Ethnopharmacological relevance Cardiotoxicity caused by doxorubicin (DOX) has become the most important toxicity that hinders its clinical application. Tongmai Yangxin (TMYX) Pill is a Chinese patent medicine composed of the ancient classic prescriptions Zhiguorice decoction and Shengmai powder. Aim of the study The present study aimed to investigate whether and how TMYX ameliorated the DOX-induced cardiotoxicity via an m6A-dependent mechanism. Materials and methods CCK-8, JC-1 fluorescence mitochondrial membrane potential analysis, ROS fluorescence, TUNEL assay, and oxygen consumption rate assays were performed to evaluate the protective effects of TMYX on cardiomyocytes which were treated with DOX. Results In vivo, TMYX administration effectively improved cardiac function and restored mitochondrial function. For the cardiomyocytes in vitro, TMYX alleviated the cardiomyocytes’ apoptosis by recovering mitochondrial energy metabolism that was repressed by DOX treatment. Besides, TMYX reduced the m6A methylation level and promoted m6A demethylase ALKBH5 expression in DOX-treated cardiomyocytes. Mechanistically, TMYX repressed the BNIP3 mRNA stability in an ALKBH5/m6A-dependent manner to improve cardiomyocytes mitochondrial energy metabolism. Conclusion These findings illustrated a remarkable protective role of TMYX against DOX-induced cardiotoxicity through ameliorating cardiomyocyte mitochondrial energy metabolism, which provided a new perspective for the mechanism of Chinese medicine compound in the treatment of cardiotoxicity.

Cancer cells adapt to hypoxia through coordinated transcriptional and metabolic reprogramming; however, how metabolite transport integrates these processes with immune regulation remains poorly understood. Here, we identify SLCO4A1 as a hypoxia-inducible transporter that links metabolic adaptation to immune evasion. Mechanistically, hypoxia activates AMPK, which promotes TFE3 nuclear translocation and stability, enabling direct transcriptional activation of SLCO4A1. Functionally, SLCO4A1 relocalizes to the plasma membrane under hypoxia and regulates bidirectional metabolite transport. Loss of SLCO4A1 selectively impairs tumor growth under hypoxic conditions in vitro and in vivo, while re-expression restores proliferation. Metabolomic analyses further reveal that SLCO4A1 promotes the export of xanthosine, which acts as an extracellular immunosuppressive metabolite that attenuates NK cell activation, induces IL-6 production, and reprograms immune cell metabolism. Collectively, our findings define an AMPK–TFE3–SLCO4A1 signaling axis as an immunometabolic checkpoint that couples hypoxia-driven metabolic reprogramming to suppression of anti-tumor immunity. Targeting SLCO4A1 or xanthosine-mediated signaling may therefore represent a potential strategy to enhance NK cell–dependent anti-tumor responses in hypoxic cancers.

8058 Background: For patients with resectable, locally advanced EGFR-mutated NSCLC, traditional neoadjuvant chemotherapy yields suboptimal efficacy. While EGFR-TKIs are standard in the adjuvant therapy, their role in neoadjuvant therapy is under active investigation. Methods: This single-arm, phase II study evaluated neoadjuvant firmonertinib plus platinum-based chemotherapy in patients with stage II-IIIB EGFR-mutated NSCLC. The primary endpoint was major pathological response (MPR), the major second endpoint were pathological complete response (pCR), objective response rate (ORR), R0 resection rate and rate of downstaging. Results: Among the 13 patients currently enrolled, 11 completed 4 cycles of neoadjuvant therapy, and 9 underwent radical surgery. The MPR rate and the pCR rate are both currently at 0. The ORR is 77.8%, and the radical resection rate reaches 100%. The TNM tumor stage reduction rate is 66.7%. The incidence of grade 3/4 adverse events is 11.1%, and there are no 5-grade adverse events. Conclusions: Firmonertinib with chemotherapy as neoadjuvant in II-IIIB EGFR-mutated NSCLC demonstrated a promising surgical conversion rate and a manageable safety profile, supporting its feasibility for further study. Clinical trial information: NCT06890182 .

