Role of tumor-derived exosomes mediated immune cell reprograming in cancer.

Tumor-derived exosomes (TDEs), as topologies of tumor cells, not only carry biological information from the mother, but also act as messengers for cellular communication. It has been demonstrated that TDEs play a key role in inducing an immunosuppressive tumor microenvironment (TME). They can reprogram immune cells indirectly or directly by delivering inhibitory proteins, cytokines, RNA and other substances. They not only inhibit the maturation and function of dendritic cells (DCs) and natural killer (NK) cells, but also remodel M2 macrophages and inhibit T cell infiltration to promote immunosuppression and create a favorable ecological niche for tumor growth, invasion and metastasis. Based on the specificity of TDEs, targeting TDEs has become a new strategy to monitor tumor progression and enhance treatment efficacy. This paper reviews the intricate molecular mechanisms underlying the immunosuppressive effects induced by TDEs to establish a theoretical foundation for cancer therapy. Additionally, the challenges of TDEs as a novel approach to tumor treatment are discussed.

Coaxial dual-path electrochemical biosensing and logic strategy-based detection of lung cancer-derived exosomal PD-L1.

Exosomal programmed death ligand-1 (ExoPD-L1) is a vital marker of immune activation in the early stages of tumor therapy and it can inhibit anti-tumor immune responses. However, due to the low expression of ExoPD-L1 in cancer cells, it is difficult to perform highly sensitive assays and accurately differentiate cancer sources. Therefore, we constructed a coaxial dual-path electrochemical biosensor for highly accurate identification and detection of ExoPD-L1 from lung cancer based on chemical-biological coaxial nanomaterials and nucleic acid molecular signal amplification strategies. The measurements showed that the detected ExoPD-L1 concentrations ranged from 6 × 102 particles per mL to 6 × 108 particles per mL, and the detection limit was 310 particles per mL. Compared to other sensors, the electrochemical biosensor designed in this study has a lower detection limit and a wider detection range. Furthermore, we also successfully identified lung cancer-derived ExoPD-L1 by analyzing multiple protein biomarkers expressed on exosomes through the "AND" logic strategy. This sensor platform is expected to realize highly sensitive detection and accurate analysis of multiple sources of ExoPD-L1 and provide ideas for the clinical detection of ExoPD-L1.

Injectable Hydrogels Including Magnetic Nanosheets for Multidisciplinary Treatment of Hepatocellular Carcinoma via Magnetic Hyperthermia.

Relapse and unresectability have become the main obstacle for further improving hepatocellular carcinoma (HCC) treatment effect. Currently, single therapy for HCC in clinical practice is limited by postoperative recurrence, intraoperative blood loss and poor patient outcomes. Multidisciplinary therapy has been recognized as the key to improving the long-term survival rate for HCC. However, the clinical application of HCC synthetic therapy is restricted by single functional biomaterials. In this study, a magnetic nanocomposite hydrogel (CG-IM) with iron oxide nanoparticle-loaded mica nanosheets (Iron oxide nanoparticles@Mica, IM) is reported. This biocompatible magnetic hydrogel integrated high injectability, magnetocaloric property, mechanical robustness, wet adhesion, and hemostasis, leading to efficient HCC multidisciplinary therapies including postoperative tumor margin treatment and percutaneous locoregional ablation. After minimally invasive hepatectomy of HCC, the CG-IM hydrogel can facilely seal the bleeding hepatic margin, followed by magnetic hyperthermia ablation to effectively prevent recurrence. In addition, CG-IM hydrogel can inhibit unresectable HCC by magnetic hyperthermia through the percutaneous intervention under ultrasound guidance.

Zuogui pill disrupt the malignant cycle in breast cancer bone metastasis through the Piezo1-Notch-1-GPX4 pathway and active molecules fishing.

BACKGROUND: Breast cancer bone metastasis is closely associated with the bone microenvironment. Zuogui Pill (ZGP), a clinically approved formulation in China, effectively regulates the bone microenvironment for the prevention and treatment of osteoporosis. PURPOSE: Few reports have utilized the ZGP for bone metastasis models. This study investigated the intervention and bone-protective properties of ZGP against breast cancer bone metastasis, explored the potential mechanism, and screened for its active compositions by molecules fishing. METHODS: To investigate the intervention efficacy of ZGP and its protein-level mechanism of action, the mouse bone metastasis model and in vitro cell co-culture model were constructed. Affinity ultrafiltration, molecular docking, cellular thermal shift assay and physical scale detection were used to investigate the affinity components of the RANKL protein in ZGP. RESULTS: The administration of ZGP combined with zoledronic acid inhibited the development of tumors and secondary lung metastasis in mice. This translated to a prolonged survival period and enhanced quality of life. ZGP could disrupt the malignant cycle by modulating the Piezo1-Notch-1-GPX4 signaling pathway in the "bone-cancer" communication in the cell co-culture model. Furthermore, 25 chemical components of ZGP were identified, with 10 active compounds exhibiting significant affinity for the RANKL protein. CONCLUSION: The findings of this work highlighted ZGP's potential for intervening in the progression of breast cancer bone metastasis. Thus, this investigation served as an experimental foundation for expanding the application scope of ZGP and for advancing drug development efforts in bone metastasis treatment.

