Kill Cancer Cells Research Articles

Synergistic inhibitory effect of atmospheric pressure plasma and berberine on non‑small cell lung cancer cells via inducing apoptosis.

Non-small cell lung cancer (NSCLC) is a type of lung cancer, the incidence and mortality rate have been high, and the use of monotherapy is easy to make patients develop tolerance. Atmospheric pressure plasma (APP) is an emerging technology for killing cancer cells in recent years, and combination of berberine (BBR) mechanism has not been fully elucidated for NSCLC. The article's primary goal is to investigate the effect of combination on NSCLC and its associated characterization. Antiproliferative effects were detected by cell viability assay and colony formation, and flow cytometry analysis of apoptosis and cycling showed that the combination synergistically induced apoptosis. Then, extracellular reactive oxygen species (ROS)levels and DCFH-DA-based kits examined intracellular ROS levels, and their effects on mitochondrial membrane potential were measured. Study reveals that co-induced apoptosis is associated with ROS accumulation. Subsequently, Western blotting (WB) detected the expression of epidermal growth factor receptor (EGFR), and the important signaling pathway proteins Ras/ERK and AKT/mTOR. Results showed that it could downregulation of EGFR protein expression and inhibit of activation of ERK/AKT signaling pathways. Simultaneous wound healing assay and epithelial-to-mesenchymal transition (EMT) marker detection were performed for the assessment of migration and EMT ability of NSCLC cells. Combination therapy inhibited migration and EMT of NSCLC cells. The results of this study show that the combination can synergistically induce apoptosis of NSCLC by regulating ROS production. EGFR downregulation and AKT/ERK signaling pathway inhibition are linked to the synergistic effect.

Lysosome-Mitochondria Cascade Targeting Nanoparticle Drives Robust Pyroptosis for Cancer Immunotherapy.

The subcellular distribution of cargoes plays a crucial role in determining cell fate and therapeutic efficacy. However, achieving the precise delivery of therapeutics to specific intracellular targets remains a significant challenge. Here, we present a trimodular and acid/enzyme-gated nanoplatform (TAEN) that undergoes disassembly within acidic endosomes and then is cleaved by lysosomal cathepsin B to facilitate efficient and targeted transport of released cargoes into mitochondria compartments. By utilizing this nanovehicle, we successfully achieve selective sorting of photosensitizer molecules into mitochondria with a colocalization coefficient of up to 0.98, leading to the generation of reactive oxygen species stress specifically within the mitochondria for potent pyroptosis-based cancer therapy. The induction of mitochondrial stress triggers the intrinsic apoptotic pathway as well as caspase-3/gasdermin-E (GSDME) cascade, resulting in an enhanced cancer cell killing efficacy by nearly 2 orders of magnitude as compared to lysosomal stress. Furthermore, due to its superior capability to stimulate both innate and adaptive immune responses, our mitochondria-sorted nanophotosensitizer exhibits robust antitumor immune efficacy in multiple tumor-bearing mice models. This study not only provides insights into engineering nanomedicines for subcellular targeted delivery but also offers a valuable toolkit for advanced research in the field of nanobiology at subcellular resolution.

Nanoformula Design for Inducing Non-Apoptotic Cell Death Regulation: A Powerful Booster for Cancer Immunotherapy.

Cancer treatment has witnessed revolutionary advancements marked by the emergence of immunotherapy, specifically immune checkpoint blockade (ICB). However, the inherent low immunogenicity of tumor cells and the intricate immunosuppressive network within the tumor microenvironment (TME) pose significant challenges to the further development of immunotherapy. Nanotechnology has ushered in unprecedented opportunities and vast prospects for tumor immunotherapy. Nevertheless, traditional nano-formulations often rely on inducing apoptosis to kill cancer cells, which encounters the issue of immune silencing, hindering effective tumor immune activation. The non-apoptotic modes of regulated cell death (RCD), including pyroptosis, ferroptosis, autophagy, necroptosis, and cuproptosis, have gradually garnered attention. These non-apoptotic cell death pathways can induce effective immunogenic cell death (ICD), enhancing cancer immunotherapy. This review comprehensively explores advanced nano-formulation design strategies and their applications in enhancing cancer immunotherapy by promoting non-apoptotic RCD in recent years. It also discusses the potential advantages of these strategies in inducing tumor-specific non-apoptotic RCD. By deeply understanding the significance of non-apoptotic RCD in synergistic cancer immunotherapy, this article provides valuable insights for developing more advanced nano-delivery systems that can robustly induce highly immunogenic non-apoptotic modes, offering novel research and development avenues to address the clinical challenges encountered by immunotherapy represented by ICB.

