Induction Of Apoptosis In Cancer Cells Research Articles

Chimeric antigen receptor dendritic cells targeted delivery of a single tumoricidal factor for cancer immunotherapy

BackgroundChimeric antigen receptor (CAR)-T cells have been used to treat blood cancers by producing a wide variety of cytokines. However, they are not effective in treating solid cancers and can cause severe side-effects, including cytokine release syndrome. TNFα is a tumoricidal cytokine, but it markedly increases the protein levels of cIAP1 and cIAP2, the members of inhibitor of apoptosis protein (IAP) family of E3 ubiquitin ligase that limits caspase-induced apoptosis. Degradation of IAP proteins by an IAP antagonist does not effectively kill cancer cells but enables TNFα to strongly induce cancer cell apoptosis. It would be a promising approach to treat cancers by targeted delivery of TNFα through an inactive adoptive cell in combination with an IAP antagonist.MethodsHuman dendritic cells (DCs) were engineered to express a single tumoricidal factor, TNFα, and a membrane-anchored Mucin1 antibody scFv, named Mucin 1 directed DCs expressing TNFα (M-DCsTNF). The efficacy of M-DCsTNF in recognizing and treating breast cancer was tested in vitro and in vivo.ResultsMucin1 was highly expressed on the surface of a wide range of human breast cancer cell lines. M-DCsTNF directly associated with MDA-MB-231 cells in the bone of NSG mice. M-DCsTNF plus an IAP antagonist, SM-164, but neither alone, markedly induce MDA-MB-231 breast cancer cell apoptosis, which was blocked by TNF antibody. Importantly, M-DCsTNF combined with SM-164, but not SM-164 alone, inhibited the growth of patient-derived breast cancer in NSG mice.ConclusionAn adoptive cell targeting delivery of TNFα combined with an IAP antagonist is a novel effective approach to treat breast cancer and could be expanded to treat other solid cancers. Unlike CAR-T cell, this novel adoptive cell is not activated to produce a wide variety of cytokines, except for additional overexpressed TNF, and thus could avoid the severe side effects such as cytokine release syndrome.

G-quadruplex-Based Artificial Transmembrane Channels Induce Cancer Cell Apoptosis by Perturbing Potassium Ion Homeostasis.

Transmembrane ion transport modality has received a widespread attention due to its apoptotic activation toward anticancer cell activities. In this study, G-quadruplex-based potassium-specific transmembrane channels have been developed to facilitate the intracellular K+ efflux, which perturbs the cellular ion homeostasis thereby inducing cancer cell apoptosis. Cholesterol-tag, a lipophilic anchor moiety, serves as a rudiment for the G-quadruplex immobilization onto the membrane, while G-quadruplex channel structure as a transport module permits ion binding and migration along the channels. A c-Myc sequence tagged with two-cholesterol is designed as a representative lipophilic G-quadruplex, which forms intramolecular parallel G-quadruplex with three stacks of G-quartets (Ch2-Para3). Fluorescence transport assay demonstrates Ch2-Para3 a high transport activity (EC50 = 10.9 × 10-6 m) and an ion selectivity (K+/Na+ selectivity ratio of 84). Ch2-Para3 mediated K+ efflux in cancer cells is revealed to purge cancer cells through K+ efflux-mediated cell apoptosis, which is confirmed by monitoring the changes in membrane potential of mitochondria, leakage of cytochrome c, reactive oxygen species yield, as well as activation of a family of caspases. The lipophilic G-quadruplex exhibits obvious antitumor activity in vivo without systemic toxicity. This study provides a functional scheme aimed at generating DNA-based selective artificial membrane channels for the purpose of regulating cellular processes and inducing cell apoptosis, which shows a great promising for anticancer therapy in the future.

Discovery of Cytotoxic Nitric Oxide-Releasing Piperlongumine Derivatives Targeting Wnt/β-Catenin in Colon Cancer Cells.

