A novel SLC3A2-targeting antibody-drug conjugate exerts potent antitumor efficacy in head and neck squamous cell cancer.

The development of innovative therapeutic strategies for head and neck squamous cell carcinoma (HNSCC) is a critical medical requirement. Antibody-drug conjugates (ADC) targeting tumor-specific surface antigens have demonstrated clinical effectiveness in treating hematologic and solid malignancies. Our investigation revealed high expression levels of SLC3A2 in HNSCC tissue and cell lines. This study aimed to develop a novel anti-SLC3A2 ADC and assess its antitumor effects on HNSCC both in vitro and in vivo. This study developed a potent anti-SLC3A2 ADC (19G4-MMAE) and systematically investigated its drug delivery potential and antitumor efficacy in preclinical models. This study revealed that 19G4-MMAE exhibited specific binding to SLC3A2 and effectively targeted lysosomes. Moreover, 19G4-MMAE induced a significant accumulation of reactive oxygen species (ROS) and apoptosis in SLC3A2-positive HNSCC cells. The compound demonstrated potent antitumor effects derived from MMAE against SLC3A2-expressing HNSCC in preclinical models, displaying a favorable safety profile. These findings suggest that targeting SLC3A2 with an anti-SLC3A2 ADC could be a promising therapeutic approach for treating HNSCC patients.

Improved antitumor effects elicited by an oncolytic HSV-1 expressing a novel B7H3nb/CD3 BsAb.

Oncolytic viruses have emerged as a promising modality for cancer treatment due to their unique abilities to directly destroy tumor cells and modulate the tumor microenvironment. Bispecific T-cell engagers (BsAbs) have been developed to activate and redirect cytotoxic T lymphocytes, enhancing the antitumor response. To take advantage of the specific infection capacity and carrying ability of exogenous genes, we generated a recombinant herpes simplex virus type 1 (HSV-1), HSV-1dko-B7H3nb/CD3 or HSV-1dko-B7H3nb/mCD3, carrying a B7H3nb/CD3 or B7H3nb/mCD3 BsAb that replicates and expresses BsAb in tumor cells in vitro and in vivo. The new generation of oncolytic viruses has been genetically modified using CRISPR/Cas9 technology and the cre-loxp system to increase the efficiency of HSV genome editing. Additionally, we used two fully immunocompetent models (GL261 and MC38) to assess the antitumor effect of HSV-1dko-B7H3nb/mCD3. Compared with the HSV-1dko control virus, HSV-1dko-B7H3nb/mCD3 induced enhanced anti-tumor immune responses and T-cell infiltration in both GL261 and MC38 models, resulting in improved treatment efficacy in the latter. Furthermore, flow cytometry analysis of the tumor microenvironment confirmed an increase in NK cells and effector CD8+ T cells, and a decrease in immunosuppressive cells, including FOXP3+ regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and CD206+ macrophages (M2). Overall, our study identified a novel camel B7H3 nanobody and described the genetic modification of the HSV-1 genome using CRISPR/Cas9 technology and the cre-loxp system. Our findings indicate that expressing B7H3nb/CD3 BsAb could improve the antitumor effects of HSV-1 based oncolytic virus.

Delivery of CD47-SIRPα checkpoint blocker by BCMA-directed UCAR-T cells enhances antitumor efficacy in multiple myeloma.

In the treatment of relapsed or refractory multiple myeloma patients, BCMA-directed autologous CAR-T cells have showed excellent anti-tumor activity. However, their widespread application is limited due to the arguably cost and time-consuming. Multiple myeloma cells highly expressed CD47 molecule and interact with the SIRPα ligand on the surface of macrophages, in which evade the clearance of macrophages through the activation of "don't eat me" signal. In this study, a BCMA-directed universal CAR-T cells, BC404-UCART, secreting a CD47-SIRPα blocker was developed using CRISPR/Cas9 gene-editing system. BC404-UCART cells significantly inhibited tumor growth and prolonged the survival of mice in the xenograft model. The anti-tumor activity of BC404-UCART cells was achieved via two mechanisms, on the one hand, the UCAR-T cells directly killed tumor cells, on the other hand, the BC404-UCART cells enhanced the phagocytosis of macrophages by secreting anti-CD47 nanobody hu404-hfc fusion that blocked the "don't eat me" signal between macrophages and tumor cells, which provides a potential strategy for the development of novel "off-the-shelf" cellular immunotherapies for the treatment of multiple myeloma.

