Xinjian Fang

Extracellular vesicles (EVs) from immune cells represent a novel drug delivery system with inherent anti‐tumor properties. To remodel the immunosuppressive tumor microenvironment and mediate multimodal therapy, we produced neutrophil nanovesicles at high yield and loaded them with drug (doxorubicin, DOX), near‐infrared region II fluorescent dye (FD1080), and PD‐1 inhibitor (TFA) through a simple extrusion method and further modified them with DSPE‐PEG2000‐cRGD to enhance their tumor‐targeting ability. The RGD‐NNV@FD1080&DOX/TFA exhibited excellent photothermal effect and efficiently suppressed tumor progression in mouse xenograft tumor, PDX, and lung metastasis models. Upon laser irradiation, the RGD‐NNV@FD1080&DOX/TFA elicited the activation of anti‐tumor immunity with increased infiltration of mature dendritic cells (DCs), CD8 ⁺ T cells, and decreased infiltration of regulatory T cells (Tregs) in tumors. Single‐cell RNA sequencing revealed that the combination therapy increased the subtype of cytotoxic and memory T cells while decreasing that of exhausted T cells, and re‐polarized M2 TAMs and N2 TANs. The re‐challenge model further confirmed that RGD‐NNV@FD1080&DOX/TFA exerted effective long‐term immune memory in mouse models and displayed excellent biosafety in vivo. Overall, we designed a simple and potentially clinically applicable nanovesicle‐based nanomedicine delivery system that exhibits a highly efficient anti‐tumor effect by remodeling the tumor immune microenvironment and activating anti‐tumor immunity.

Long non‐coding RNAs (lncRNAs) constitute a critical class of regulatory molecules involved in cancer biology and play pivotal roles in tumor initiation and progression. Nevertheless, the biological functions of many newly identified lncRNAs in non‐small cell lung cancer (NSCLC), as well as their potential therapeutic relevance, remain insufficiently characterized. In this study, high‐throughput sequencing analysis of paired NSCLC tumor tissues and adjacent non‐tumorous samples revealed that LINC00973 is significantly upregulated in tumor specimens. Moreover, elevated LINC00973 expression was found to be closely associated with poor clinical outcomes in patients with NSCLC. Functional assays showed that LINC00973 knockdown inhibits NSCLC cell proliferation, migration, and invasion while inducing apoptosis, whereas overexpression produces opposite effects. These observations were confirmed in vivo, where LINC00973 depletion markedly suppressed tumor growth and metastasis. Mechanistically, LINC00973 interacts with and stabilizes deltex E3 ubiquitin ligase 3L (DTX3L), preventing its ubiquitination‐mediated degradation and activating the AKT signaling pathway. Therapeutically, RGD‐modified exosome‐mediated delivery of LINC00973 siRNA significantly inhibited NSCLC progression in mouse models. Moreover, a synthetic biology‐based strategy enabling hepatic production of exosomes carrying LINC00973‐targeting siRNA achieved robust anti‐tumor effects. Together, these findings establish LINC00973 as an oncogenic lncRNA that promotes NSCLC progression via DTX3L stabilization and highlight LINC00973 as a promising therapeutic target.

Neutrophils, serving as crucial innate immune cells, exert anti-tumor effects through cytotoxic mediators, antibody-dependent responses, and coordination o

Immunotherapy has emerged as a hot topic in the treatment of non-small cell lung cancer (NSCLC) with remarkable success. Compared to chemotherapy patients, the 5-year survival rate for immunotherapy patients is 3-fold higher, approximately 4%–5% versus 15%–16%, respectively. Immunotherapies include chimeric antigen receptor T-cell (CAR-T) therapy, tumor vaccines, immune checkpoint inhibitors, and so forth. Among them, immune checkpoint inhibitors are in the spotlight. Common immune checkpoint inhibitors (ICIs) currently in clinical use include programmed death receptor-1(PD-1)/programmed death ligand-1(PD-L1) and cytotoxic T lymphocyte-associated antigen 4(CTLA-4). This article focuses on monotherapy and combination therapy of CTLA-4 and PD-1/PD-L1 immune checkpoint inhibitors. In particular, the combination therapy of ICIs includes the combination of ICIs and chemotherapy, the combination therapy of dual ICIs, the combination of ICIs and anti-angiogenic drugs, the combination of ICIs and radiotherapy, and the combination of ICIs inhibitors and tumor vaccines and so forth. This article focuses on the combination therapy of ICIs with chemotherapy, the combination therapy of dual ICIs, and the combination therapy of ICIs with anti-angiogenic drugs. The efficacy and safety of ICIs as single agents in NSCLC have been demonstrated in many trials. However, ICIs plus chemotherapy regimens offer significant advantages in the treatment of NSCLC with little to no dramatic increase in toxicity, while combined dual ICIs significantly reduce the adverse effects (AEs) of chemotherapy. ICIs plus anti-angiogenic agents regimen improves anti-tumor activity and safety and is expected to be the new paradigm for the treatment of advanced NSCLC. Despite some limitations, these agents have achieved better overall survival rates. In this article, we review the current status and progress of research on ICIs in NSCLC in recent years, aiming to better guide the individualized treatment of NSCLC patients.