To investigate the incidence, clinicopathological characteristics, and prognostic impact of SMARCA4 mutations in breast cancer, we conducted a retrospective cohort study using the MSK-CHORD database, enrolling 4,032 patients categorized into SMARCA4 mutant (1.22

Non-small cell lung cancer (NSCLC) is the most common pathological type of lung cancer, characterized by high morbidity and mortality. Traditional treatments, including surgery, chemotherapy, and radiotherapy, have long been the mainstay of management. However, the advent of targeted therapy and immunotherapy, particularly immune checkpoint inhibitors (ICIs) such as anti-PD-1/PD-L1 antibodies, has significantly improved patient survival outcomes. These advancements have transformed the therapeutic landscape for early-stage, locally advanced, and advanced NSCLC without actionable gene mutations. Despite multiple ICIs being approved for clinical use, critical questions regarding the optimal beneficiary population and predictive biomarkers remain under investigation. To address these challenges, the Yangtze River Delta Lung Cancer Cooperation Group (ECLUNG; Youth Committee) has formulated an expert consensus on the diagnosis and treatment of NSCLC with ICIs. This consensus aims to provide standardized and evidence-based recommendations to optimize diagnostic precision and therapeutic decision-making in NSCLC.

2540 Background: T-cell exhaustion and poor persistence limit tumor infiltrated lymphocytes (TILs) efficacy in solid tumors. GK01 is an autologous tumor-reactive T-cell product enriched for stem cell memory T cells (TSCM: CD45RA + CD62L + ) and diverse T-cell receptor (TCR) clonotypes to promote durable engraftment. We conducted GUARDIAN-01 (NCT06954558), a phase I study of GK01 plus IL-2 in advanced solid tumors. Methods: This single-arm, open-label study enrolled patients with advanced solid tumors (ECOG PS 0-1; measurable disease per RECIST v1.1). Patients received standard lymphodepletion, GK01 (5×10 9 -1×10 11 cells per manufacturing yield), and IL-2 (300,000 IU/kg IV q12h, up to 5 days). Repeat infusion was permitted at investigator discretion based on clinical benefit. Primary endpoint was safety; secondary endpoints included objective response rate (ORR), disease control rate (DCR), and cellular kinetics via absolute lymphocyte count (ALC) and TCR sequencing. Results: From March 2025 to January 2026, 6 patients were enrolled (median age 53.5 years; median 2 prior lines; tumor types included gastric n = 3, pancreatic n = 1, penile SCC n = 1, and melanoma n = 1). Manufacturing succeeded in all patients; median time from tissue procurement to infusion was 28 days (range 25-39). Infused GK01 exhibited median TSCM frequency of 71% (range 42-92%) and demonstrated robust expansion and stemness properties. Upon tumor challenge, these T cells secreted IFN-γ at a median of 1,632 pg/mL (range, 35 - 4,886). Median dose was 2.8×10 10 cells (range 1.4×10 10 -8.8×10 10 ); 2 patients received repeat infusion. The median total IL-2 dose administered was 4 (range 1-5), with the first dose administered approximately 6 hours after GK01 infusion. No dose-limiting toxicities (DLTs) occurred. G3/4 adverse events were exclusively hematologic (neutropenia, thrombocytopenia, leukopenia, lymphopenia in all patients), attributable to lymphodepletion. Chills, fever, and erythroderma occurred in all patients but G1-2, resolving within 2 weeks. At median follow-up of 169 days (range 80-297), ORR was 66.7% (4/6 PR; 2/6 SD), and DCR was 100%. The median peak ALC reached at 11.3×10 9 /L (range 4.9-22.7) at days 7-9 post-infusion, remained elevated at 3.1×10 9 /L (range 2.0-6.4) at 1 month. Among patients with available peripheral-blood samples (n = 4), product-derived TCR clonotypes comprised 94% of the circulating repertoire at day 7 and 92% at 2 months. Conclusions: In this first-in-human study, GK01 plus IL-2 demonstrated a favorable safety profile with no DLTs and manageable toxicity. The TSCM-enriched product achieved a 67% ORR and 100% DCR, with product-derived clonotypes persisting at > 90% of the T-cell repertoire at 2 months. These findings validate the stemness-enriched T-cell platform and support expansion cohorts in selected solid tumor indications. Clinical trial information: NCT06954558 .