Piperlongumine (1) increases reactive oxygen species (ROS) levels and induces apoptosis in cancer cells through various pathways. Nitric oxide (NO) donors have demonstrated potent anticancer activities with exogenous NO being oxidized by ROS in the tumor microenvironment to form highly reactive N-oxides (RNOS). This amplifies oxidative stress cascade reactions, ultimately inducing cancer cell apoptosis. To exploit this synergy, a series of NO-releasing piperlongumine derivatives (2-5) were designed and synthesized. These compounds were expected to release NO in cancer cells, simultaneously generating piperlongumine derivative fragments to enhance the anticancer effects. Compound 6, structurally similar to compounds 2-5 but not releasing NO, served as a control. Among these derivatives, compound 5 exhibited the most potent antiproliferative activity against HCT-116 cells and efficiently released NO in this cell line. Further investigation revealed that compound 5 inhibited colon cancer cell proliferation by modulating β-catenin expression, which is a pivotal protein in the Wnt/β-catenin signaling pathway. These findings highlight compound 5 as a promising candidate for colon cancer treatment targeting the Wnt/β-catenin pathway.

Biomimetic nanosystems harnessing NIR-II photothermal effect and hypoxia-responsive prodrug for self-amplifying and synergistic tumor treatment

Tumor microenvironment-activated prodrugs have emerged as a promising strategy in precision medicine. However, the endogenous stimuli in the tumor microenvironment are often insufficient and unevenly distributed, impeding efficient and rapid prodrug conversion, necessitating the incorporation of complementary therapeutic strategies to amply treatment effectiveness. This study presents a self-synergistic therapeutic approach that combines hypoxia-activated paclitaxel prodrug (pro-PTX) with near-infrared-II (NIR-II) light-triggered photothermal therapy (PTT) for boosted tumor treatment. Initially, an organic polymer with strong NIR-II light harvesting capability, efficient photo-to-heat conversion, and excellent photostability was meticulously synthesized by introducing electron-withdrawing trifluoromethyl substituent. The high-performance NIR-II photothermal polymer then served as the matrix to encapsulate the hypoxia-responsive pro-PTX prodrug, forming the nanocore, on which the cell membrane derived from natural killer (NK) cells was further cloaked. The biomimetic nanopaltform exhibited a superior affinity towards tumor cells compared to normal cells, owing to the inherent tumor-recognition capability of NK cell membrane proteins. Upon exposure to NIR-II laser, the photothermal agent induced localized hyperthermia, facilitating not only direct tumor eradication but also exacerbating hypoxia within the tumor microenvironment. This, in turn, expedited the release of hypoxia-responsive prodrugs. Consequently, the synergistic effect of NIR-II PTT and chemotherapy efficiently induced cancer cell apoptosis and inhibited tumor growth. The developed nanoplatform, integrating hypoxia-responsive prodrug, high-performance NIR-II PTT agent-mediated complementary phototherapy, and NK cell-inspired active targeting, represents a promising strategy for precise and boosted tumor treatment.

Novel 131-iodine labeled and ultrasound-responsive nitric oxide and reactive oxygen species controlled released nanoplatform for synergistic sonodynamic/nitric oxide/chemodynamic/radionuclide therapy

Nitric oxide (NO) and reactive oxygen species (ROS) embody excellent potential in cancer therapy. However, as a small molecule, their targeted delivery and precise, controllable release are urgently needed to achieve accurate cancer therapy. In this paper, a novel US-responsive bifunctional molecule (SD) and hyaluronic acid-modified MnO2 nanocarrier was developed, and a US-responsive NO and ROS controlled released nanoplatform was constructed. US can trigger SD to release ROS and NO simultaneously at the tumor site. Thus, SD served as acoustic sensitizer for sonodynamic therapy and NO donor for gas therapy. In the tumor microenvironment, the MnO2 nanocarrier can effectively deplete the highly expressed GSH, and the released Mn2+ can make H2O2 to produce .OH by Fenton-like reaction, which exhibited a strong chemodynamic effect. The high concentration of ROS and NO in cancer cell can induce cancer cell apoptosis ultimately. In addition, toxic ONOO–, which was generated by the reaction of NO and ROS, can effectively cause mitochondrial dysfunction, which induced the apoptosis of tumor cells. The 131I was labeled on the nanoplatform, which exhibited internal radiation therapy for tumor therapy. In −vitro and −vivo experiments showed that the nanoplatform has enhanced biocompatibility, and efficient anti-tumor potential, and it achieves synergistic sonodynamic/NO/chemodynamic/radionuclide therapy for cancer.