Self-assembly of DNA-hyperbranched aggregates catalyzed by a dual-targets recognition probe for miRNAs SERS detection in single cells.

MicroRNAs (miRNAs) are very important for the early diagnosis and prognosis of tumors. In this work, we achieved the simultaneous detection of microRNA-155 (miR-155) and microRNA-21 (miR-21) with a dual target recognition probe (DRP) based on the nonlinear hybridization chain reaction (HCR). The multi-branched DNA products, three-dimensional multi-hotspot DNA dendrimers (3DmhD) were used in the amplification of the target miRNAs signal. The DRP is constructed with a core of gold nanocages (AuNCs), modified by nucleic acid probes and labeled with Raman signaling molecules ROX and Cy3. Experiments demonstrated that DRP could activate the multi-branched DNA reaction and generate 3DmhD in the presence of miR-155 and miR-21, which can achieve effective amplification of miR-21 and miR-155. When Surface Enhanced Raman Scattering (SERS) analysis was performed on 3DmhD, the multi-hot spot effect of 3DmhD significantly enhanced the signals of ROX and Cy3, allowing ultra-sensitive detection of miR-21 and miR-155 in vitro. To our delight, DRP also exhibited sensitive specificity and significant signal amplification for intracellular miRNAs. These results revealed that DRP has the potential to screen tumor cells by analyzing the expression levels of intracellular miRNAs.

Combination of microfluidic chips and biosensing for the enrichment of circulating tumor cells.

It has been reported that more than 90% of cancer patients are died from cancer metastasis. Circulating tumor cells (CTCs) could detach from solid tumors to form new lesions via blood transport and play an important role in cancer metastasis and progression. As part of the liquid biopsy, the investigation and analysis toward CTCs are of great importance for prognosis assessment and tumor precision medical treatment. Unfortunately, the enrichment of circulating tumor cells has been a huge challenge due to the fact that CTCs are very rare and vulnerable. Thus, a number of effective strategies have been developed for the enrichment of CTCs. This paper discusses the advantages and disadvantages of label-free and label-based methods commonly used in the isolation of CTCs. In particular, we systematically review the most recent advances in the combination of microfluidic chips and biosensing for the enrichment of circulating tumor cells. Finally, we put forward the current barriers that need to be overcome and developmental trends in the CTCs research.

Immune Effect of Active Components of Traditional Chinese Medicine on Triple-Negative Breast Cancer.

Triple-negative breast cancers are heterogeneous, poorly prognostic, and metastatic malignancies that result in a high risk of death for patients. Targeted therapy for triple-negative breast cancer has been extremely challenging due to the lack of expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. Clinical treatment regimens for triple-negative breast cancer are often based on paclitaxel and platinum drugs, but drug resistance and side effects from the drugs frequently lead to treatment failure, thus requiring the development of new therapeutic platforms. In recent years, research on traditional Chinese medicine in modulating the immune function of the body has shown that it has the potential to be an effective treatment option against triple-negative breast cancer. Active components of herbal medicines such as alkaloids, flavonoids, polyphenols, saponins, and polysaccharides have been shown to inhibit cancer cell proliferation and metastasis by activating inflammatory immune responses and can modulate tumor-related signaling pathways to further inhibit the invasion of triple-negative breast cancer. This paper reviews the immunomodulatory mechanisms of different herbal active ingredients against triple-negative breast cancer and provides an outlook on the challenges and directions of development for the treatment of triple-negative breast cancer with herbal active ingredients.

Ultrasensitive Dual-Signal Detection of Telomerase and MiR-21 Based on Boolean Logic Operations.

Telomerase and micro-RNAs (miRNAs) are simultaneously upregulated in a variety of tumor cells and have emerged as promising tumor markers. However, sensitive detection of telomerase and miRNAs in situ remains a great challenge due to their low expression levels. Here, we designed a Boolean logic "AND" signal amplification strategy based on functionalized ordered mesoporous nanoparticles (FOMNs) to achieve ultrasensitive detection of telomerase and miR-21 in living tumor cells. Briefly, the strategy uses telomerase as an input to enable the release of DNA3-ROX-BHQ hairpins by making the wrapping DNA1 form a DNA-a hairpin with the joint participation of dNTPs. Subsequently, DNA2-Ag, DNA3-ROX-BHQ, and the second input miR-21 participated in hybridization chain reaction to amplify fluorescence and Raman signals. Experimental results showed the intensity of output dual signals relevant to the expression levels of telomerase and miR-21. The Ag nanoparticles (AgNPs) not only enhanced the fluorescence signals but also allowed to obtain more sensitive Raman signals. Therefore, even if expression of tumor markers is at a low level, the FOMN-based dual-signal logic operation strategy can still achieve sensitive detection of telomerase and miR-21 in situ. Furthermore, FOMNs can detect miR-21 expression levels in a short time. Consequently, this strategy has a potential clinical application value in detection of tumor markers and the assessment of tumor treatment efficacy.