As an emerging biomarker, tumor mutational burden (TMB) has attracted increasing attention from clinicians in predicting the efficacy of tumor immunotherapy. Currently, TMB is detected primarily by whole-exome sequencing or targeted panel sequencing on high-throughput sequencing platforms. However, the lack of uniformity in detection methods, threshold settings, and reporting formats, as well as the significant differences in TMB values among different cancer types, have hindered the standardized application of this biomarker in clinical practice. This consensus focuses on the definition, standardization of detection, clinical significance, and limitations of TMB, and provides consensus recommendations for the clinical application of TMB in real-world practice in China. This consensus is aimed at helping clinicians and laboratory personnel understand the clinical significance and testing standards of TMB, promoting more accurate interpretation of test results, and improving patient care.

Malignant peritoneal mesothelioma (MPeM) is a malignant tumor originating from the peritoneum. In recent years, the incidence of MPeM has been increasing. Because MPeM is insidious in onset and of strong local invasiveness, and most patients are found in advanced stage, early screening and treatment of the population at the high risk of malignant mesothelioma are of vital importance. The main treatment methods for MPeM include cytoreductive surgery, hyperthermic intraperitoneal chemotherapy, systemic chemotherapy and immunotherapy. To promote the homogenization and normalization of the diagnosis and treatment of malignant peritoneal mesothelioma, based on existing clinical research evidence, the Chinese Alliance of Research for Mesothelioma (ChARM) formulated the National Expert Consensus on the Clinical Diagnosis and Treatment of Malignant Peritoneal Mesothelioma in combination with expert opinions nationwide. The contents of expert consensus cover epidemiology, diagnosis, treatment and prognosis follow-up.

Intrinsic resistance of small cell lung cancer (SCLC) to immunotherapy underscores our limited understanding of how tumors can evade immune responses. Here we demonstrated that neural cell adhesion molecule 1 (NCAM1, also called CD56) facilitates disease progression, tumor stemness, and resistance to NK cell-mediated cytotoxicity in SCLC. Mechanistically, cis-binding of NCAM1 with its ligand L1CAM on the surface of identical tumor cell occupied considerable antigenic epitopes of L1CAM, and thereby prevented L1CAM from trans-binding with CD56+ NK cells to form immune-synapse structures, which may render the tumor cells more resistant to NK cell-mediated cytotoxicity in SCLC. Additionally, CHMP4B, a member of the ESCRT complex involved in plasma membrane repair, were essential for SCLC stemness and NK cell-mediated cytotoxicity, and NCAM1 can protect SCLC cells from immune attack and stem cell renewal by interacting with CHMP4B. SCLC specimens with concurrent high expression of NCAM1 and CHMP4B exhibited lower cytotoxic immune cell infiltration, were located farther from cytotoxic immune cells, and were associated with inferior clinical outcomes. These findings reveal potential mechanisms of NCAM1 in sustaining SCLC stemness and resisting cytolytic attack, and provide a potential target of CHMP4B against self-renewal and immunoresistance.