Recent advances on quinoxalines as target-oriented chemotherapeutic anticancer agents through apoptosis.

The current review outlines all possible recent synthetic platforms to quinoxaline derivatives and the potent stimulated apoptosis mechanisms targeted by anticancer therapies. The currently reported results disclosed that quinoxaline derivatives had promising anticancer potencies against a wide array of cancer cell lines, better than the reference drugs, through target inhibition. This review summarizes some potent quinoxaline derivatives with their synthesis strategies and their potential activities against various molecular targets. Quinoxalines can be considered an important scaffold for apoptosis inducers in cancer cells through inhibiting some molecular targets, so they can be further developed as target-oriented chemotherapeutics.

Synthesis and antitumor activity of dolutegravir derivatives bearing 1,2,3-triazole moieties

Modification of marketed drugs is an important way to develop drugs because its safety and clinical applicability. Oxygen-nitrogen heterocycles are a class of important active substances discovered in the process of new drug development. Dolutegravir, an HIV drug with a nitrogen-oxygen heterocycle structure, has the potential ability to inhibit cell survival. In order to find and explore novel anti-tumor drugs, new dolutegravir derivatives bearing different 1,2,3-triazole moieties were prepared via click reactions. In vitro biological experiments performed in several lung cancer cell lines suggested that these novel compounds displayed potent anti-tumor ability. Especially, the compound 9e with a substituent of 2-methyl-3-nitrophenyl and the compound 9p with a substituent of 3-trifluoromethylphenyl were effective against PC-9 cell line with IC50 values of 3.83 and 3.17 µM, respectively. Moreover, compounds 9e and 9p were effective against H460 and A549 cells. Further studies suggested that compounds 9e and 9p could induce cancer cell apoptosis in PC-9 and H460, inhibit cancer cell proliferation, change the cell cycle, and increase the level of reactive oxygen species (ROS) which further induce tumor cell apoptosis. In addition, compounds 9e and 9p increased LC3 protein expression which was the key regulator in autophagy signaling pathway in PC-9 cells. Compound 9e also showed low toxicity against normal cells, and could be regarded as an interesting lead compound for further structure optimization.

Key residues in the VDAC2-BAK complex can be targeted to modulate apoptosis.

BAK and BAX execute intrinsic apoptosis by permeabilising the mitochondrial outer membrane. Their activity is regulated through interactions with pro-survival BCL-2 family proteins and with non-BCL-2 proteins including the mitochondrial channel protein VDAC2. VDAC2 is important for bringing both BAK and BAX to mitochondria where they execute their apoptotic function. Despite this important function in apoptosis, while interactions with pro-survival family members are well characterised and have culminated in the development of drugs that target these interfaces to induce cancer cell apoptosis, the interaction between BAK and VDAC2 remains largely undefined. Deep scanning mutagenesis coupled with cysteine linkage identified key residues in the interaction between BAK and VDAC2. Obstructive labelling of specific residues in the BH3 domain or hydrophobic groove of BAK disrupted this interaction. Conversely, mutating specific residues in a cytosol-exposed region of VDAC2 stabilised the interaction with BAK and inhibited BAK apoptotic activity. Thus, this VDAC2-BAK interaction site can potentially be targeted to either inhibit BAK-mediated apoptosis in scenarios where excessive apoptosis contributes to disease or to promote BAK-mediated apoptosis for cancer therapy.