CDA Formulations: Potentially the Standard Care of Breast, Lung and Liver Cancers

Breast and lung cancers are very common, which are the top two leading causes of death from cancer. Hepatomas are not as common. But hepatomas are not responding well to therapies currently available. Cancer incidence and mortality keep on increasing ever since these statistics became public records, which are an indication of the failure of the health profession to control cancer. Cancer therapies approved in the past are mostly based on killing of cancer cells which are wrong to solve only a fraction of cancer problems. To effectively solve cancer, we must eliminate all factors contributing to the evolution of cancer. Cancer evolves due to wound unhealing because of the collapse of chemo-surveillance. Wound healing requires the proliferation and the terminal differentiation of progenitor stem cells (PSCs), which are embryonic stem cells to initiate the development of organs and tissues. Methylation enzymes (MEs) play a pivotal role on the regulation of cell replication and differentiation. Because of this pivotal role, MEs are exceptionally subjected to double allosteric regulations, on the individual enzymes by steroid hormone and on the enzyme complex by telomerase and chemo-surveillance. MEs of embryonic stem cells (ESCs) including PSCs are abnormal due to association with telomerase, which are important for the functions of these cells for the development of fetus and wound healing. The build-up of normal stem cells with abnormal MEs is strictly under regulations by contact inhibition, ten-eleven translocator -1 (TET-1) enzyme to direct lineage transitions and chemo-surveillance to destabilize abnormal MEs. When such safety mechanisms fail, clinical symptoms arise. Obviously, the most appropriate solution of diseases due to wound unhealing is to restore safety mechanisms created by the nature. Cell differentiation agent -2 (CDA-2) is our creation of cancer drug to target on abnormal MEs. CDA-2 was approved by the Chinese FDA as an adjuvant to supplement cytotoxic therapy of cancer against breast, non-small cell lung cancers and primary hepatomas in 2004, and as a mono-therapeutic agent for the therapy of myelodysplastic syndromes (MDSs) in 2017. MDSs are diseases attributable entirely to cancer stem cells (CSCs). CDA-2 was the best drug for the therapy of MDSs, and therefore should be considered the standard care of MDSs. Breast, non-small cell lung cancers and primary hepatomas responded well to CDA-2. The therapeutic end point of CDA-2 is the terminal differentiation of cancer cells which cannot make tumor to disappear. Evidently, terminal differentiation of CSCs is the only option to solve CSCs. The solution of CSCs is very critical to the success of cancer therapy. Therefore, CDA formulations are potentially the standard care of breast and lung cancers and primary hepatomas.

L-Cystine-Based Polyurethane as a Drug-Delivery Vehicle in Targeted Cancer Therapy and Biomedical Applications.

Controlled and sustained drug release is a critical aspect of drug-delivery systems (DDSs) that can be used in chemotherapy while ensuring therapy effectiveness and biosafety. Hence, polyurethane (PU) is modified using a biomolecule Cystine (CYS) for protracted drug release, aiming to enhance cancer treatment efficacy while minimizing adverse side effects in tumor patients. To confirm the formation of a polymer structure, characterization techniques such as NMR and FTIR are used, and the morphology is determined using SEM. Biocompatibility of the synthesized polymers is evaluated through cellular assessments, including MTT assay, cell adhesion, and antibacterial assay along with drug release using an anticancer drug, Paclitaxel (PTX). Notably, the incorporation of PTX in the polymer matrix results in minimal mortality (85% viable cells) rates in healthy cells (3T3), in contrast to a 56% mortality rate observed with the pure drug. While PTX shows a burst release and kills cancer cells only for the first 24 h, PU loaded with the drug shows sustained release and kills the cancer cells for 3 days. This vehicle selectively kills 59% of SiHA cells after a consecutive study of 3 days, which highlights the potential of this newly designed vehicle for effective drug delivery, particularly in anticancer treatments. Moreover, cystine's antibacterial property adds up with PU; hence, PU shows antibacterial activity against Staphylococcus aureus (MIC, 20 μg/mL) and also acts as a reductive oxygen species scavenger. Therefore, modifying PU with CYS has shown sustained release of PTX along with a selective effect on cells, underscoring its significance as a superior delivery agent and supported by a shred of convincing evidence.