The distribution characteristics of microplastics (MPs) in paired breast cancer tumor and para-tumor tissues, and their potential associations with clinical characteristics, remain insufficiently understood. This study included eight breast cancer patients with surgical resection whose paired tumor and para-tumor tissues were collected. The morphologies, particle sizes, and types of microplastics within the tissues were identified and characterized using Laser Direct Infrared (LDIR) spectroscopy and Scanning Electron Microscopy (SEM). Moreover, correlations between microplastic abundance and patients’ demographic and clinical characteristics were analyzed. SEM imaging revealed diverse morphologies—granular, fibrous, and irregular—often exhibiting folds and fractures. The majority of microplastic particles were within the 20–100 μm size range. Multiple types of polymeric microplastics—including Fluororubber (Flu), polyethylene (PE), polyethylene terephthalate, polypropylene, and polyvinyl chloride (PVC)—were detected in all paired samples. Notably, the abundance of Flu, PE, and PVC was significantly higher in tumor tissues compared to para-tumor tissues. Correlation analyses identified exploratory associations between selected microplastic types, body mass index, and certain tumor biomarkers. These findings provide preliminary evidence of tissue-specific MP distribution in breast cancer and support further investigation into the potential biological relevance of microplastics in breast cancer.

Abstract: Germ cell tumors of the mediastinum (GCTM) are a type of extragonadal tumor, accounting for <5% of both mediastinal tumors and germ cell tumors. Based on histopathological classification, GCTMs can be divided into three major types: teratomas, seminomatous germ cell tumors, and non-seminomatous germ cell tumors, which can be further subdivided into subtypes such as yolk sac tumors and choriocarcinomas. Due to the scarcity and diversity of GCTMs, there is a lack of clear international standards in diagnosis and treatment, leading to clinical challenges such as high misdiagnosis rates and non-standardized treatment. To promote the standardization of GCTM management, experts from the Pan-Yangtze River Delta Alliance of Research for Thymomas (PRD-ART) conducted panel discussions, integrating the medical evidence in pathology, molecular biology, and new drug development, to create clinical recommendations for diagnosis, treatment, and follow-up. This expert consensus: 1) emphasizes molecular testing in clinical management, 2) encourages multidisciplinary consultation to facilitate personalized therapies, 3) promotes international collaboration to validate novel biomarkers and therapies, and 4) suggests the use of real-world, umbrella trial designs to address the scarcity and heterogeneity problems. These measures aim to standardize and improve the clinical management of GCTMs.

BackgroundThe majority of locally advanced esophageal squamous cell carcinoma (ESCC) patients do not achieve a pathological complete response (NPCR) after neoadjuvant chemoimmunotherapy (NCIT), and their prognosis exhibits significant heterogeneity. This study aimed to establish a pathological subtyping system for NPCR patients to guide precision adjuvant therapy.MethodsWe conducted a retrospective analysis of 243 patients with locally advanced ESCC who underwent NCIT followed by esophagectomy. NPCR patients were categorized into three pathological subtypes based on the anatomical sites of residual disease: T+N+ (residual tumor in both primary site and lymph nodes), T+N0 (residual tumor confined to primary site only), and T0N+ (residual disease in lymph nodes only). Survival outcomes were compared, and the efficacy of adjuvant immunotherapy was evaluated within each subtype. Prognostic nomograms for disease-free survival (DFS) and overall survival (OS) were constructed and validated.ResultsAmong 176 NPCR patients, the novel subtyping system achieved significant prognostic stratification. The T+N+ subtype demonstrated the poorest survival outcomes, while the T0N+ subtype did not significantly differ from the PCR cohort. Notably, adjuvant immunotherapy provided significant survival benefits exclusively in the T+N0 subtype (DFS: HR = 3.45, 95% CI: 1.17-10.17, P = 0.025; OS: HR = 4.17, 95% CI: 1.07-16.23, P = 0.039), with no significant benefits observed in either the T+N+ or T0N+ subtypes. Based on these findings, we developed and internally validated prognostic nomograms integrating pathological subtype, ypTNM stage, and other key clinicopathological variables, which demonstrated good predictive accuracy (C-index >0.75) for individualized risk assessment.ConclusionWe propose a novel and practical pathological subtyping framework for NPCR ESCC patients that effectively resolves prognostic heterogeneity and identifies, the T+N0 subtype as the primary beneficiary of adjuvant immunotherapy. The developed nomograms provide a user-friendly tool to facilitate personalized postoperative management and adjuvant therapy decisions.