Unlocking the therapeutic potential: Green synthesized zinc oxide/silver nanoparticles from Sophora pachycarpa for anticancer activity, gene expression analysis, and antibacterial applications

Hematologic malignancies and bloodstream infections rank among the most lethal medical conditions. Research on new treatments for these diseases is crucial. In this study, we investigated the anticancer properties and molecular mechanisms of zinc oxide nanoparticles doped with silver synthesized using a green approach involving Sophora pachycarpa (S. pachycarpa) plant seed extract (SPS@ZnO/Ag NPs). Additionally, we explored the antibacterial effects of these nanoparticles and S. pachycarpa extract. The SPS@ZnO/Ag NPs were characterized using XRD, FTIR, zeta potential, EDS, FESEM, and TEM analyses. Subsequently, we assessed the viability of K562 cells in the presence of different nanoparticles and extract. Molecular mechanisms underlying cell death were examined through flow cytometry analysis, Hoechst staining, and relative expression of pro-apoptotic genes (Apaf-1, Cytochrome c, Caspases 3, 6, 9) relative to the gene B-actin. Also, BAX/BCL2 ratio was determined. Antibacterial effects were evaluated against Gram-negative and Gram-positive bacteria. The results confirmed successful synthesis of spherical SPS@ZnO/Ag NPs with positive surface charge, purity, and size ranging from 50 to 65 nm. SPS@ZnO/Ag NPs significantly reduced K562 cell viability compared to S. pachycarpa extract and chemical nanoparticles, with the 1:1 ratio of zinc oxide and silver nitrate exhibiting the highest cell death. The findings from flow cytometry analysis, Hoechst staining, and molecular pathway analysis indicate that SPS@ZnO/Ag NPs induce cancer cell death through apoptosis. Evaluation of antibacterial properties demonstrated the destruction of all studied strains by SPS@ZnO/Ag NPs. Overall, our study demonstrates that green synthesis, in comparison to chemical synthesis, exerts a notable impact on the anticancer properties of zinc oxide nanoparticles doped with silver. Moreover, SPS@ZnO/Ag NPs exhibit targeted induction of cancer cell apoptosis, showcasing their potential application in biomedical fields.

Putting the STING back into BH3-mimetic drugs for TP53-mutant blood cancers

TP53-mutant blood cancers remain a clinical challenge. BH3-mimetic drugs inhibit BCL-2 pro-survival proteins, inducing cancer cell apoptosis. Despite acting downstream of p53, functional p53 is required for maximal cancer cell killing by BH3-mimetics through an unknown mechanism. Here, we report p53 is activated following BH3-mimetic induced mitochondrial outer membrane permeabilization, leading to BH3-only protein induction and thereby potentiating the pro-apoptotic signal.TP53-deficient lymphomas lack this feedforward loop, providing opportunities for survival and disease relapse after BH3-mimetic treatment. The therapeutic barrier imposed by defects in TP53 can be overcome by direct activation of the cGAS/STING pathway, which promotes apoptosis of blood cancer cells through p53-independent BH3-only protein upregulation. Combining clinically relevant STING agonists with BH3-mimetic drugs efficiently kills TRP53/TP53-mutant mouse B lymphoma, human NK/T lymphoma, and acute myeloid leukemia cells. This represents a promising therapy regime that can be fast-tracked to tackle TP53-mutant blood cancers in the clinic.

Cyclic peroxides and analogs: Antibacterial, antimalarial, and cytotoxic marine products from Xisha sponge Diacarnus sp.

A chemical investigation of the dichloromethane extract from the Xisha sponge Diacarnus sp. revealed seven undescribed norterpene cyclic peroxides, named diacarperoxides T–Z, and five unreported related norterpenes, named diacarnoids E–I, and eleven previously reported compounds. The structures of these isolated compounds, including their absolute configurations, were elucidated based on extensive spectroscopic analyses, electronic circular dichroism (ECD) calculations, Snatzke's method, [Rh2(OCOCF3)4]-induced ECD spectra, and modified Mosher's method. Bioassays were performed to assess the antibacterial activity against six pathogenic bacteria, cytotoxicities toward three cancer cell lines, and antimalarial activity against Plasmodium parasites. Most of the cyclic peroxides exhibited substantial antibacterial activity (MIC 1–8 μg/mL). Diacarperoxide W and nuapapuin A showed substantial antimalarial activity with IC50 values of 0.98 and 2.83 μM. Moreover, many compounds exhibited <50% cell survival rates, and IC50 values of 0.22–6.33 μM. The apoptosis assay showed that nuapapuin A induced cancer cell apoptosis in a dose-dependent manner.

