Tumor Therapy Research Articles

MMP-2 Responsive Gold Nanorods Loaded with HSP-70 siRNA for Enhanced Photothermal Tumor Therapy.

Gold nanorods (Au NRs) are a valuable photothermal nanomaterial for tumor therapy. However, when treated with Au NRs for photothermal therapy, the expression of heat shock proteins in tumors will increase, which will induce heat resistance in tumor cells and reduce the photothermal therapeutic effect of Au NRs. By RNA interference, the expression of heat shock proteins would be effectively inhibited to improve the efficasy of tumor photothermal therapy. However, deep and noninvasive tissue penetration remains a great obstacle to applying siRNA successfully. Thus, the nanoplatform AGC/HSP-70 siRNA was designed for enhanced photothermal tumor therapy by RNA interference. In the AGC/HSP-70 siRNA complex, the Au-S bond modified the matrix metalloproteinase-2 (MMP-2)-sensitive peptide GPLGLAG on the surface of gold nanorods. Moreover, the natural basic polysaccharide (chitosan) was reacted with the peptide by an amide bond for delivering heat shock protein 70 silencing siRNA (HSP-70 siRNA). Modifying the MMP-2-sensitive linker could cause more Au NRs to accumulate in tumors to exert a photothermal effect and promote the penetration of HSP-70 siRNA and chitosan complexes into deep tumor tissues. In vitro experiments indicated that the enzymolysis of the MMP-2-sensitive linker for AGC/HSP-70 siRNA could promote the cellular uptake and perinuclear distribution of HSP-70 siRNA in tumor cells, which may be due to the smaller size and positive electricity of the complexes. All of these results ensured the efficient gene silencing effect of HSP-70 siRNA to enhance the photothermal therapeutic effect of Au NRs in tumor tissues, as demonstrated by the gene silencing and cellular apoptotic experiments. In vivo experiments further proved that the AGC/HSP-70 siRNA nanoplatform efficiently improved the photothermal effect of Au NRs. In summary, this work proved that AGC/HSP-70 siRNA is a promising drug delivery strategy for enhancing the photothermal therapy of tumors by regulating the photothermal sensitivity of deep tumor cells as well as retaining more Au NRs in tumor tissues, and also provides a novel strategy for tumor photothermal therapy.

Enhancing the tissue penetration to improve sonodynamic immunotherapy for pancreatic ductal adenocarcinoma using membrane-camouflaged nanoplatform.

Sonodynamic therapy (SDT) is a promising strategy as an "in situ vaccine" to enhance activation of antitumor immune responses in solid tumors. However, the dense extracellular matrix (ECM) in pancreatic ductal adenocarcinoma (PDAC) lead to hypoxia and limited penetration of most drugs, aggravating the immunosuppressive tumor microenvironment and limiting the efficacy of synergistic sonodynamic immunotherapy. Therefore, it is essential to regulate ECM in order to alleviate tumor hypoxia and enhance the efficacy of sonodynamic immunotherapy for PDAC. The CPIM nanoplatform, consisting of a macrophage membrane-coated oxygen and drug delivery system (CM@PFOB-ICG-α-Mangostin), was synthesized using ultrasound and extrusion methods. The in vivo homologous targeting and hypoxia alleviation capabilities of CPIM were evaluated through near-infrared (NIR) imaging and photoacoustic (PA) imaging. The tumor growth inhibition potential and ability to reprogram the tumor microenvironment by the CPIM nanoplatform were also investigated. Co-delivery of α-Mangostin inhibits CAFs and enhances stromal depletion, thereby facilitating better infiltration of macromolecules. Additionally, the nanoemulsion containing perfluorocarbon (PFC) can target tumor cells and accumulate within them through homologous targeting. The US irradiation results in the rapid release of oxygen, serving as a potential source of sonodynamic therapy for hypoxic tumors. Moreover, CPIM reshapes the immunosuppressive microenvironment increasing the population of cytotoxic T lymphocytes (CTLs), and enhancing their anti-tumor immune response through the use of anti-PDL1 antibodies to block immune checkpoints. The present study offers a potential strategy for the co-delivery of oxygen and α-Mangostin, aiming to enhance the penetration of tumors to improve SDT. This approach effectively addresses the existing limitations of immune checkpoint blockade (ICB) treatment in solid tumors, while simultaneously boosting the immune response through synergistic sonodynamic immunotherapy.