Harnessing the Power of Radiation to Battle Cancer

Cancer is a major challenge for modern healthcare and, unfortunately, many people are confronted with this disease during their lives. Radiotherapy, which uses high-energy rays to destroy cancer cells, has been successfully used for many decades. However, traditional radiotherapy can only be used to treat one or a few cancer spots, and it damages the healthy tissues surrounding these spots. In this article, we introduce another treatment that uses radiation to beat multiple cancer spots in a very precise manner: targeted radionuclide therapy. You will get to know the “weapons” that kill cancer cells and how these weapons are delivered only to the cancer cells. Finally, you will learn about a powerful molecule that can be used as a “scout” to find the cancer cells and carry a “weapon” to kill those cells.

NIR Diradical-Featured Croconaine Nanoagent for Cancer Photoacoustic Imaging and Photothermal Therapy.

Radical-featured organic materials usually demonstrate significantly narrower bandgap than that of regular organic materials, which is beneficial for near-infrared (NIR) absorption and non-radiative decay process, making them good candidates for photothermal agents (PTAs) of photothermal therapy (PTT). However, most organic radicals are too short-lived to be separated and stable. Herein, a stable pyrylium-croconaine (CR) dye CR845 with high diradical character was synthesized and assembled into CR845 nanoparticles (NPs) to explore the photoacoustic imaging (PAI) and photothermal therapeutic performance under NIR irradiation in vitroand in vivo. CR845 exhibited a stable NIR absorption at 845 nm (ε= 3.37 × 105L mol-1cm-1) and a relatively high photothermal conversion efficiency (PCE) of 58.8%. When assembled into nanoparticles, CR845 NPs showed good photostability, good biocompatibility, favorable NIR photoacoustic potential, effective cancer cell killing and complete tumor elimination upon 850 nm laser irradiation. The work demonstrates a diradical-featured CR PTA with favorable PAI/PTT effects, which can help to provide new ideas for the development of NIR PTAs, and further promote the application of organic radical materials in the field of biomedicine.

Fluorous-tagged bortezomib supramolecular nanomedicine for cancer therapy

Lipidation is a well-established post-translational modification strategy to modulate the structure and function of proteins and peptides. Lipids can improve the overall or local hydrophobicity of the biomolecule, boosting its affinity with the cell membranes. Lipidation, despite its great potential, remains an underutilized technique for translating bioactive molecules into the clinic. Herein, we have optimized the lipidation strategy by involving the fluorous lipidation combined with supramolecular engineering, which can be facilely achieved by grafting an anticancer peptide drug (bortezomib, BTZ) with a series of fluorous lipids bearing a catechol moiety via the dynamic catechol-boronate ester bond. Compared with BTZ, the fluorous-tagged BTZ nanomedicine exhibited an on-demand and traceless release behavior, and enhanced therapeutic effect and biocompatibility. More importantly, the fluorous tag could improve the serum stability of the supramolecular nanomedicine, which allowed efficient in vivo utilization of BTZ to kill cancer cells. This work introduces a novel lipidation strategy for bioactive peptides via the integration of fluorination chemistry and supramolecular engineering strategies.

Effects of virus-induced immunogenic cues on oncolytic virotherapy

Oncolytic virotherapy is a promising form of cancer treatment that uses viruses to infect and kill cancer cells. In addition to their direct effects on cancer cells, the viruses stimulate various immune responses partly directed against the tumour. Efforts are made to genetically engineer oncolytic viruses to enhance their immunogenic potential. However, the interplay between tumour growth, viral infection, and immune responses is complex and not fully understood, leading to variable and sometimes counterintuitive therapeutic outcomes. Here, we employ a spatio-temporal model to shed more light on this interplay. We investigate systematically how the properties of virus-induced immunogenic signals (their half-life, rate of spread, and potential to promote T-cell-mediated cytotoxicity) affect the therapeutic outcome. Our simulations reveal that strong immunogenic signals, combined with faster diffusion rates, improve the spread of immune activation, leading to better tumour eradication. However, replicate simulations suggest that the outcome of virotherapy is more stochastic than generally appreciated. Our model shows that virus-induced immune responses can interfere with virotherapy, by targeting virus-infected cancer cells and/or by impeding viral spread. In the presence of immune responses, the mode of virus introduction is important, with systemic viral delivery throughout the tumour yielding the most favourable outcomes. The timing of virus introduction also plays a critical role; depending on the efficacy of the immune response, a later start of virotherapy can be advantageous. Overall, our results emphasise that the rational design of oncolytic viruses requires optimising virus-induced immunogenic signals and strategies that balance viral spread with immune activity for improved therapeutic success.