An Anti-CD7 Antibody-Drug Conjugate Target Showing Potent Antitumor Activity for T-Lymphoblastic Leukemia (T-ALL).

Acute T-lymphoblastic leukemia (T-ALL) is a type of leukemia that can occur in both pediatric and adult populations. Compared to acute B-cell lymphoblastic leukemia (B-ALL), patients with T-cell T-ALL have a poorer therapeutic efficacy. In this study, a novel anti-CD7 antibody-drug conjugate (ADC, J87-Dxd) was successfully generated and used for T-ALL treatment. Firstly, to obtain anti-CD7 mAbs, we expressed and purified the CD7 protein extracellular domain. Utilizing hybridoma technology, we obtained three anti-CD7 mAbs (J87, G73 and A15) with a high affinity for CD7. Both the results of immunofluorescence and Biacore assay indicated that J87 (KD = 1.54 × 10-10 M) had the highest affinity among the three anti-CD7 mAbs. In addition, an internalization assay showed the internalization level of J87 to be higher than that of the other two mAbs. Next, we successfully generated the anti-CD7 ADC (J87-Dxd) by conjugating DXd to J87 via a cleavable maleimide-GGFG peptide linker. J87-Dxd also possessed the ability to recognize and bind CD7. Using J87-Dxd to treat T-ALL cells (Jurkat and CCRF-CEM), we observed that J87-Dxd bound to CD7 was internalized into T-ALL cells. Moreover, J87-Dxd treatment significantly induced the apoptosis of Jurkat and CCRF-CEM cells. The IC50 (half-maximal inhibitory concentration) value of J87-Dxd against CCRF-CEM obtained by CCK-8 assay was 6.3 nM. Finally, to assess the antitumor efficacy of a J87-Dxd in vivo, we established T-ALL mouse models and treated mice with J87-Dxd or J87. The results showed that on day 24 after tumor inoculation, all mice treated with J87 or PBS died, whereas the survival rate of mice treated with J87-Dxd was 80%. H&E staining showed no significant organic changes in the heart, liver, spleen, lungs and kidneys of all mice. In summary, we demonstrated that the novel anti-CD7 ADC (J87-Dxd) had a potent and selective effect against CD7-expressing T-All cells both in vitro and in vivo, and could thus be expected to be further developed as a new drug for the treatment of T-ALL or other CD7-expression tumors.

Fc receptor-like 5 (FCRL5)-directed CAR-T cells exhibit antitumor activity against multiple myeloma.

Multiple myeloma (MM) remains a challenging hematologic malignancy despite advancements in chimeric antigen receptor T-cell (CAR-T) therapy. Current targets of CAR-T cells used in MM immunotherapy have limitations, with a subset of patients experiencing antigen loss resulting in relapse. Therefore, novel targets for enhancing CAR-T cell therapy in MM remain needed. Fc receptor-like 5 (FCRL5) is a protein marker with considerably upregulated expression in MM and has emerged as a promising target for CAR-T cell therapeutic interventions, offering an alternative treatment for MM. To further explore this option, we designed FCRL5-directed CAR-T cells and assessed their cytotoxicity in vitro using a co-culture system and in vivo using MM cell-derived xenograft models, specifically focusing on MM with gain of chromosome 1q21. Given the challenges in CAR-T therapies arising from limited T cell persistence, our approach incorporates interleukin-15 (IL-15), which enhances the functionality of central memory T (TCM) cells, into the design of FCRL5-directed CAR-T cells, to improve cytotoxicity and reduce T-cell dysfunction, thereby promoting greater CAR-T cell survival and efficacy. Both in vitro and xenograft models displayed that FCRL5 CAR-T cells incorporating IL-15 exhibited potent antitumor efficacy, effectively inhibiting the proliferation of MM cells and leading to remarkable tumor suppression. Our results highlight the capacity of FCRL5-specific CAR-T cells with the integration of IL-15 to improve the therapeutic potency, suggesting a potential novel immunotherapeutic strategy for MM treatment.