Variable-RBE-induced NTCP predictions for various side-effects following proton therapy for brain tumors – Identification of high-risk patients and risk mitigation

Background and purposeDisregarding the increase of relative biological effectiveness (RBE) may raise the risk of acute and late adverse events after proton beam therapy (PBT). This study aims to explore the relationship between variable RBE (above 1.1)-induced normal tissue complication probabilities (NTCP) and patient-specific factors, identify patients at high risk of RBE-induced NTCP increase, and assess risk mitigation by incorporating RBE variability into treatment planning. Materials and methodsWe retrospectively analyzed 105 primary brain tumor patients treated with PBT (RBE = 1.1). We calculated differences in estimated NTCP (ΔNTCP) using a variable RBE-weighted dose (DRBE, Wedenberg model) and a constant RBE-weighted dose (DRBE=1.1), across 16 NTCP models. These differences were correlated with patient-specific characteristics. Based on ΔNTCP, patients were classified as high risk (32 %) or low risk (68 %) for adverse events due to RBE-induced NTCP. This classification was compared with alternative classifications based on (a) relevant patient-specific characteristics, (b) DRBE=1.1, and (c) the difference between DRBE and DRBE=1.1 (ΔD), assessing the balanced accuracy. The potential to reduce RBE-induced NTCP through track-end and linear energy transfer (LET) optimization was evaluated in six example patients. ResultsUsing a variable RBE instead of a constant one resulted in NTCP increases (up to 32 percentage points). Variable-RBE-induced NTCP increases were strongly negatively correlated with the distance between the clinical target volume (CTV) and the organ at risk (OAR) for most side-effects, and positively correlated with CTV volume for certain side-effects. High increases were associated with (a) specific patient factors, particularly the proximity of the CTV to OARs, (b) DRBE=1.1, and (c) ΔD, with a balanced accuracy of 0.88, 0.94, and 0.86, respectively. Optimization of track-ends and LET considerably reduced NTCP values, achieving a mean reduction of 31 % for optimized OARs. ConclusionThe risk of variable-RBE-induced NTCP strongly depends on patient-specific factors and the considered side-effect. A small distance between the tumor and OARs notably increases the risk. Integrating biologically-guided objectives into treatment planning can effectively mitigate the risk.

Stable Alkyne‐Bridged Conjugated Polymer Nanoparticles With a High NIR‐II Photothermal Conversion Efficiency of 71% for Effective Photothermal Tumor Therapy

AbstractOrganic photothermal materials (PTMs) in the near‐infrared (NIR) range (1000–1700 nm) are more favorable for photothermal therapy (PTT) therapeutic applications because of their greater depth of tissue penetration and better biosafety. However, the photothermal conversion efficiency (PCE) of the few NIR‐II‐responsive organic PTMs that have been investigated is still slightly low. Here, a stable alkyne‐bridged conjugated polymer, BBT‐BTE, are explored with a high PCE for tumor ablation within the NIR‐II window. The BBT‐BTE synthesized by the Stille coupling reaction has strong NIR‐II absorption, and their nanoparticles (NPs) achieved a 71% PCE under 1064 nm laser excitation, with good photothermal stability. BBT‐BTE NPs are shown to be effective in completely ablating tumors without any recurrence in both in vitro and in vivo experiments. Additionally, the biosafety of these NPs is further proven by biochemical analysis and tissue biopsy. This study developed a high‐performance NIR‐II PTM and offered practical and feasible insights into the design of efficient photothermal materials specifically for the NIR‐II window.