Cytotoxic activity and apoptosis induction by supernatant of Lentilactobacillus buchneri on HT-29 colon cancer cells

Background and Objectives: Colorectal cancer (CRC) is the fourth most commonly diagnosed cancer and the third most deadly cancer in the world. According to recent experimental reports, probiotics and their derivatives protect CRC patients from treatment-related side effects. Therefore, the present study aimed to investigate the cytotoxic impact of the cell-free supernatant (CFS) of Lentilactobacillus buchneri on the HT-29 cancer cell line.&#x0D; Materials and Methods: In the current study, we used the L. buchneri CFS, which was well isolated and identified in our previous investigation from traditional yogurt in the Arak region of Iran. The apoptosis induction in HT-29 cancer cells was assessed by cell cytotoxicity, flow cytometry, and qRT-PCR.&#x0D; Results: L. buchneri CFS inhibited the proliferation of HT-29 cancer cells in a time- and dose-dependent manner. The apoptotic effect of CFS was further supported by the flow cytometry data, which showed that the maximum incidence of apoptosis 50 was observed in HT-29 cancer cells treated with the IC concentration of CFS after 72 hours. CFS of L. buchneri also exerted the up-regulating effect on the expression of pro-apoptotic genes including BAX, CASP9, and CASP3. L. buchneri CFS at an IC 50 dose induced cell cycle arrest in the G0/G1 phase in HT-29 cells.&#x0D; Conclusion: This study indicates that L. buchneri CFS can prevent colorectal cancer (CRC) development in patients by inducing cancer cell apoptosis. This finding suggests that the CFS of L. buchneri could be used as a therapeutic agent for the control of CRC.

Making the Brightest Ones Dim: Maximizing the Photothermal Conversion Efficiency of BODIPY-Based Photothermal Agents.

The successful implementation of photothermal therapy (PTT) in cancer treatment hinges on the development of highly effective photothermal agents (PTAs). Boron dipyrromethene (BODIPY) dyes, being well known for their high brightness and quantum efficiencies, are the antithesis of PTAs. Nonetheless, a systematic exploration of the photophysics and photothermal characteristics of a series of π-extended BODIPY dyes with high absorptivity in the near-infrared (NIR) region has achieved superior photothermal conversion efficiencies (>90%), in both monomeric state and nanoparticles after encapsulation in a biocompatible polyethyleneglycol 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy-(polyethylene glycol)-2000]. Optimal PTA candidates combine strong NIR absorption provided by extended donor-acceptor conjugation and an optimization of the electronic and steric effects of meso-substituents to maximize photothermal conversion performance. The PTT-optimized meso-CF3-BODIPY, TCF3PEn exhibits exceptional efficacy in inducing cancer cell apoptosis and in vivo tumor ablation using low-power NIR laser irradiation (0.3 Wcm-2, 808 nm) as well as excellent biological safety, underscoring its potential for advancing light-induced cancer therapies.

Stearoyl-CoA desaturase 1 inhibition induces ER stress-mediated apoptosis in ovarian cancer cells

Ovarian cancer is a leading cause of death among gynecologic tumors, often detected at advanced stages. Metabolic reprogramming and increased lipid biosynthesis are key factors driving cancer cell growth. Stearoyl-CoA desaturase 1 (SCD1) is a crucial enzyme involved in de novo lipid synthesis, producing mono-unsaturated fatty acids (MUFAs). Here, we aimed to investigate the expression and significance of SCD1 in epithelial ovarian cancer (EOC). Comparative analysis of normal ovarian surface epithelial (NOSE) tissues and cell lines revealed elevated SCD1 expression in EOC tissues and cells. Inhibition of SCD1 significantly reduced the proliferation of EOC cells and patient-derived organoids and induced apoptotic cell death. Interestingly, SCD1 inhibition did not affect the viability of non-cancer cells, indicating selective cytotoxicity against EOC cells. SCD1 inhibition on EOC cells induced endoplasmic reticulum (ER) stress by activating the unfolded protein response (UPR) sensors and resulted in apoptosis. The addition of exogenous oleic acid, a product of SCD1, rescued EOC cells from ER stress-mediated apoptosis induced by SCD1 inhibition, underscoring the importance of lipid desaturation for cancer cell survival. Taken together, our findings suggest that the inhibition of SCD1 is a promising biomarker as well as a novel therapeutic target for ovarian cancer by regulating ER stress and inducing cancer cell apoptosis.