The potential of mRNA vaccines in cancer nanomedicine and immunotherapy.

Owing to their outstanding performance against COVID-19, mRNA vaccines have brought great hope for combating various incurable diseases, including cancer. Differences in the encoded proteins result in different molecular and cellular mechanisms of mRNA vaccines. With the rapid development of nanotechnology and molecular medicine, personalized antigen-encoding mRNA vaccines that enhance antigen presentation can trigger effective immune responses and prevent off-target toxicities. Herein, we review new insights into the influence of encoded antigens, cytokines, and other functional proteins on the mechanisms of mRNA vaccines. We also highlight the importance of delivery systems and chemical modifications for mRNA translation efficiency, stability, and targeting, and we discuss the potential problems and application prospects of mRNA vaccines as versatile tools for combating cancer.

EpCAM-targeting CAR-T cell immunotherapy is safe and efficacious for epithelial tumors.

The efficacy of CAR-T cells for solid tumors is unsatisfactory. EpCAM is a biomarker of epithelial tumors, but the clinical feasibility of CAR-T therapy targeting EpCAM is lacking. Here, we report pre- and clinical investigations of EpCAM-CAR-T cells for solid tumors. We demonstrated that EpCAM-CAR-T cells costimulated by Dectin-1 exhibited robust antitumor activity without adverse effects in xenograft mouse models and EpCAM-humanized mice. Notably, in clinical trials for epithelial tumors (NCT02915445), 6 (50%) of the 12 enrolled patients experienced self-remitted grade 1/2 toxicities, 1 patient (8.3%) experienced reversible grade 3 leukopenia, and no higher-grade toxicity reported. Efficacy analysis determined two patients as partial response. Three patients showed >23 months of progression-free survival, among whom one patient experienced 2-year progress-free survival with detectable CAR-T cells 200 days after infusion. These data demonstrate the feasibility and tolerability of EpCAM-CAR-T therapy.

Lipid-Polymer Hybrid Nanoparticles with Both PD-L1 Knockdown and Mild Photothermal Effect for Tumor Photothermal Immunotherapy.

In developing countries, the incidence of colorectal cancer (CRC) is on the rise. The combination of programmed cell death ligand-1 (PD-L1) siRNA (siPD-L1) and mild photothermal therapy (PTT) is a promising strategy for CRC treatment. In this study, dopamine-modified polyethylenimine (PEI) was prepared to fabricate an IR780 and siPD-L1 codelivery lipid-polymer hybrid nanoparticle (lip@PSD-siP) for the photothermal immunotherapy of CRC. The modification of dopamine can significantly reduce the cytotoxicity of PEI. lip@PSD-siP can be effectively taken up by CT26 cells and successfully escaped from lysosomes after entering the cells for 4 h. After CT26 cells were transfected with lip@PSD-siP, the PD-L1 positive cell rate decreased by 82.4%, and its PD-L1 knockdown effect was significantly stronger than the positive control Lipo3000-siP. In vivo studies showed that lip@PSD-siP-mediated mild PTT and efficient PD-L1 knockdown exhibited primary and distal tumor inhibition, metastasis delay, and rechallenged tumor inhibition. The treatment with lip@PSD-siP significantly promoted the maturation of dendritic cells in lymph nodes. The amount of T cell infiltration in the tumor tissues increased significantly, and the frequency of CD8+ T cells and CD4+ T cells was significantly higher than that of other groups. The percentage of immunosuppressive regulatory cells (Tregs) in the tumor tissue on the treatment side decreased by 88% compared to the PBS group, and the proportion of CD8+CD69+ T cells in the distal tumor tissue was 2.8 times that of the PBS group. The memory T cells of mice in the long-term antitumor model were analyzed. The results showed that after treatment with lip@PSD-siP, the frequency of effector memory T cells (Tem cells) significantly increased, suggesting the formation of immune memory.