ADAM10 modulates the efficacy of T-cell-mediated therapy in solid tumors.

T-cell-mediated therapeutic strategies are the most potent effectors of cancer immunotherapy. However, an essential barrier to this therapy in solid tumors is disrupting the anti-cancer immune response, cancer-immunity cycle, T-cell priming, trafficking and T-cell cytotoxic capacity. Thus, reinforcingtheanti-cancer immune response is needed to improve the effectiveness of T-cell-mediated therapy. Tumor-associated protease ADAM10, endothelial cells (ECs) and cytotoxic CD8+ Tcells engage in complex communication via adhesion, transmigration and chemotactic mechanisms to facilitate an anti-cancer immune response. The precise impact of ADAM10 on the intricate mechanisms underlying these interactions remains unclear. This paper broadly explores how ADAM10, through different routes, influences the efficacy of T-cell-mediated therapy. ADAM10 cleaves CD8+ T-cell-targeting genes and impacts their expression and specificity. In addition, ADAM10 mediates the interactions of adhesion molecules with Tcells and influences CD8+ T-cell activity and trafficking. Thus, understanding the role of ADAM10 in these events may lead to innovative strategies for advancing T-cell-mediated therapies.

Metal-Organic Nanomaterials for Tumor Metabolic Blockade and Image to Increase Tumor Therapy.

The abnormal energy metabolism level of a tumor reduces the efficiency of chemotherapy. Metal-organic nanomaterials (MONs) with high drug loading efficiency, easy processes of synthesis, and controlled drug release have shown great potential in metabolic blocking and enhancement of tumor therapy. These metal-organic nanomedicines have been reported to modulate glycolysis or oxidative phosphorylation to provide monotherapy or combined therapies in tumorous treatments. In addition, the encapsulation or coordination of fluorescent dyes into MONs endowed them with the imaging ability of tumor metabolism. Herein, this Perspective summarizes the progress of MONs as therapeutic agents or imaging probes for application during tumor metabolic blocking or imaging, providing solid inspiration for biomedical applications of effective biomaterials. In addition, the current drawbacks of MONs for further biological applications in the future were discussed, giving stimulation of innovation and development in biomedical applications of MONs.

Multimodal Photodynamic Therapy by Inhibiting the Nrf2/ARE Signaling Pathway in Tumors.

Photodynamic therapy (PDT) has been widely used in the clinical therapy of various tumors, especially superficial tumors. However, the tumor microenvironment presents hypoxia, as well as the inherent antioxidant system (e.g., Nrf2) of tumor cells limits the therapeutic outcomes. Herein, a cascade-responsive "oxidative stress amplifier" (named EZ@TD) is designed by encapsulating manganese-doped carbon dots acting as a photosensitizer and catalase (CAT)-like nanozyme within pH-sensitive ZIF-8 and Zn2+-activated DNAzyme for relieving hypoxia and efficient Nrf2 gene disruption to enhance PDT. It is demonstrated that EZ@TD synergistically inhibited tumor growth and activated the antitumor immune response by inhibiting the Nrf2/ARE signaling pathway in tumors. We provide a new paradigm for amplifying intracellular oxidative stress by interfering with various signaling pathways.

Insights into Metabolic Reprogramming in Tumor Evolution and Therapy.

Background: Cancer remains a global health challenge, characterized not just by uncontrolled cell proliferation but also by the complex metabolic reprogramming that underlies its development and progression. Objectives: This review delves into the intricate relationship between cancer and its metabolic alterations, drawing an innovative comparison with the cosmological concepts of dark matter and dark energy to highlight the pivotal yet often overlooked role of metabolic reprogramming in tumor evolution. Methods: It scrutinizes the Warburg effect and other metabolic adaptations, such as shifts in lipid synthesis, amino acid turnover, and mitochondrial function, driven by mutations in key regulatory genes. Results: This review emphasizes the significance of targeting these metabolic pathways for therapeutic intervention, outlining the potential to disrupt cancer's energy supply and signaling mechanisms. It calls for an interdisciplinary research approach to fully understand and exploit the intricacies of cancer metabolism, pointing toward metabolic reprogramming as a promising frontier for developing more effective cancer treatments. Conclusion: By equating cancer's metabolic complexity with the enigmatic nature of dark matter and energy, this review underscores the critical need for innovative strategies in oncology, highlighting the importance of unveiling and targeting the "dark energy" within cancer cells to revolutionize future therapy and research.