Ten chaetoglobosin alkaloids were isolated from the fermentation culture of a soil-derived fungus, Chaetomium sp., and their structures with absolute configurations were characterized by spectroscopic methods including high-resolution mass spectrometry (HRMS), nuclear magnetic resonance (NMR), X-ray diffraction analysis, and electronic circular dichroism, as well as comparison with literature data. Among them, three compounds (1-3) have not been described previously, and compound 8 is reported for the first time as a new natural product. A preliminary cytostatic screening revealed good inhibitory activity for 1, 6, and 8 against the A549 cell line (lung), and for 1, 2, 4, 6, and 8 against the MDA-MB231 cell line (breast). Further exploration demonstrated that compound 8 exerted in vitro antitumor activity by inducing significant apoptosis and S-phase cycle arrest, as well as blocking the migration and invasion of MDA-MB231 cells.

Anlotinib, an anti-angiogenic agent, has demonstrated significant anti-tumor effects in non-small cell lung cancer (NSCLC). However, whether anlotinib exerts its anti-tumor activity in NSCLC through ferroptosis, and its underlying mechanisms, remain unclear. This study revealed that anlotinib effectively inhibited the proliferation of NSCLC cells in a time- and dose-dependent manner. Treatment with anlotinib resulted in increased levels of ferroptosis targets (lipid reactive oxygen species and malondialdehyde) and p53 protein expression, while decreasing glutathione levels and the protein expression of solute carrier family 7 member 11 (xCT) and glutathione peroxidase 4 (GPX4). Notably, the ferroptosis inhibitor, Ferrostatin-1 (Fer-1), or the p53 inhibitor, Pifithrin-α (PFT-α), reversed the observed effects on ferroptosis induction in NSCLC cells. Consistently, our in vivo studies showed accelerated tumor growth rates for the anlotinib/Fer-1 group and the anlotinib/PFT-α group compared with administration of anlotinib alone. However, anlotinib-induced ferroptosis was suppressed in p53-deficient cells. Collectively, these findings confirm that anlotinib exerts potent anti-tumor effects both in vitro and in vivo by inducing ferroptosis by modulating the p53/xCT/GPX4 pathway specifically within NSCLC cells.

Malignant mesothelioma of the tunica vaginalis testis (MMTVT) is a rare malignancy originating from mesothelial cells of the testicular tunica vaginalis. Due to its insidious onset and local aggressiveness, most patients are diagnosed at an advanced stage. The treatment modalities for MMTVT primarily include surgery, chemotherapy, and radiotherapy. With the advent of immunotherapy, patient survival has further improved. To standardize and homogenize the diagnosis and treatment of MMTVT in China, the Chinese Alliance of Research for Mesothelioma, combining existing research evidence and nationwide expert opinions, has formulated a national expert consensus on the clinical diagnosis and treatment of MMTVT. This consensus encompasses epidemiology, diagnosis, treatment, prognosis, and follow-up.