Tumor-associated macrophage-related strategies for glioma immunotherapy.

High-grade glioma is one of the deadliest primary tumors of the central nervous system. Despite the many novel immunotherapies currently in development, it has been difficult to achieve breakthrough results in clinical studies. The reason may be due to the suppressive tumor microenvironment of gliomas that limits the function of specific immune cells (e.g., T cells) which are currently the primary targets of immunotherapy. However, tumor-associated macrophage, which are enriched in tumors, plays an important role in the development of GBM and is becoming a research hotspot for immunotherapy. This review focuses on current research advances in the use of macrophages as therapeutic targets or therapeutic tools for gliomas, and provides some potential research directions.

Immune-checkpoint protein VISTA in allergic, autoimmune disease and transplant rejection.

Negative checkpoint regulators (NCRs) reduce the T cell immune response against self-antigens and limit autoimmune disease development. V-domain Ig suppressor of T cell activation (VISTA), a novel immune checkpoint in the B7 family, has recently been identified as one of the NCRs. VISTA maintains T cell quiescence and peripheral tolerance. VISTA targeting has shown promising results in treating immune-related diseases, including cancer and autoimmune disease. In this review, we summarize and discuss the immunomodulatory role of VISTA, its therapeutic potential in allergic, autoimmune disease, and transplant rejection, as well as the current therapeutic antibodies, to present a new method for regulating immune responses and achieving durable tolerance for the treatment of autoimmune disease and transplantation.

Engineering MMP-2 Activated Nanoparticles Carrying B7-H3 Bispecific Antibodies for Ferroptosis-Enhanced Glioblastoma Immunotherapy.

Administration of bispecific antibodies (biAbs) in tumor therapy is limited by their short half-life and off-target toxicity. Optimized strategies or targets are needed to overcome these barriers. B7-H3 (CD276), a member of the B7 superfamily, is associated with poor survival in glioblastoma (GBM) patients. Moreover, a dimer of EGCG (dEGCG) synthesized in this work enhanced the IFN-γ-induced ferroptosis of tumor cells in vitro and in vivo. Herein, we prepared recombinant anti-B7-H3×CD3 biAbs and constructed MMP-2-sensitive S-biAb/dEGCG@NPs to offer a combination treatment strategy for efficient and systemic GBM elimination. Given their GBM targeted delivery and tumor microenvironment responsiveness, S-biAb/dEGCG@NPs displayed enhanced intracranial accumulation, 4.1-, 9.5-, and 12.3-fold higher than that of biAb/dEGCG@NPs, biAb/dEGCG complexes, and free biAbs, respectively. Furthermore, 50% of GBM-bearing mice in the S-biAb/dEGCG@NP group survived longer than 56 days. Overall, S-biAb/dEGCG@NPs can induce GBM elimination by boosting the ferroptosis effect and enhancing immune checkpoint blockade (ICB) immunotherapy and may be successful antibody nanocarriers for enhanced cancer therapy.

A drug screening to identify novel combinatorial strategies for boosting cancer immunotherapy efficacy.