Oncolytic Viruses as Reliable Adjuvants in CAR-T Cell Therapy for Solid Tumors

Although impactful scientific advancements have recently been made in cancer therapy, there remains an opportunity for future improvements. Immunotherapy is perhaps one of the most cutting-edge categories of therapies demonstrating potential in the clinical setting. Genetically engineered T cells express chimeric antigen receptors (CARs), which can detect signals expressed by the molecules present on the surface of cancer cells, also called tumor-associated antigens (TAAs). Their effectiveness has been extensively demonstrated in hematological cancers; therefore, these results can establish the groundwork for their applications on a wide range of requirements. However, the application of CAR-T cell technology for solid tumors has several challenges, such as the existence of an immune-suppressing tumor microenvironment and/or inadequate tumor infiltration. Consequently, combining therapies such as CAR-T cell technology with other approaches has been proposed. The effectiveness of combining CAR-T cell with oncolytic virus therapy, with either genetically altered or naturally occurring viruses, to target tumor cells is currently under investigation, with several clinical trials being conducted. This narrative review summarizes the current advancements, opportunities, benefits, and limitations in using each therapy alone and their combination. The use of oncolytic viruses offers an opportunity to address the existing challenges of CAR-T cell therapy, which appear in the process of trying to overcome solid tumors, through the combination of their strengths. Additionally, utilizing oncolytic viruses allows researchers to modify the virus, thus enabling the targeted delivery of specific therapeutic agents within the tumor environment. This, in turn, can potentially enhance the cytotoxic effect and therapeutic potential of CAR-T cell technology on solid malignancies, with impactful results in the clinical setting.

Dual-emission carbon dots-based biosensor for polarity/targeting bimodal recognition and mild photothermal therapy of tumor

It is essential to develop a multifunctional nanoplatform for biosensing, tumor diagnosis and treatment simultaneously. Herein, dual-emission fluorescent carbon dots (HA-CDs) were fabricated via a one-pot solvothermal method using spinach powder as carbon source and hyaluronic acid (HA) as targeting agent. The obtained HA-CDs exhibited outstanding optical properties, good targeted tumor and excellent photothermal conversion performance. Interestingly, HA-CDs can sensitively perceive the changes in polar environments attributed to the inherent ratiometric fluorescence characteristics, and combined with the intrinsic targeting tumor ability achieved tumor cell recognition. More importantly, the HA-CDs possess good photothermal conversion efficiency of 21.2 % to be beneficial for photothermal therapy of tumors. The survival rate of HeLa cells incubated with HA-CDs dramatically decreased to 14 % after 660 nm laser irradiation, revealing the significant tumor inhibition of HA-CDs in vitro. Notably, through individual intraperitoneal and intratumoral injection, it was found that HA-CDs demonstrated a similar tumor suppressed effect on 4T1 tumor-bearing mice exposed to laser irradiation, fully uncovering that HA-CDs can efficiently accumulate at tumor site by intraperitoneal injection. Besides, the histopathological analysis of major organs ex vivo revealed a good biosafety profile. Collectively, this strategy of designed HA-CDs provides a new multifunctional nanoplatform for potential clinical application.