Abstract 2103: Small extracellular vesicles derived from macrophages show anti-tumor effects in MDA-MB-231 cells

Abstract Triple-negative breast cancer is the primary cause of death in women globally due to the absence of targeted receptors on the tumor, making it hard to treat. In addition, the rapid spread of triple-negative breast cancer makes it difficult to manage using current treatment options such as lumpectomies, mastectomies, radiation, and chemotherapy. The survival rate for patients with triple-negative breast cancer is only 8-16%. Therefore, there is a critical need to develop new and effective treatment options. The objective of this study was to investigate the potential of M1 macrophage-derived exosomes to induce cancer cell apoptosis. To test this, we isolated M1 macrophage-derived exosomes to see their effects on triple-negative breast cancer MDA-MB-231 cells. We induce polarization in RAW 264.7 macrophage cells via lipopolysaccharide (LPS). Macrophage polarization was characterized using an enzyme-linked immunosorbent assay (ELISA), real-time PCR, nitric oxide production, and bright field microscopy. We characterized exosomes using nanoparticle tracking analysis (NTA) and scanning electron microscopy (SEM). The apoptosis marker, caspase 3/7 activation, was assessed using confocal microscopy in MDA-MB-231 cells. M1 macrophage-derived exosomes were isolated, characterized, and incubated with breast cancer cells to see their anticancer effects. Data showed the induction of apoptosis in 48 hours in triple-negative breast cancer cells. We conclude that exosomes derived from M1 macrophages may have the capability to induce apoptosis in triple-negative breast cancer. Citation Format: Parth Desai, Anjali Kumari, Saqer Al Abdullah, Kristen Dellinger. Small extracellular vesicles derived from macrophages show anti-tumor effects in MDA-MB-231 cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2103.

Desirable L-asparaginases for treating cancer and current research trends.

Amino acid depletion therapy is a promising approach for cancer treatment. It exploits the differences in the metabolic processes between healthy and cancerous cells. Certain microbial enzymes induce cancer cell apoptosis by removing essential amino acids. L-asparaginase is an enzyme approved by the FDA for the treatment of acute lymphoblastic leukemia. The enzymes currently employed in clinics come from two different sources: Escherichia coli and Erwinia chrysanthemi. Nevertheless, the search for improved enzymes and other sources continues because of several factors, including immunogenicity, in vivo instability, and protease degradation. Before determining whether L-asparaginase is clinically useful, research should consider the Michaelis constant, turnover number, and maximal velocity. The identification of L-asparaginase from microbial sources has been the subject of various studies. The primary goals of this review are to explore the most current approaches used in the search for therapeutically useful L-asparaginases and to establish whether these investigations identified the crucial characteristics of L-asparaginases before declaring their therapeutic potential.

Structure-based approaches for the design of 6-aryl-1-(3,4,5-trimethoxyphenyl)-1H-benzo[d][1,2,3]triazoles as tubulin polymerization inhibitors

The colchicine binding site on tubulin has been widely acknowledged as an attractive target for anticancer drug exploitation. Here, we reported the structural optimization of the lead compound 4, which was proved in our previous work as a colchicine binding site inhibitor (CBSI). Based on docking researches for the active binding conformation of compound 4, a series of novel 6-aryl-1-(3,4,5-trimethoxyphenyl)-1H-benzo[d][1,2,3]triazole derivatives (9a–9x) were developed by replacing a CH group in the 1H-benzo[d]imidazole skeleton of compound 4 with a nitrogen atom as a hydrogen bond acceptor. Among them, compound 9a showed the strongest antiproliferative activity with IC50 values ranging from 14 to 45 nM against three human cancer cell lines (MCF-7, SGC-7901 and A549), lower than that of compound 4. Mechanistic studies indicated that compound 9a could inhibit tubulin polymerization, destroy the microtubule skeleton, block the cell cycle in G2/M phase, induce cancer cell apoptosis, prevent cancer cell migration and colony formation. Moreover, compound 9a significantly inhibited tumor growth in vivo without observable toxicity in the mice 4T1 xenograft tumor model. In conclusion, this report shows a successful case of the structure-based design approach of a potent tubulin polymerization inhibitor for cancer treatment.