Paraptosis is a non-apoptotic form of programmed cell death, distinct from classical apoptosis in morphology and mechanism. It has been implicated in tumor resistance and immune microenvironment remodeling, but its role in breast cancer (BC) remains unclear. We classified patients into two subtypes based on the expression of paraptosis-related genes. Then, we systematically analyzed the prognosis and tumor microenvironment (TME) associated with these subtypes. In addition, we developed a risk score, named the paraptosis-related risk score (PRRS). We comprehensively analyzed the correlation of paraptosis with BC prognosis, TME, immune score, and drug sensitivity. Then, we performed in vitro experiments to verify the effect of PI4KB on BC. The PRRS can effectively predict the prognosis and immunity of BC. Low PRRS was associated with a favorable prognosis, characterized by reduced tumor purity and enhanced immune cell infiltration. In addition, PRRS can help identify patients who are suitable for specific drug therapies. Finally, we found that PI4KB was highly expressed in BC. Knockdown of PI4KB expression significantly suppressed BC cell proliferation and migration. Our study establishes a robust framework for BC subtype classification and prognostic prediction, providing novel guidance for personalized therapeutic strategies.

ABSTRACT Primary malignant pericardial mesothelioma (PMPM), a rare pericardium‐derived malignancy, urgently requires standardized diagnostic and therapeutic protocols. This consensus, established by the Chinese Alliance of Research for Mesothelioma (ChARM) through the integration of evidence‐based research and multicenter clinical expertise, addresses the following critical aspects: The disease is characterized by insidious progression and local invasiveness with the majority of cases diagnosed at advanced stages. Current multimodal therapeutic strategies include radical surgery, platinum‐based combination chemotherapy, and precision radiotherapy. The introduction of PD‐1/PD‐L1 inhibitors has extended median survival to up to 24 months. The consensus emphasizes the diagnostic utility of multimodal imaging combined with histopathological immunohistochemical analysis. Furthermore, a stratified prognostic model incorporating tumor biomarkers is proposed to standardize follow‐up surveillance protocols, ensuring a systematic monitoring of disease progression and therapeutic efficacy.

Background:The impact of STK11/KEAP1 co-mutations on the efficacy of immunotherapy in patients with SMARCA4-mutant advanced non-small cell lung cancer (NSCLC) remains incompletely understood. Our aim was to investigate the effects of STK11/KEAP1 co-mutations on the clinical prognosis of patients with SMARCA4-mutant advanced NSCLC receiving immunotherapy. Methods:We obtained 2,098 patients with stage IIIB-IV NSCLC from the cBioPortal database. Patients harboring EGFR, ALK, ROS1 and RET mutations were excluded. The impacts of SMARCA4 and STK11/KEAP1 co-mutations on the efficacy of chemoimmunotherapy were analyzed, along with their associations with tumor mutational burden (TMB), programmed cell death ligand 1 (PD-L1) expression, and patient prognosis. Results:Among 2,098 patients with NSCLC, SMARCA4-mutant patients accounted for 7.7% (162/2,098), and wild-type patients accounted for 92.3% (1,936/2,098). SMARCA4 mutations are more common in elderly patients, smokers, and patients with adrenal metastasis. Compared with SMARCA4 wild-type patients, SMARCA4-mutant patients had significantly greater TMB (P<0.001) and poorer median overall survival (mOS) (10.6 vs. 17.5 months, P<0.001). Further analysis revealed that patients with SMARCA4 class I alterations had significantly shorter mOS (8.7 vs. 14.1 months, P=0.008) and median first-line treatment progression-free survival (mPFS1) (3.7 vs. 6.6 months, P=0.003) than those with class II alterations. Multivariate regression analysis confirmed that SMARCA4 mutations significantly increased the risk of death [hazard ratio (HR) =1.329, 95% confidence interval (CI): 1.106-1.596, P=0.002]. Compared with chemotherapy, chemoimmunotherapy significantly prolonged mPFS1 (5.6 vs. 3.9 months, P=0.01) but not mOS (10.8 vs. 9.5 months, P=0.91) in patients with SMARCA4 mutations. Among patients receiving first-line chemoimmunotherapy, TMB levels had no significant effect on mPFS1 (5.6 vs. 6.6 months, P=0.83) or mOS (8.5 vs. 10.8 months, P=0.38), but PD-L1-positive patients had significantly longer mPFS1 (8.3 vs. 5.1 months, P=0.02) and mOS (18.9 vs. 9.3 months, P=0.03). SMARCA4 and STK11/KEAP1 co-mutations were not significantly correlated with TMB (P=0.85) or PD-L1 expression (P=0.08). However, the patients with SMARCA4 and STK11/KEAP1 co-mutations had significantly shorter mPFS1 (4.5 vs. 13.3 months, P<0.001) and mOS (8.7 vs. 20.1 months, P=0.005) in the chemoimmunotherapy group. Among SMARCA4-mutant patients, those without STK11/KEAP1 co-mutations derived longer mPFS1 (13.3 vs. 5.6 months, P=0.01) benefits from immunotherapy. In contrast, this benefit markedly reduced mPFS1 (4.5 vs. 2.9 months, P=0.16) in patients with STK11/KEAP1 co-mutations, suggesting that STK11/KEAP1 may affect the immunological efficacy in patients with SMARCA4 mutations. Conclusions:Patients with SMARCA4-mutant NSCLC can benefit from chemoimmunotherapy. However, STK11/KEAP1 co-mutations were associated with poorer prognosis and reduced immunotherapy efficacy in SMARCA4-mutant advanced NSCLC. Moreover, STK11/KEAP1 co-mutations may serve as key stratification markers for predicting the potential benefit of immunotherapy in SMARCA4-mutant NSCLC.