Micro RNA-175 Targets Claudin-1 to Inhibit Madin–Darby Canine Kidney Cell Adhesion

Background: The Madin–Darby canine kidney (MDCK) cell line constitutes a key component of influenza vaccine production, but its dependence on adherent growth limits cell culture density and hinders vaccine yield. There is evidence that the use of gene editing techniques to inhibit cell adhesion and establish an easily suspended cell line can improve vaccine yield; however, the mechanisms underlying MDCK cell adhesion are unclear. Methods: In this study, we used transcriptomics to analyse differentially expressed mRNAs and miRNAs in adherent and suspension cultures of MDCK cells. Results: We found that claudin-1 (CLDN1) expression was downregulated in the suspension MDCK cells and that CLDN1 promotes MDCK cell–extracellular matrix adhesion. Additionally, microRNA (miR)-175 expression was upregulated in the suspension MDCK cells. Importantly, we demonstrated that miR-175 inhibits MDCK cell adhesion by targeting the CLDN1 3′-untranslated region (UTR). These findings contribute to a more comprehensive understanding of the regulatory mechanisms modulating cell adhesion and provide a basis for establishing suspension-adapted, genetically engineered cell lines. Our work could also facilitate the identification of targets for tumour therapy.

Breast Cancer Disseminated Tumor Cells: Do They Stay and Fight or Run and Hide?

Many solid tumors including breast cancer can exhibit early dissemination and dormancy-in which cancer cells spread early in the disease process and survive long periods without detectable growth. These early disseminated tumor cells sometimes reactivate and lead to incurable metastatic disease years or even decades after curative-intent therapy for the primary tumor. We are just beginning to understand the role of the immune system in this process in part because of improvements in immunocompetent models as well as technological advances such as single-cell genomics and spatial transcriptomics. In this issue of Cancer Research, Bushnell and colleagues showed that NK cells are important in this context. The authors found that disseminated tumor cells and quiescent cells express higher levels of MHC 1 but are resistant to NK-cell-mediated immunity. The proposed mechanism involves the STING pathway and transcription factors Sox2 and Bach1. As other studies have highlighted the importance of T-cell immunity, this work reaffirms the importance and diversity of immune regulation of dormancy and suggests the need for future studies to flesh out mechanistic details and predict when each type of immunity is most important. See related article by Bushnell et al., p. 3337.

NOVEL HETEROCYCLIC COMPOUNDS AS KINASE INHIBITORS WITH ANTICANCER ACTIVITY IN MEDULLOBLASTOMA

Abstract AIMS Medulloblastoma is the most common malignant brain tumor of childhood. Protein kinases are often overexpressed and constitute targets for the development of novel molecularly-targeted therapies in brain tumors. Here, we report the synthesis of new derivatives with kinase inhibitory activity and their anticancer activity in an early screening in medulloblastoma cells. METHOD The synthesis route was performed through six steps using a proper amino acid as starting material. The inhibitory activity of the final derivatives on the protein kinase was measured by fluorescence. Cultured DAOY medulloblastoma cells were used to examine anticancer activity. RESULTS The compounds display potent inhibitory activity on viability of DAOY medulloblastoma cells. The more promising derivative shows IC50 in the μM range in inhibiting the targeted protein kinase. CONCLUSION Further optimization of compounds in this series is currently being carried out. The encouraging preliminary results have revealed potential novel strategies for inhibiting kinase activity for the treatment of medulloblastoma.