Development and Characterization of an Oncolytic Human Adenovirus-Based Vector Co-Expressing the Adenovirus Death Protein and p14 Fusion-Associated Small Transmembrane Fusogenic Protein.

Human adenovirus (HAdV)-based oncolytic vectors, which are designed to preferentially replicate in and kill cancer cells, have shown modest efficacy in human clinical trials in part due to poor viral distribution throughout the tumor mass. Previously, we showed that expression of the p14 fusion-associated small transmembrane (FAST) fusogenic protein could enhance oncolytic HAdV efficacy and reduce tumor growth rate in a human xenograft mouse model of cancer. We now explore whether co-expression of the adenovirus death protein (ADP) with p14 FAST protein could synergize to further enhance oncolytic vector efficacy. ADP is naturally encoded within the early region 3 (E3) of HAdV, a region which is frequently removed from HAdV-based vectors, and functions to enhance cell lysis and progeny release. We evaluated a variety of approaches to achieve optimal expression of the two proteins, the most efficient method being insertion of an expression cassette within the E3 deletion, consisting of the coding sequences for p14 FAST protein and ADP separated by a self-cleaving peptide derived from the porcine teschovirus-1 (P2A). However, the quantities of p14 FAST protein and ADP produced from this vector were reduced approximately 10-fold compared to a similar vector-expressing only p14 FAST protein and wildtype HAdV, respectively. Compared to our original oncolytic vector-expressing p14 FAST protein alone, reduced expression of p14 FAST protein and ADP from the P2A construct reduced cell-cell fusion, vector spread, and cell-killing activity in human A549 adenocarcinoma cells in culture. These studies show that a self-cleaving peptide can be used to express two different transgenes in an armed oncolytic HAdV vector, but also highlight the challenges in maintaining adequate transgene expression when modifying vector design.

Logic-gated and contextual control of immunotherapy for solid tumors: contrasting multi-specific T cell engagers and CAR-T cell therapies.

CAR-T cell and T cell engager therapies have demonstrated transformational efficacy against hematological malignancies, but achieving efficacy in solid tumors has been more challenging, in large part because of on-target/off-tumor toxicities and sub-optimal T cell anti-tumor cytotoxic functions. Here, we discuss engineering solutions that exploit biological properties of solid tumors to overcome these challenges. Using logic gates as a framework, we categorize the numerous approaches that leverage two inputs instead of one to achieve better cancer selectivity or efficacy in solid tumors with dual-input CAR-Ts or multi-specific TCEs. In addition to the "OR gate" and "AND gate" approaches that leverage dual tumor antigen targeting, we also review "contextual AND gate" technologies whereby continuous cancer-selective inputs such a pH, hypoxia, target density, tumor proteases, and immune-suppressive cytokine gradients can be creatively incorporated in therapy designs. We also introduce the notion of "output directionality" to distinguish dual-input strategies that mechanistically impact cancer cell killing or T cell fitness. Finally, we contrast the feasibility and potential benefits of the various approaches using CAR-T and TCE therapeutics and discuss why the promising "IF/THEN" and "NOT" gate types pertain more specifically to CAR-T therapies, but can also succeed by integrating both technologies.

Adenoviral delivery of the CIITA transgene induces T-cell-mediated killing in glioblastoma organoids.

