of pSYK, p65, p-p65, and PD-L1 were all elevated, while knockdown of p65 or pSYK in LMP2A-transfected DLBCL cells resulted in PD-L1 inhibition. Our work indicates that LMP2A may mimic BCR and trigger the SYK/NF-κB signaling, which subsequently influences the PD-L1 levels of tumor cells and the tumor immune microenvironment, thus facilitating the immune evasion of lymphoma cells. These findings may have clinical implications for modulating or improving the therapeutic strategies of patients with EBV+ DLBCL.