A NEW INTERNATIONAL ACCELERATOR PROGRAMME FOR NOVEL BRAIN TUMOUR THERAPIES

Abstract AIMS Developing a comprehensive translational programme for brain tumours involves navigating numerous challenges, including preclinical study robustness, safety, clinical trial design, understanding and addressing regulatory requirements, and commercialisation. Recognising the difficulty of this journey, the Brain Tumour Research Novel Therapeutics Accelerator (BTR-NTA) was launched in 2023. The BTR-NTA is an accelerator programme providing independent expert guidance to de-risk drug or device development through systematic evaluation. The international, multidisciplinary BTR-NTA Committee spans expertise across the entire therapeutic development pathway. Supported by Brain Tumour Research, BTR-NTA is free for academics and available at nominal cost for industry. METHOD Researchers at any stage of therapeutic development may apply to BTR-NTA. Accepted applicants proceed as follows: 1. Applicants complete a form highlighting their current and prospective data and findings. All materials are covered under a confidentiality agreement that protects their intellectual property; 2. Applicants’ proposals are reviewed by the BTR-NTA Committee; 3. The Applicants and BTR-NTA Committee meet in-person to constructively evaluate the work; and 4. Applicants receive a comprehensive report with feedback on strengths, identification of potential risks, and guidance on next steps. The BTR-NTA Committee dedicates time for in-person meetings with each applicant, and extensive time pre and post-meeting. RESULTS Since the launch of BTR-NTA, 13 international groups have applied to the programme and three groups have had their therapies reviewed in-person by the BTR-NTA committee to date. Of the groups who provided feedback on the programme, 100% intended to adjust or refine their future work based on the BTR-NTA Committee’s input and the average rating of the programme’s helpfulness was 9.5/10. CONCLUSION The ultimate goal of BTR-NTA is to help researchers with a potential therapy for brain tumours navigate the development journey and reach the clinic in an efficient way. This programme will support development of novel therapies to improve outcomes for brain tumour patients.

The role of the Ki-67 labelling index as an independent prognostic factor in indonesian glioma patients.

Gliomas are the most common type of brain tumor. However, interpreting glioma morphology is subjective, and identifying mitosis can be challenging. This can impact the determination of the patient's tumor grade, therapy, and prognosis. In addition, the Ki-67 expression level, which reflects the tumor cells' ability to proliferate, is closely related to the patient's survival. This study aims to find a correlation between Ki-67 expression and the overall survival (OS) of glioma patients in the Indonesian population. Ninety-one glioma patients from Sardjito General Hospital were collected for formalin-fixed embedded paraffin (FFPE) samples, and the Ki-67 labeling index (LI) was calculated by determining the percentage of labeled nuclei per 1000 cells using a 40x objective lens in a randomized area (average method). The OS was calculated from the day of pathology diagnosis until death or the last follow-up (for censored cases). Kaplan-Meier survival analysis was used to analyze the OS. Individuals aged ≥60 with high-grade tumors, infratentorial gliomas, and a Ki-67 LI ≥10% had a shorter OS. The p-values associated with these factors were 0.001, 0.018, and 0.006, respectively. In multivariate analysis, age and tumor grade did not significantly correlate with OS. Glioma patients with a Ki-67 LI ≥10% have a significantly shorter OS than those with a lower Ki-67 LI, indicating that Ki-67 LI is an independent prognostic factor in Indonesian glioma patients.

Straightforward, Highly Useful, Innovative and Cost-Effective Method with Potential to Improve Personalized Diagnosis: Sectioning of Prostatectomy Specimen with a Single Blade

Abstract Introduction/Objective There is potential for devices with an adjustable base and a single blade to precisely cut parallel slices of a prostatectomy specimen at a set preferred thickness to improve pathology practice by standardizing the tissue for histological review, allowing for precise punch biopsies of the slices for molecular diagnostics for biobanking and personalized therapy. The current standard method of sectioning the prostate involves serially sectioning the prostatectomy specimen by hand with a sharp long knife, leading to uneven sections. Methods/Case Report A device with an adjustable base was developed at a regional Veteran Affairs Medical Center (VAMC) that consists of two sets of multiple, vertically arranged parallel and flat bars measuring 10 cm in height, 1.5 cm in width and 0.3 cm in thickness spaced 0.4 cm from each other, resembling a comb with flat teeth. After inking, orientation, and removal of the seminal vesicles and apex and base margins, the prostatectomy specimen is immobilized between the two combs and sliced in parallel from apex to base to produce parallel consistent prostate slices. The ability to obtain punch biopsies from precise areas of the prostate was reviewed. Results (if a Case Study enter NA) The device results in uniform 4 mm thick oriented smooth specimen slices of good quality with minimal distortion. The device allows for the obtaining of punch biopsies taken at precise locations of the prostate corresponding to specific imaging locations (highly useful for biobanking or obtaining diagnostic tissue for molecular diagnostics for personalized therapy). The adjustable nature of the device and single blade gives the device flexibility in the specimen. Conclusion This device with an adjustable base and single blade allows for safe and precise parallel slicing. This is highly useful obtaining diagnostic standardized tissue, for obtaining biobank specimens and for obtaining material of precise location for molecular studies to guide the personalized therapy of tumors.