Trastuzumab is currently a key targeted drug for HER2-positive gastric cancer (GC), but there are common problems of drug resistance and cardiotoxicity in clinical treatment, resulting in poor therapeutic effects. Exosomes are natural nanocarriers for drug delivery and engineered exosomes have been widely used in translational medicine research. This study is designed to compare the anti-tumor effects and adverse effects between engineered exosomes carrying HER2 siRNA and trastuzumab. The stable cell line of iRGD-293T was constructed by using lentiviruses, and iRGD-293T and 293T cells were transfected with si-HER2 and exosomes were isolated by ultra-centrifugation. Functional experiments were performed to examine the inhibitory effects of iRGD-exo-si-HER2 and trastuzumab on both HER2-positive GC cells and mouse xenograft models. Blood biochemical indexes were used to test the adverse effects, especially cardiotoxicity. The engineered exosomes modified by iRGD peptide showed higher tumor affinity compared to control exosomes in vitro and in vivo. si-HER2 delivered by iRGD-exosomes significantly inhibited the proliferation and promoted apoptosis of HER2-positive GC cells, and iRGD-exo-si-HER2 significantly reduced the expression of HER2 in GC cells in vitro and in vivo, showing similar efficacy as trastuzumab but with lower cardiac side effects. Our data indicated that iRGD-exo-si-HER2 shows good anti-tumor effect both in vivo and in vitro, and has fewer side effects compared with trastuzumab. And this study suggested that engineering exosomes with si-HER2 can serve as novel strategy for the treatment of HER2-positive GC.

Microplastics are ubiquitous environmental contaminants worldwide. Although studies have shown their potential to harm human health, the relationship between microplastics and tumors remains unclear. The intestine is the primary site for microplastics absorption, thus the impact of microplastics on colorectal cancer merits further investigation. Our results indicate that the endocytosis protein clathrin, highly expressed in cancer cells, plays a crucial role in the massive ingestion of microplastics. Further research reveals that microplastics ingestion enhances lipid absorption in colorectal cancer cells by activating the NF-κB signaling pathway. Accumulation of lipids, in turn, suppresses pyroptosis by inhibiting NLRP3/Caspase-1/GSDMD axis, thereby promoting cellular drug resistance. Moreover, microplastics accelerate colorectal cancer development in mice and enhance tumor resistance to oxaliplatin. In summary, microplastics regulate lipid metabolism and pyroptosis in colorectal cancer, emerging as a novel contributor to chemotherapy resistance in colorectal cancer against the backdrop of escalating microplastics pollution.