The immunosuppressive nature of the tumor microenvironment poses a significant challenge to effective immunotherapies against glioblastoma (GB). Boosting the immune response is critical for successful therapy. Here, we adopted a cancer gene therapy approach to induce T-cell-mediated killing of the tumor through increased activation of the immune system. Patient-based three-dimensional (3D) GB models were infected with a replication-deficient adenovirus (AdV) armed with the class II major histocompatibility complex (MHC-II) transactivator (CIITA) gene (Ad-CIITA). Successful induction of surface MHC-II was achieved in infected GB cell lines and primary human GB organoids. Infection with an AdV carrying a mutant form of CIITA with a single amino acid substitution resulted in cytoplasmic accumulation of CIITA without subsequent MHC-II expression. Co-culture of infected tumor cells with either peripheral blood mononuclear cells (PBMCs) or isolated T-cells led to dramatic breakdown of GB organoids. Intriguingly, both wild-type and mutant Ad-CIITA, but not unarmed AdV, triggered immune-mediated tumor cell death in the co-culture system, suggesting an at least partially MHC-II-independent process. We further show that the observed cancer cell killing requires the presence of either CD8+ or CD4+ T-cells and direct contact between GB and immune cells. We did not, however, detect evidence of activation of canonical T-cell-mediated cell death pathways. Although the precise mechanism remains to be determined, these findings highlight the potential of AdV-mediated CIITA delivery to enhance T-cell-mediated immunity against GB.

Targeting carbohydrate metabolism in colorectal cancer - synergy between DNA-damaging agents, cannabinoids, and intermittent serum starvation.

Chemotherapy is a therapy of choice for many cancers. However, it is often inefficient for long-term patient survival and is usually accompanied by multiple adverse effects. The adverse effects are mainly associated with toxicity to normal cells, frequently resulting in immune system depression, nausea, loss of appetite and metabolic changes. In this respect, the combination of chemotherapy with cannabinoids, especially non-psychoactive, such as cannabidiol, cannabinol and other minor cannabinoids, as well as terpenes, may become very useful. This is especially pertinent because the mechanisms of anticancer effects of cannabinoids on cancer cells are often different from conventional chemotherapeutics. In addition, cannabinoids help alleviate chemotherapy-induced adverse effects, regulate sleep and appetite, and are shown to have analgesic properties. Another component for achieving potential anti-cancer synergism is regulating nutrient availability and metabolism by calorie restriction and intermittent fasting in cancer cells. As tumours require a lot of energy to grow and because glucose is constantly available, malignant cells often opt to use glucose as a primary source of ATP production through substrate-level phosphorylation (fermentation) rather than through oxidative phosphorylation. Thus, periodic depletion of cancer cells of primary fuel, glucose, could result in a strong synergy in killing cancer cells by chemo- and possibly radiotherapy when combined with cannabinoids. This commentary will discuss what is known about such combinatorial treatments, including potential mechanisms and future protocols.

A B7-H3–Targeted CD28 Bispecific Antibody Enhances the Activity of Anti–PD-1 and CD3 T-cell Engager Immunotherapies

Abstract T-cell activation is a multistep process requiring T-cell receptor engagement by peptide–MHC complexes (Signal 1) coupled with CD28-mediated costimulation (Signal 2). Tumors typically lack expression of CD28 ligands, so tumor-specific Signal 1 (e.g., neoepitope presentation) without costimulation may be ineffective or even induce T-cell anergy. We designed the bispecific antibody XmAb808 to co-engage the tumor-associated antigen B7-H3 with CD28 to promote T-cell costimulation within the tumor microenvironment. XmAb808 costimulation was measured by its ability to activate and expand T cells and enhance T cell–mediated cancer cell killing in cocultures of human peripheral blood mononuclear cells and cancer cells and in mice engrafted with human peripheral blood mononuclear cells and tumor xenografts. XmAb808 avidly bound cancer cells and stimulated IL2 and IFNγ secretion from T cells cocultured with cancer cells engineered to deliver Signal 1 to T cells via a surface-expressed anti-CD3 antibody. XmAb808 enhanced expression of the antiapoptotic factor Bcl-xL and CD25, promoting survival and IL2-dependent expansion of T cells coupled with increased T cell–mediated cytotoxicity in vitro. XmAb808 combined with an EpCAM×CD3 bispecific antibody to enhance target cell killing through IL2-dependent expansion of CD25+ T cells. This combination also suppressed pancreatic tumor xenograft growth in mice. Furthermore, XmAb808 combined with an anti–programmed cell death protein 1 antibody to suppress breast tumor xenograft growth in mice. XmAb808 as monotherapy and in combination with an anti–programmed cell death protein 1 antibody is currently in clinical development in patients with advanced solid tumors. Our results suggest that XmAb808 may also combine with tumor antigen–targeted anti-CD3 (Signal 1) T-cell engagers.