P53 ABNORMAL ENDOMETRIAL CANCERS – ANALYSIS OF PD-1 CO-EXPRESSION BY CD4 HELPER AND CD8 CYTOTOXIC T-CELL SUBTYPES IN THE TUMOR MICROENVIRONMENT

Abstract Introduction/Objective Endometrial cancer is classified into four molecular subtypes of which the p53 abnormal variant is biologically aggressive. Programmed cell death protein 1 (PD-1) is a cell surface receptor and a vital inhibitor of the immune response. Programmed death ligand 1 (PD-L1) is a trans-membrane co-inhibitory factor of the immune response. PD-1 / PDL-1 interaction inhibits the activation and survival of T cells and decreases cytokine secretion. Some cancer cells express PD-L1, which then bind to PD-1 expressed on tumor specific T cells, and escape destruction by the T cells. The CD4/CD8 T cell immune response in the p53 abnormal variant has not been adequately evaluated with respect to the PD-1/PD-L1 pathway. Understanding this immune microenvironment is important to assess the potential use of anti-PD-1 targeted tumor therapy. Methods/Case Report Twenty cases of p53 abnormal endometrial cancers were obtained. All cases were PDL-1 +ve by immunohistochemistry. Two dual stains were performed - PD-1/CD4 and PD-1/CD8 antibodies. Six high-power fields (40x objective) with the greatest concentration of lymphocytes were counted. The total number of CD4 or CD8-only cells was recorded for each of the two stained slides for each case. The total number of PD- 1/CD4 and PD-1/CD8 positive cells were counted and recorded. The results were tabulated, and a paired t-test statistical analysis was performed to compare the total number of CD4 and CD8 cells and the percentage of PD-1/CD4 cells with the percentage of PD-1/CD8 positive cells. Results (if a Case Study enter NA) A statistically significant increase in the number of CD8 (Mean = 383) compared to CD4 cells (Mean = 317) was seen in the tumor microenvironment (p-value=0.0023). Evaluating PD-1 expression, the converse was true, and the percentage of PD-1/CD4 cells (Mean = 13.035%) was increased compared to the percentage of PD-1/CD8 cells (Mean = 9.205%), achieving statistical significance (p-value=0.0116). Conclusion The statistically significant increase in CD8 cells in the tumor and its stroma suggests that a robust cytotoxic response is being mounted to this high-risk molecular variant. The concurrent increase in CD4/PD-1 positive lymphocytes provides an appropriate microenvironment for the use of anti-PD-1 immunotherapy, since blockade of PD-1 on CD4 helper T cells may augment the tumor ablative cytotoxic properties of the CD8 positive lymphocytes. This includes reinvigoration of exhausted CD8+ T cells. Anti-PD-1 may also prevent the inhibition of PD-1 positive CD8 cells.

Phototheranostic LPP-QDs-IR-820 Nanocomposites for Specific NIR-II Imaging of Lymphatic and Photothermal Therapy of Cervical Tumors.