Potent Apoptosis Induction by a Novel Trispecific B7-H3xCD16xTIGIT 2+1 Common Light Chain Natural Killer Cell Engager.

Valued for their ability to rapidly kill multiple tumor cells in succession as well as their favorable safety profile, NK cells are of increasing interest in the field of immunotherapy. As their cytotoxic activity is controlled by a complex network of activating and inhibiting receptors, they offer a wide range of possible antigens to modulate their function by antibodies. In this work, we utilized our established common light chain (cLC)-based yeast surface display (YSD) screening procedure to isolate novel B7-H3 and TIGIT binding monoclonal antibodies. The chicken-derived antibodies showed single- to low-double-digit nanomolar affinities and were combined with a previously published CD16-binding Fab in a 2+1 format to generate a potent NK engaging molecule. In a straightforward, easily adjustable apoptosis assay, the construct B7-H3xCD16xTIGIT showed potent apoptosis induction in cancer cells. These results showcase the potential of the TIGIT NK checkpoint in combination with activating receptors to achieve increased cytotoxic activity.

Structure-based discovery of potent CARM1 inhibitors for colorectal cancer therapy

Coactivator-associated arginine methyltransferase 1 (CARM1) plays an important role in cell proliferation and gene expression, and is highly expressed in a variety of tumor tissues. Guided by our previous reported structure of DCPR049_12, we focused on designing and evaluating selective CARM1 inhibitors, resulting in the identification of compound 11f as a promising lead candidate. Compound 11f displayed potent inhibition of CARM1 (IC50 = 9 nM). Comprehensive evaluations, including in vitro metabolic stability assessments, molecular modelling, cellular studies, and in vivo anti-tumor studies, confirmed that it induced cancer cell apoptosis and specifically inhibited CARM1's methylation function. Notably, compound 11f displayed significant anti-proliferative effects on colorectal cancer cell lines, showcasing its potential for targeted therapies against CARM1-related diseases. This study provides valuable insights for the future development of specific and effective CARM1 inhibitors.

Black phosphorus-based nanoparticles induce liver cancer cell mitochondrial apoptosis and immune cell tumor infiltration for enhancing dendritic cell therapy

Cellular immunotherapy is a crucial aspect of current tumor immunotherapy, though it presents several challenges such as immune cell dysfunction, limited recognition of neoantigens, and inadequate lymphocyte infiltration into the tumor microenvironment. This study proposes a novel approach utilizing a combination of dendritic cell (DC)-based cellular immunotherapy and a photothermal nanoadjuvant black phosphorus (BP) nanoparticles to overcome these challenges. A new platform called PLGA@BP-R848, which consists of modifying poly-(lactic-co-glycolic acid) (PLGA) onto BP nanosheets loading the immune adjuvant R848. The PLGA@BP-R848 nanoparticles demonstrated exceptional drug delivery and release capabilities, as well as a photothermal effect, biocompatibility, and the ability to activate the mitochondrial apoptotic pathway Blc-2-Bax-Cytochrome c-caspase-3 and inhibit the PI3K-AKT-mTOR signaling pathway. In a hepatocellular carcinoma mouse model, the binding of PLGA@BP-R848 nanoparticles and dendritic cells primed with GPC3 peptides, successfully induced a systemic anti-tumor immune response. PLGA@BP-R848 nanoparticles bolster immune cell infiltration into tumors and induce cancer cell apoptosis. The synergistic therapy involving dendritic cells and photothermal nanoadjuvant effectively suppressed tumor growth, and facilitated the formation of tertiary lymphatic structures (TLS) in tumors. This study presents a novel approach in using photothermal nanoadjuvants to advance antitumor effect of cellular immunotherapy, such as DCs therapy.