Macropinocytosis-targeted peptide-docetaxel conjugate for bystander pancreatic cancer treatment

Oncogenic Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are highly prevalent in pancreatic ductal adenocarcinoma (PDAC) and have garnered attention as potential targets for targeted therapies, such as KRAS inhibitors. However, the limited therapeutic efficacy of KRAS allele-specific inhibitors necessitate an efficient pan-KRAS cancer cell killing strategy. Here, we have examined enhanced macropinocytosis pathway in KRAS mutant cancer cells and report improved intracellular delivery of albumin-based therapeutics. We further established an albumin-binding peptide-docetaxel conjugate platform (MPD3), which has a caspase-3 cleavable feature, for macropinocytosis-targeted bystander payload delivery and realization of bystander killing of pan-KRAS cancer cells, complemented with caspase-3 mediated activation of MPD3 to bolster tumoral accumulation of cytotoxic payloads. Utilization of in vitro co-culture system of pan-KRAS cancer cells and pharmacodynamic marker staining revealed potent bystander killing effects of MPD3, highlighting MPD3 as an efficient delivery platform against pan-KRAS cancer. Moreover, MPD3 elicited robust anti-tumor activities in both local and liver metastatic PDAC tumor models in mice. Overall, this work establishes a paradigm for developing translational pan-KRAS cancer treatment and broadens the applicability of albumin binding peptide-drug conjugate against albumin-metabolism enriched cancers.

Alternate MHC I antigen presentation pathways allow CD8+ T-cell recognition and killing of cancer cells in the absence of ß2M or TAP.

Major histocpmpatibilty complex class I (MHC I) antigen presentation allows CD8+ T cells to detect and eliminate cancerous or virally infected cells. The MHC I pathway is not essential for cell growth and viability and consequently cancers and viruses can evade control by CD8+ T cells by inactivating antigen presentation. In cancers, two common ways for this evasion are the loss of either the MHC I light chain (ß2M) or the cytosol-to-endoplasmic reticulum (ER) peptide transporter (TAP). ß2M-null cells are generally thought to lack the MHC I pathway because the MHC I heavy chain by itself lacks the proper conformation for peptide display. TAP-null cells are thought to have severely defective MHC I antigen presentation because they are incapable of supplying peptides from the cytosol to MHC I molecules in the ER. However, we have found that highly reactive memory CD8+ T cells could still recognize cells that completely lacked ß2M or TAP. This was at least in part because in TAPnull cells, the Sec62 component of the Sec61 translocon supported the transfer of cytosolic peptides into the ER. In ß2M-negative cells, free MHC I heavy chains were able to bind peptides and assume a conformation that was sufficiently recognized by CD8+ T cells. This process required ER chaperones and the peptide-loading complex. We found that these mechanisms supported antigen presentation at a level that was sufficient for memory CD8+ T cells to kill melanoma cells both in vitro and in tumor-bearing mice. The implications for tumor immunotherapy are discussed.

Cisplatin-functionalized dual-functional bone substitute granules for bone defect treatment after bone tumor resection

Invasive bone tumors pose a significant healthcare challenge, often requiring systemic chemotherapy and limb salvage surgery. However, these strategies are hampered by severe side effects, complex post-resection bone defects, and high local recurrence rates. To address this, we developed dual-functional bone substitute biomaterials by functionalizing commercially available bone substitute granules (Bio-Oss® and MBCP®+) with the established anticancer agent cisplatin. Physicochemical characterization revealed that Bio-Oss® granules possess a higher surface area and lower crystallinity compared to MBCP®+ granules, which enhances their capacity for cisplatin adsorption and release. In co-cultures with metastatic breast and prostate cancer cells (MDA-MB-231 and PC3) and bone marrow stromal cells (hBMSCs), cisplatin-functionalized granules and their releasates exhibited dose-dependent cytotoxic effects on cancer cells while having less impact on hBMSCs. Furthermore, investigations on the mechanism of action indicated that cisplatin induced significant cell cycle arrest and apoptosis in MDA-MB-231 and PC3 cells, contrasting with minimal effects on hBMSCs. In a rat femoral condyle defect model, cisplatin-functionalized granules did not evoke adverse effects on bone tissue ingrowth or new bone formation. Importantly, local application of cisplatin-functionalized granules resulted in negligible cisplatin accumulation without signs of apoptotic damage in kidneys and livers. Taken together, we here provide hard evidence that cisplatin-functionalized granules maintain a favorable balance between biosafety, anticancer efficacy, and bone regenerative capacity. Consequently, loading granular bone substitutes with cisplatin holds promise for local treatment of bone defects following bone tumor resections, presenting a safe and potentially more effective alternative to systemic cisplatin administration. Statement of SignificanceCurrent treatments in combating malignant bone tumors are hampered by severe side effects, high local tumor recurrence, and complex bone defects after surgery. This study explores a facile manufacturing method to render two types of commercially available bone substitute granules (Bio-Oss® and MBCP®+) suitable for local delivery of cisplatin. The use of cisplatin-functionalized granules has shown promising results both in killing cancer cells in a dose-dependent manner and in aiding bone regeneration. Importantly, this local treatment strategy avoids the systemic toxicity associated with traditional chemotherapy to excretory organs. This dual-functional strategy represents a significant advancement in bone cancer treatment, offering a safe and more efficient alternative that could improve outcomes for patients following bone tumor resection.