Precise theranostics of tumors is intricately linked to the early detection and monitoring of lymph nodes (LN) and metastases, making the targeted localization of LNs essential for tumor identification. However, designing LN-targeting probes remains a significant challenge due to issues such as lymphatic uptake, biocompatibility, and fluorescence stability. To address these challenges, near-infrared II (NIR-II) fluorescence probes are developed through meticulous analysis of LN physiological structure and passive targeting strategy for LN detection and tumor therapy. An LPP-QDs-IR-820 nanocomposite (NCs) is engineered, comprising the IR-820 molecules and ultrabright PbS@CdS quantum dots (QDs), which are encapsulated within a liposome-SH-mPEG2000 polymer matrix. These NCs demonstrates remarkable lymphatic enrichment, facilitating real-time tracking of LN via electrostatic repulsion and extracellular matrix effects. Importantly, the NCs exhibit negligible in vivo toxicity and high biocompatibility. The intense NIR-II fluorescence emissions of IR-820 and PbS@CdS QDs confer upon the NCs a high NIR-II fluorescence quantum yield (6%). The cervical tumors and their deep microvessels are clearly observed via NIR-II fluorescence imaging. Moreover, the photothermal properties of IR-820 enable the NCs to achieve a photothermal conversion efficiency of 36.56%, leading to effective photothermal therapy in cervical tumor mice.

Modulating the Electronic Structure of MnNi2S3 Nanoelectrodes to Activate Pyroptosis for Electrocatalytic Hydrogen-Immunotherapy.

Hydrogen (H2) therapy has demonstrated antitumor effect, but the therapeutic efficacy is restricted by the low solubility and nontarget delivery of H2. Electrolysis of H2O by electrocatalysts sustainably releases enormous amounts of H2 and inspires the precise delivery of H2 for tumor therapy. Herein, manganese-doped Ni2S3 nanoelectrodes (MnNi2S3 NEs) are designed for the electrocatalytic delivery of H2 and the activation of antitumor immunity to effectively potentiate H2-immunotherapy. Ni atoms featuring empty 3d orbitals reduce the initial energy barrier of the hydrogen evolution reaction (HER) by promoting the adsorption of H2O. Moreover, Mn atoms with different electronegativity modulate the electronic structure of Ni atoms and facilitate the desorption of the generated H2, thus enhancing the HER activity of the MnNi2S3 NEs. Based on the high HER activity, controllable delivery of H2 for electrocatalytic hydrogen therapy (EHT) is achieved in a voltage-dependent manner. Mechanistically, MnNi2S3 NE-mediated EHT induces mitochondrial dysfunction and oxidative stress, which subsequently activates pyroptosis through the typical ROS/caspase-1/GSDMD signaling pathway. Furthermore, MnNi2S3 NE-mediated EHT enhances the infiltration of CD8+ T lymphocytes into tumors and reverses the immunosuppressive microenvironment. This work demonstrates an electrocatalyst with high HER activity for synergistic gas-immunotherapy, which may spark electrocatalyst-based tumor therapy strategies.

Novel ultrathin ferrous sulfide nanosheets: Towards replacing black phosphorus in anticancer nanotheranostics

Biodegradable two-dimensional nanomaterials could be a significant breakthrough in the field of oncology nanotheranostic agents, which are rapidly emerging as promising candidates for tumor theranostic applications. Herein, a novel biodegradable ferrous sulfide nanosheet (FeS NS) is developed. Compared to the traditional photothermal material, black phosphorus nanosheet (BP NS), FeS demonstrates superior degradability and enhanced photothermal performance, and making it ideal for efficient photothermal therapy (PTT) of tumors. In the acidic tumor microenvironment, FeS degrades and releases H2S, which inhibits mitochondrial respiration and ATP production. This process leads to a reduction in heat shock protein expression, lowering the resistance of tumor cells to photothermal stimulation, and improving the efficacy of PTT. The released Fe2+ exhibits efficient peroxidase activity, triggering ferroptosis in tumor cells. Furthermore, due to its superparamagnetic nature, FeS NSs could accumulate at the tumor site and provide a strong magnetic resonance imaging (MRI) signal for imaging-guided tumor therapy. Overall, as a promising alternative to BP, the FeS NSs are a potentially innovative nanotheranostic agent of tumors, offering a synergistic approach to ferroptosis−PTT with MRI guidance.