BACKGROUND: Chimeric antigen receptor (CAR) T cells and immune checkpoint blockades (ICBs) have made remarkable breakthroughs in cancer treatment, but the efficacy is still limited for solid tumors due to tumor antigen heterogeneity and the tumor immune microenvironment. The restrained treatment efficacy prompted us to seek new potential therapeutic methods. METHODS: In this study, we conducted a small molecule compound library screen in a human BC cell line to identify whether certain drugs contribute to CAR T cell killing. Signaling pathways of tumor cells and T cells affected by the screened drugs were predicted via RNA sequencing. Among them, the antitumor activities of JK184 in combination with CAR T cells or ICBs were evaluated in vitro and in vivo. RESULTS: We selected three small molecule drugs from a compound library, among which JK184 directly induces tumor cell apoptosis by inhibiting the Hedgehog signaling pathway, modulates B7-H3 CAR T cells to an effector memory phenotype, and promotes B7-H3 CAR T cells cytokine secretion in vitro. In addition, our data suggested that JK184 exerts antitumor activities and strongly synergizes with B7-H3 CAR T cells or ICBs in vivo. Mechanistically, JK184 enhances B7-H3 CAR T cells infiltrating in xenograft mouse models. Moreover, JK184 combined with ICB markedly reshaped the tumor immune microenvironment by increasing effector T cells infiltration and inflammation cytokine secretion, inhibiting the recruitment of MDSCs and the transition of M2-type macrophages in an immunocompetent mouse model. CONCLUSION: These data show that JK184 may be a potential adjutant in combination with CAR T cells or ICB therapy.

Lipid Nanoparticle Delivery System for mRNA Encoding B7H3-redirected Bispecific Antibody Displays Potent Antitumor Effects on Malignant Tumors.

The therapeutic use of bispecific T-cell engaging (BiTE) antibodies has shown great potential for treating malignancies. BiTE can simultaneously engage CD3ε on T cells and tumor antigen on cancer cells, thus exerting an effective antitumor effect. Nevertheless, challenges in production, manufacturing, and short serum half-life of BiTE have dampened some of the promise and impeded the pace of BiTE-based therapeutics to combat diseases. Nowadays, in vitro-transcribed mRNA has achieved programmed production, which is more flexible and cost-effective than the traditional method of producing recombinant antibody. Here, the authors have developed a BiTE-based mRNA treatment by encapsulating mRNA encoding B7H3×CD3 BiTE into a novel ionizable lipid nanoparticles (LNPs). The authors have found that LNPs have high transfection efficiency, and the hepatosplenic targeting capability of produce high concentrations of BiTE. Above all, a single intravenous injection of BiTE mRNA-LNPs could achieve high levels of protein expression in vivo and significantly prolonged the half-life of the BiTE, which can elicit robust and durable antitumor efficacy against hematologic malignancies and melanoma. Therefore, their results suggested that the therapeutic strategy based on mRNA expression of B7H3×CD3 BiTE is of potential research value and has promising clinical application prospects.

CXCL11-armed oncolytic adenoviruses enhance CAR-T cell therapeutic efficacy and reprogram tumor microenvironment in glioblastoma.

Glioblastoma (GBM) is the most aggressive primary malignant brain cancer and urgently requires effective treatments. Chimeric antigen receptor T (CAR-T) cell therapy offers a potential treatment method, but it is often hindered by poor infiltration of CAR-T cells in tumors and highly immunosuppressive tumor microenvironment (TME). Here, we armed an oncolytic adenovirus (oAds) with a chemokine CXCL11 to increase the infiltration of CAR-T cells and reprogram the immunosuppressive TME, thus improving its therapeutic efficacy. In both immunodeficient and immunocompetent orthotopic GBM mice models, we showed that B7H3-targeted CAR-T cells alone failed to inhibit GBM growth but, when combined with the intratumoral administration of CXCL11-armed oAd, it achieved a durable antitumor response. Besides, oAd-CXCL11 had a potent antitumor effect and reprogramed the immunosuppressive TME in GL261 GBM models, in which increased infiltration of CD8+ T lymphocytes, natural killer (NK) cells, and M1-polarized macrophages, while decreased proportions of myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs) and M2-polarized macrophages were observed. Furthermore, the antitumor effect of the oAd-CXCL11 was CD8+ T cell dependent. Our findings thus revealed that CXCL11-armed oAd can improve immune-virotherapy and can be a promising adjuvant of CAR-T therapy for GBM.