Extracellular vesicles (EVs) are cell‐derived nanosized vesicles that mediate cell‐to‐cell communication via transporting bioactive molecules and thus are critically involved in various physiological and pathological conditions. EVs contribute to different aspects of cancer progression, such as cancer growth, angiogenesis, metastasis, immune evasion, and drug resistance. EVs induce the resistance of cancer cells to chemotherapy, radiotherapy, targeted therapy, antiangiogenesis therapy, and immunotherapy by transferring specific cargos that affect drug efflux and regulate signaling pathways associated with epithelial‐mesenchymal transition, autophagy, metabolism, and cancer stemness. In addition, EVs modulate the reciprocal interaction between cancer cells and noncancer cells in the tumor microenvironment (TME) to develop therapy resistance. EVs are detectable in many biofluids of cancer patients, and thus are regarded as novel biomarkers for monitoring therapy response and predicting prognosis. Moreover, EVs are suggested as promising targets and engineered as nanovehicles to deliver drugs for overcoming drug resistance in cancer therapy. In this review, the biological roles of EVs and their mechanisms of action in cancer drug resistance are summarized. The preclinical studies on using EVs in monitoring and overcoming cancer drug resistance are also discussed.

Liquid biopsy, characterized by minimally invasive detection through biofluids such as blood, saliva, and urine, has emerged as a revolutionary strategy for cancer diagnosis and prognosis prediction. Exosomes are a subset of extracellular vesicles (EVs) that shuttle molecular cargoes from donor cells to recipient cells and play a crucial role in mediating intercellular communication. Increasing studies suggest that exosomes have a great promise to serve as novel biomarkers in liquid biopsy, since large quantities of exosomes are enriched in body fluids and are involved in numerous physiological and pathological processes. However, the further clinical application of exosomes has been greatly restrained by the lack of high-quality separation and component analysis methods. This review aims to provide a comprehensive overview on the conventional and novel technologies for exosome isolation, characterization and content detection. Additionally, the roles of exosomes serving as potential biomarkers in liquid biopsy for the diagnosis, treatment monitoring, and prognosis prediction of cancer are summarized. Finally, the prospects and challenges of applying exosome-based liquid biopsy to precision medicine are evaluated.

Neutrophil-derived exosomes induce tumor cell apoptosis by delivering cytotoxic proteins and activating caspase signaling pathway.

Long non-coding RNA (lncRNA) DANCR (also known as ANCR)—differentiation antagonizing non-protein coding RNA, was first reported in 2012 to suppress differentiation of epithelial cells. Emerging evidence demonstrates that DANCR is a cancer-associated lncRNA abnormally expressed in many cancers (e.g., lung cancer, gastric cancer, breast cancer, hepatocellular carcinoma). Increasing studies suggest that the dysregulation of DANCR plays critical roles in cancer cell proliferation, apoptosis, migration, invasion, and chemoresistance in vitro and tumor growth and metastasis in vivo. Mechanistic analyses show that DANCR can serve as miRNA sponges, stabilize mRNAs, and interact with proteins. Recent research reveals that DANCR can be detected in many body fluids such as serum, plasma, and exosomes, providing a quick and convenient method for cancer monitor. Thus DANCR can be used as a promising diagnostic and prognostic biomarker and therapeutic target for various types of cancer. This review focuses on the role and mechanism of DANCR in cancer progression with an emphasis on the clinical significance of DANCR in human cancers.