Exosomes, extracellular vesicles with diameters ranging from 30 to 150 nm, are widely present in various body fluids. Recently, microRNAs (miRNAs) have been identified in exosomes, the biogenesis, release, and uptake of which may involve the endosomal sorting complex required for transport (ESCRT complex) and relevant proteins. After release, exosomes are taken up by neighboring or distant cells, and the miRNAs contained within modulate such processes as interfering with tumor immunity and the microenvironment, possibly facilitating tumor growth, invasion, metastasis, angiogenesis and drug resistance. Therefore, exosomal miRNAs have a significant function in regulating cancer progression. Here, we briefly review recent findings regarding tumor-derived exosomes, including RNA sorting and delivering mechanism. We then describe the intercommunication occurring between different cells via exosomal miRNAs in tumor microenvironmnt, with impacts on tumor proliferation, vascularization, metastasis and other biological characteristics. Finally, we highlight the potential role of these molecules as biomarkers in cancer diagnosis and prognosis and tumor resistance to therapeutics.

Exosomes are extracellular vesicles released by many cell types and have been attributed for their roles in many diseases including cancer. Exosomes secreted by tumor cells and stromal cells are critical mediators of intercellular communication in tumor microenvironments. Long noncoding RNAs (lncRNAs) are selectively sorted into exosomes and can regulate cancer onset and progression in a variety of ways. In this review, we summarize the characteristics of exosomal lncRNAs and their dysregulation in multiple types of cancer. We provide an overview of current research on exosomal lncRNAs in tumor microenvironments, especially the functions of exosomal lncRNAs in regulating tumor biology. A deeper understanding of the role of exosomal lncRNAs in the tumor microenvironment may help provide new diagnostic and prognostic markers for cancer.

Highlights d Tumor-secreted CTSC promotes breast-to-lung metastasis by regulating neutrophils d CTSC activates membrane-bound PR3 of neutrophils to upregulate IL-1b secretion d CTSC enhances neutrophil recruitment into metastatic niches and induces NETosis d Targeting CTSC with AZD7986 effectively inhibits lung metastasis in mice

Yes-associated protein 1 (YAP1) exerts significant effects in various malignancies. However, the oncogenic role of YAP1 remains controversial, and the mechanism by which YAP1 regulates non-coding RNAs is still largely unknown. The present study aimed to assess the effect of YAP1 on the malignant behaviors of colorectal carcinoma (CRC) and explore the underlying regulatory mechanism of the YAP1–MALAT1–miR-126-5p axis. YAP1 was highly expressed in CRC tissues as assessed by GSE20916 and its expression was negatively correlated with overall survival in 83 CRC cases. Meanwhile, YAP1 promoted proliferation, invasion, and migration in colon cancer cells, in vitro and in vivo. MALAT1 was obviously expressed, with differential expression of 11 lncRNAs in HCT116 cells after transfection with siYAP1 or si-Ctl. Based on bioinformatics prediction, immunoprecipitation (IP), and chromatin immunoprecipitation (ChIP), the interaction of YAP1 with TCF4/β-catenin was regulated by MALAT1. Bioinformatics prediction, dual luciferase assay, RNA-IP, and RNA pull-down assay demonstrated that YAP1-induced MALAT1 promoted the expression of metastasis-associated molecules such as VEGFA, SLUG, and TWIST, by sponging miR-126-5p in CRC. These findings indicated that the YAP1–MALAT1–miR-126-5p axis could control angiogenesis and epithelial–mesenchymal transition in CRC, providing potential biomarkers and therapeutic targets for CRC.

Liver metastasis, the leading cause of colorectal cancer mortality, exhibits a highly heterogeneous and suppressive immune microenvironment. Here, we sequenced 97 matched samples by using single-cell RNA sequencing and spatial transcriptomics. Strikingly, the metastatic microenvironment underwent remarkable spatial reprogramming of immunosuppressive cells such as MRC1+ CCL18+ M2-like macrophages. We further developed scMetabolism, a computational pipeline for quantifying single-cell metabolism, and observed that those macrophages harbored enhanced metabolic activity. Interestingly, neoadjuvant chemotherapy could block this status and restore the antitumor immune balance in responsive patients, whereas the nonresponsive patients deteriorated into a more suppressive one. Our work described the immune evolution of metastasis and uncovered the black box of how tumors respond to neoadjuvant chemotherapy. Significance: We present a single-cell and spatial atlas of colorectal liver metastasis and found the highly metabolically activated MRC1+ CCL18+ M2-like macrophages in metastatic sites. Efficient neoadjuvant chemotherapy can slow down such metabolic activation, raising the possibility to target metabolism pathways in metastasis. This article is highlighted in the In This Issue feature, p. 1

The successful use of electrochemiluminescence (ECL) in immunoassay for clinical diagnosis requires development of novel ECL signal probes. Herein, we report lanthanide (Ln) metal−organic frameworks (LMOFs) as ECL signal emitters in the ECL immunoassay. The LMOFs were prepared from precursors containing Eu (III) ions and 5-boronoisophthalic acid (5-bop), which could be utilized to adjust optical properties. Investigations of ECL emission mechanisms revealed that 5-bop was excited with ultraviolet photons to generate a triplet-state, which then triggered Eu (III) ions for red emission. The electron-deficient boric acid decreased the energy-transfer efficiency from the triplet-state of 5-bop to Eu (III) ions; consequently, both were excited with highefficiency at single excitation. In addition, by progressively tailoring the atomic ratios of Ni/Fe, NiFe composites (Ni/Fe 1:1) were synthesized with more available active sites, enhanced stability, and excellent conductivity. As a result, the self-luminescent europium LMOFs displayed excellent performance characteristics in an ECL immunoassay with a minimum detectable limit of 0.126 pg mL −1 , using Cytokeratins21-1 (cyfra21-1) as the target detection model. The probability of false positive/false negative was reduced dramatically by using LMOFs as signal probes. This proposed strategy provides more possibilities for the application of lanthanide metals in analytical chemistry, especially in the detection of other disease markers.

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Diverse immune cells in the tumor microenvironment form a complex ecosystem, but our knowledge of their heterogeneity and dynamics within hepatocellular carcinoma (HCC) still remains limited. To assess the plasticity and phenotypes of immune cells within HBV/HCV-related HCC microenvironment at single-cell level, we performed single-cell RNA sequencing on 41,698 immune cells from seven pairs of HBV/HCV-related HCC tumors and non-tumor liver tissues. We combined bio-informatic analyses, flow cytometry, and multiplex immunohistochemistry to assess the heterogeneity of different immune cell subsets in functional characteristics, transcriptional regulation, phenotypic switching, and interactions. We identified 29 immune cell subsets of myeloid cells, NK cells, and lymphocytes with unique transcriptomic profiles in HCC. A highly complex immunological network was shaped by diverse immune cell subsets that can transit among different states and mutually interact. Notably, we identified a subset of M2 macrophage with high expression of CCL18 and transcription factor CREM that was enriched in advanced HCC patients, and potentially participated in tumor progression. We also detected a new subset of activated CD8+ T cells highly expressing XCL1 that correlated with better patient survival rates. Meanwhile, distinct transcriptomic signatures, cytotoxic phenotypes, and evolution trajectory of effector CD8+ T cells from early-stage to advanced HCC were also identified. Our study provides insight into the immune microenvironment in HBV/HCV-related HCC and highlights novel macrophage and T-cell subsets that could be further exploited in future immunotherapy.