Evaluation of B7-H3 Targeted Immunotherapy in a 3D Organoid Model of Craniopharyngioma.

A craniopharyngioma (CP) is a rare epithelial tumor of the sellar and parasellar region. CPs are difficult to treat due to their anatomical proximity to critical nervous structures, which limits the ability of the surgeon to completely resect the lesion, exposing patients to a high risk of recurrence. The treatment of craniopharyngiomas is primarily surgery and radiotherapy. So far, neither a cell line nor an animal model has been established, and thus data on other treatment options, such as chemotherapy and immunotherapy, are limited. Here, the expression profile of the pan-cancer antigen B7-H3 in various cancer types including CP was examined by immunohistochemistry. An in vitro organoid model was established by using fresh tissue biospecimens of CP. Based on the organoid model, we evaluated the antitumor efficacy of B7-H3-targeted immunotherapy on CP. As a result, the highest expression of B7-H3 was observed in CP tissues across various cancer types. Although B7-H3-targeted chimeric antigen-receptor T cells show obvious tumor-killing effects in the traditional 2D cell culture model, limited antitumor effects were observed in the 3D organoid model. The B7-H3-targeted antibody-DM1 conjugate exhibited a potent tumor suppression function both in 2D and 3D models. In conclusion, for the first time, we established an organoid model for CP and our results support that B7-H3 might serve as a promising target for antibody-drug conjugate therapy against craniopharyngioma.

Development of therapeutic antibodies for the treatment of diseases.

Since the first monoclonal antibody drug, muromonab-CD3, was approved for marketing in 1986, 165 antibody drugs have been approved or are under regulatory review worldwide. With the approval of new drugs for treating a wide range of diseases, including cancer and autoimmune and metabolic disorders, the therapeutic antibody drug market has experienced explosive growth. Monoclonal antibodies have been sought after by many biopharmaceutical companies and scientific research institutes due to their high specificity, strong targeting abilities, low toxicity, side effects, and high development success rate. The related industries and markets are growing rapidly, and therapeutic antibodies are one of the most important research and development areas in the field of biology and medicine. In recent years, great progress has been made in the key technologies and theoretical innovations provided by therapeutic antibodies, including antibody-drug conjugates, antibody-conjugated nuclides, bispecific antibodies, nanobodies, and other antibody analogs. Additionally, therapeutic antibodies can be combined with technologies used in other fields to create new cross-fields, such as chimeric antigen receptor T cells (CAR-T), CAR-natural killer cells (CAR-NK), and other cell therapy. This review summarizes the latest approved or in regulatory review therapeutic antibodies that have been approved or that are under regulatory review worldwide, as well as clinical research on these approaches and their development, and outlines antibody discovery strategies that have emerged during the development of therapeutic antibodies, such as hybridoma technology, phage display, preparation of fully human antibody from transgenic mice, single B-cell antibody technology, and artificial intelligence-assisted antibody discovery.

The novel type II toxin-antitoxin PacTA modulates Pseudomonas aeruginosa iron homeostasis by obstructing the DNA-binding activity of Fur.