A multifunctional cascade gas-nanoreactor with MnO2 as a gatekeeper to enhance starvation therapy and provoke antitumor immune response

Glucose oxidase (GOx)-mediated starvation therapy is an effective tumor treatment that blocks energy and activates the immune response. However, the insufficient tumor immunogenicity and immunosuppressive tumor microenvironment (TME) limited its therapeutic efficacy. To address this, we have designed a multifunctional cascade gas-nanoreactor with a MnO2 coating, which serves as an out gatekeeper to encapsulate both GOx and a carbon monoxide (CO) donor (denoted as GCM). Due to the protective effect of MnO2 coating, GCM maintains better stability in normal physiological environments, enhancing the catalytic activity of GOx and minimizing toxic side effects. Upon accumulation in the tumor, the degradation of MnO2 coating exposes the GOx enzyme, thereby initiating a cascade catalysis reaction to generate hydrogen peroxide (H2O2) and release CO in the hypoxic conditions. Additionally, the released Mn2+ reacts with H2O2 to generate toxic hydroxyl radical (•OH) as chemodynamic therapy (CDT). The synergistic treatments of starvation therapy, CO gas therapy and CDT effectively kill cancer cells and amplify immunogenic cell death (ICD), maturing DC cells and activating anti-tumor immune response. Furthermore, the released CO increases M1 macrophages infiltration and reduces myeloid-derived suppressor cells (MDSCs) infiltration, thus reversing the immunosuppressive TME. This multifunctional gas-nanoreactor provides a strategy for CO gas generation to trigger a robust anti-tumor immune response and has the potential for clinical application in cancer immunotherapy. Statement of significanceA multifunctional cascade gas-nanoreactor with a MnO2 gatekeeper was developed to perform synergistic treatments involving starvation therapy, CO gas therapy and chemodynamic therapy (CDT) for tumor elimination. The MnO2 gatekeeper enhanced the catalytic activity of GOx within the nanoreactor by generating oxygen, thereby minimizing toxic side effects after intravenous injection. The gas-nanoreactor amplified ICD through synergistic treatments to mature DC cells and activate anti-tumor immune response. Furthermore, the released CO could reverse the immunosuppression of the TME to enhance cancer immunotherapy. The combination strategy utilizing the gas-nanoreactor demonstrates clinical potential for facilitating cancer immunotherapy.

Natural killer cells are required for the recruitment of CD8+ T cells and the efficacy of immune checkpoint blockade in melanoma brain metastases

Background Brain metastases (BrM) affect up to 60% of patients with metastatic melanoma and are associated with poor prognosis. While combined immune checkpoint blockade of programmed death-1 (PD-1) and cytotoxic...

Interleukins: Role in cancer and its immunotherapy

Interleukins are a very important family of cytokines; they are the messengers that assist immune cells to communicate with each other. Interleukins plays a pivotal role in innate and adaptive immune responses by balancing immune cell proliferation, differentiation and regulation. Interleukins aid immune cells in killing cancer cells while simultaneously assisting cancer cells in evading the immune response which leads tumor formation. Some interleukins are very effective at activating effector immune cells to kill cancer cells and also used for cancer immunotherapy. Interleukins are utilized in cancer immunotherapy alone or in combination with other therapies such as CAR-T, checkpoint inhibitors, or chemotherapy. In this review, we will explore the role of different interleukins in cancer and how researchers modified and therapeutically used them to treat cancer (e.g. IL-2, IL-12, IL-15, IL-17, IL-6, IL-18 etc.,).