PD-1/PD-L1 Checkpoint Inhibitors in Tumor Immunotherapy.

Programmed death protein 1 (PD1) is a common immunosuppressive member on the surface of T cells and plays an imperative part in downregulating the immune system and advancing self-tolerance. Its ligand programmed cell death ligand 1 (PDL1) is overexpressed on the surface of malignant tumor cells, where it binds to PD1, inhibits the proliferation of PD1-positive cells, and participates in the immune evasion of tumors leading to treatment failure. The PD1/PDL1-based pathway is of great value in immunotherapy of cancer and has become an important immune checkpoint in recent years, so understanding the mechanism of PD1/PDL1 action is of great significance for combined immunotherapy and patient prognosis. The inhibitors of PD1/PDL1 have shown clinical efficacy in many tumors, for example, blockade of PD1 or PDL1 with specific antibodies enhances T cell responses and mediates antitumor activity. However, some patients are prone to develop drug resistance, resulting in poor treatment outcomes, which is rooted in the insensitivity of patients to targeted inhibitors. In this paper, we reviewed the mechanism and application of PD1/PDL1 checkpoint inhibitors in tumor immunotherapy. We hope that in the future, promising combination therapy regimens can be developed to allow immunotherapeutic tools to play an important role in tumor treatment. We also discuss the safety issues of immunotherapy and further reflect on the effectiveness of the treatment and the side effects it brings.

miR-222 regulates cell growth, apoptosis, and autophagy of interstitial cells of Cajal isolated from slow transit constipation rats by targeting c-kit.

BACKGROUND: Excessive autophagy and apoptosis of the interstitial cells of Cajal (ICC) have been identified in gastrointestinal (GI) motility disorders including slow transit constipation (STC). MicroRNA 222 (miR-222) has been shown to affect GI motility. This study aimed to explore whether miR-222 influences apoptosis and excessive autophagy of isolated ICC. METHODS: miR-222, c-kit, and stem cell factor (SCF) were evaluated in colon tissues in STC rats compared with normal control by qRT-PCR and western blot analysis. The condition of autophagy of colon tissue was observed by transmission electron microscope. ICC were isolated from the colon of STC rats. Cell Counting Kit-8 (CCK-8) assay and wound healing assay were carried out to examine the cell viability and migration rate. Cell apoptosis was detected by terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) and Annexin V-Flourescein Isothiocyanate/Propidine Iodide (FITC/PI) apoptosis detection kit. Western blot analysis was performed to detect the c-kit and SCF expression; apoptosis-related proteins Bcl-2, Bax, caspase-3, and pro-caspase-3; and autophagy-related proteins LC3B and Beclin-1. The connection between miR-222 and c-kit was detected by bioinformatics and luciferase activity analysis. RESULTS: miR-222 expression was significantly higher, whereas c-kit and SCF expressions were markedly lower in STC rats' colon tissue compared with normal control. Meanwhile, STC rats exhibited excessive autophagy in colon tissue than normal control. Inhibition of miR-222 expression promoted cell proliferation as well as migration and inhibited autophagy, whereas upregulation of miR-222 had the opposite effect. In addition, miR-222 upregulation induced apoptosis and excessive autophagy compared with normal controls (NC). Western blot analysis showed that miR-222 overexpression caused decreased c-kit and SCF protein levels compared with NC. Bioinformatics and luciferase activity analysis revealed that miR-222 could be a predictive regulator of c-kit. CONCLUSION: miR-222 induces apoptosis and excessive autophagy of ICC and may serve as potential biomarker for ICC loss in STC.

Coaxial sensing bio-amplifier for ultrasensitive detections of circulating tumor DNAs.

We herein report the first attempt to engineer a coaxial-sensing 3D amplifier able to achieve dynamic self-assembly in response to a mutated-ctDNA target. A bio-nanofiber is firstly manufactured via an ingenious double-channel electrostatic spinning and DNA rolling circle replication (RCR) technology, which offered an ideal scaffold for assembly of 3D amplifier activated by target recognition. The coaxial-controllable signal amplifier presented several advantages. (1) Given its "coaxial sensing effect", the proposed bio-amplifier played the coaxial transduction for signal enrichment to vastly increase sensitivity, capable of discriminating a single-base mismatched sequence from the perfectly complementary one, using ctDNA-134A as a model analyte. (2) Due to "covalent bridges lock effect" in an identifying chip with locked nucleic acid beacons, this 3D amplifier expressed high specificity and biostability toward seven different mutated-ctDNAs. (3) Profiting from special configuration of bioactive nanofibers and DNA replication programming, this catalytic bio-amplifier possessed "signal enrichment effect", which enhanced dynamic range toward ctDNA-134A detection and hybridized without any external indicators. This innovative bio-amplifier has a detection limit of 5.1 aM for ctDNA-134A with superior specificity, excellent sensitivity, and good performance. This pioneered method was further applied for broadly differentiate cells and evaluate changes in the expression levels of intracellular mutated-ctDNAs.