Type II toxin-antitoxin (TA) systems are widely distributed in bacterial and archaeal genomes and are involved in diverse critical cellular functions such as defense against phages, biofilm formation, persistence, and virulence. GCN5-related N-acetyltransferase (GNAT) toxin, with an acetyltransferase activity-dependent mechanism of translation inhibition, represents a relatively new and expanding family of type II TA toxins. We here describe a group of GNAT-Xre TA modules widely distributed among Pseudomonas species. We investigated PacTA (one of its members encoded by PA3270/PA3269) from Pseudomonas aeruginosa and demonstrated that the PacT toxin positively regulates iron acquisition in P. aeruginosa. Notably, other than arresting translation through acetylating aminoacyl-tRNAs, PacT can directly bind to Fur, a key ferric uptake regulator, to attenuate its DNA-binding affinity and thus permit the expression of downstream iron-acquisition-related genes. We further showed that the expression of the pacTA locus is upregulated in response to iron starvation and the absence of PacT causes biofilm formation defect, thereby attenuating pathogenesis. Overall, these findings reveal a novel regulatory mechanism of GNAT toxin that controls iron-uptake-related genes and contributes to bacterial virulence.

PUMA overexpression dissociates thioredoxin from ASK1 to activate the JNK/BCL-2/BCL-XL pathway augmenting apoptosis in ovarian cancer.

ASK1-JNK signaling promotes mitochondrial dysfunction-mediated apoptosis, but the bridge between JNK and apoptosis is not fully understood. PUMA induces apoptosis through BAX/BAK. Our previous study suggests a therapeutic potential of PUMA for ovarian cancer. However, whether and how PUMA activates ASK1 remains unclear. Here, we found for the first time that PUMA activated ASK1 by dissociating thioredoxin (TRX) from ASK1, however, it neither interacted with ASK1 nor TRX. Furthermore, PUMA overexpression caused ROS release from mitochondrial. H2O2 significantly impaired the interaction of ASK1 with TRX, whereas ROS scavenger NAC effectively abrogated the H2O2 effect, partly rescued PUMA-interfered interaction of ASK1 with TRX, and also abolished ASK1 phosphorylation. Interestingly, PUMA could not impair the association of ASK1 with TRX-C32S or TRX-C35S, two TRX mutants which are no longer oxidized in response to ROS. We further showed that PUMA activated ASK1-JNK axis to phosphorylate BCL-2 and BCL-XL, further augmenting apoptosis of ovarian cancer cells. In vivo, PUMA adenovirus combined with paclitaxel significantly inhibited intrinsically cisplatin-resistant ovarian cancer growth, and caused phosphorylation of BCL-2 and BCL-XL. Our results from human ovarian cancer TMA chips also revealed a positive correlation between PUMA expression and the phosphorylation of BCL-2 and BCL-XL. More importantly, all patients had no distal metastasis, implying a possibly clinical significance. Collectively, our results reveal a new pro-apoptotic signal amplification mechanism for PUMA by which PUMA overexpression first induces ROS-mediated dissociation of TRX from ASK1, and then causes JNK activation-triggering BCL-2/BCL-XL phosphorylation, ultimately augmenting apoptosis in ovarian cancer.

Tumor-associated microglia and macrophages in glioblastoma: From basic insights to therapeutic opportunities.

Glioblastoma (GBM) is the most common and malignant primary brain tumor in adults. Currently, the standard treatment of glioblastoma includes surgery, radiotherapy, and chemotherapy. Despite aggressive treatment, the median survival is only 15 months. GBM progression and therapeutic resistance are the results of the complex interactions between tumor cells and tumor microenvironment (TME). TME consists of several different cell types, such as stromal cells, endothelial cells and immune cells. Although GBM has the immunologically "cold" characteristic with very little lymphocyte infiltration, the TME of GBM can contain more than 30% of tumor-associated microglia and macrophages (TAMs). TAMs can release cytokines and growth factors to promote tumor proliferation, survival and metastasis progression as well as inhibit the function of immune cells. Thus, TAMs are logical therapeutic targets for GBM. In this review, we discussed the characteristics and functions of the TAMs and evaluated the state of the art of TAMs-targeting strategies in GBM. This review helps to understand how TAMs promote GBM progression and summarizes the present therapeutic interventions to target TAMs. It will possibly pave the way for new immune therapeutic avenues for GBM patients.