Enhanced Osteosarcoma Immunotherapy via CaCO3 Nanoparticles: Remodeling Tumor Acidic and Immune Microenvironment for Photodynamic Therapy.

Osteosarcoma (OS) is a "cold" tumor enriched in noninflammatory M2 phenotype tumor-associated macrophages (TAMs), which limits the efficacy of immunotherapy. The acidic tumor microenvironment (TME), generated by factors such as excess hydrogen (H+) ions and high lactate levels, activates immunosuppressive cells, further promoting a suppressive tumor immune microenvironment (TIME). Therefore, a multitarget synergistic combination strategy that neutralizes the acidic TME and reprograms TAMs can be beneficial for OS therapy. Here, a calcium carbonate (CaCO3)/polydopamine (PDA)-based nanosystem (A-NPs@(SHK+Ce6)) is developed. CaCO3 nanoparticles are used to neutralize H+ ions and alleviate the suppressive TIME, and the loaded SHK not only synergizes with photodynamic therapy (PDT) but also inhibits lactate production, further reversing the acidic TME and repolarizing TAMs to consequently lead to enhanced PDT-induced tumor suppression and comprehensive beneficial effects on antitumor immune responses. Importantly, A-NPs@(SHK+Ce6), in combination with programmed cell death protein 1 (PD-1) checkpoint blockade, shows a remarkable ability to eliminate distant tumors and promote long-term immune memory function to protect against rechallenged tumors. This work presents a novel multiple-component combination strategy that coregulates the acidic TME and TAM polarization to reprogram the TIME.

Telocinobufagin inhibits osteosarcoma growth and metastasis by inhibiting the JAK2/STAT3 signaling pathway.

Osteosarcoma is the most common primary bone malignancy in children and adolescents; it exhibits rapid growth and a high metastatic potential and may thus lead to relatively high mortality. The JAK2/STAT3 signaling pathway, which plays a critical role in the occurrence and development of osteosarcoma, is a potential target for the treatment of osteosarcoma. Here, we identified the natural product telocinobufagin (TCB), which is a component isolated from toad cake, as a potent candidate with anti-osteosarcoma effects. TCB inhibited osteosarcoma cell growth, migration, invasion and induced cancer cell apoptosis. Mechanistically, TCB specifically inhibited the JAK2/STAT3 signaling pathway. More importantly, TCB significantly suppressed tumor growth and metastasis in an osteosarcoma xenograft animal model. Moreover, TCB also showed strong inhibitory effects in other cancer types, such as lung cancer, liver cancer, colon cancer, breast cancer and gastric cancer. Hence, our study reveals TCB as a potent anti-osteosarcoma therapeutic agent that inhibits the JAK2/STAT3 signaling pathway.

First-in-Maintenance Therapy for Localized High-Grade Osteosarcoma: An Open-Label Phase I/II Trial of the Anti-PD-L1 Antibody ZKAB001.

PURPOSE: We investigated the safety and preliminary efficacy of anti-PD-L1 antibody (ZKAB001) as maintenance therapy for localized patients with high-grade osteosarcoma to reduce the risk of recurrence and metastasis. PATIENTS AND METHODS: This open-label Phase I/II study was divided into dose-escalation Phase I and expansion Phase II. Phase I used a 3+3 design with ZKAB001 at three escalating doses ranging: 5, 10, 15 mg/kg every 2 weeks in 9 patients with localized high-grade osteosarcoma and Phase II tested 10 mg/kg in 12 patients for up to 24 cycles. Primary endpoints were safety and tolerability assessed using CTCAE4.0.3. RESULTS: Between October 2018 and 2019, 21 eligible patients were enrolled and accepted ZKAB001 treatment: 9 in the dose-escalation phase, and 12 in expansion phase. Six patients with disease progression withdrew from this study and follow-up is ongoing. The MTD was not defined in Phase I. All doses had a manageable safety profile. The recommended dose in Phase II was set at 10 mg/kg. Most frequent immune-related adverse events were thyroiditis (76.2%) and dermatitis (42.9%). Only 1 (4.8%) of 21 patients had a Grade 3 skin rash. The median 3-year event-free survival (EFS) and overall survival (OS) were not established; however, 24-month EFS was 71.4% (95% confidence interval, 47.2-86.0) and 2-year OS was 100%. Preliminary efficacy data showed EFS benefits in patients with PD-L1 positive or an MSI-H sub-population. CONCLUSIONS: Switching to maintenance using ZKAB001 showed an acceptable safety profile and provided preliminary evidence of clinical activity in localized patients with osteosarcoma.

Smart nanogels for cancer treatment from the perspective of functional groups.

Introduction: Cancer remains a significant health challenge, with chemotherapy being a critical treatment modality. However, traditional chemotherapy faces limitations due to non-specificity and toxicity. Nanogels, as advanced drug carriers, offer potential for targeted and controlled drug release, improving therapeutic efficacy and reducing side effects. Methods: This review summarizes the latest developments in nanogel-based chemotherapy drug delivery systems, focusing on the role of functional groups in drug loading and the design of smart hydrogels with controlled release mechanisms. We discuss the preparation methods of various nanogels based on different functional groups and their application in cancer treatment. Results: Nanogels composed of natural and synthetic polymers, such as chitosan, alginate, and polyacrylic acid, have been developed for chemotherapy drug delivery. Functional groups like carboxyl, disulfide, and hydroxyl groups play crucial roles in drug encapsulation and release. Smart hydrogels have been engineered to respond to tumor microenvironmental cues, such as pH, redox potential, temperature, and external stimuli like light and ultrasound, enabling targeted drug release. Discussion: The use of functional groups in nanogel preparation allows for the creation of multifunctional nanogels with high drug loading capacity, controllable release, and good targeting. These nanogels have shown promising results in preclinical studies, with enhanced antitumor effects and reduced systemic toxicity compared to traditional chemotherapy. Conclusion: The development of smart nanogels with functional group-mediated drug delivery and controlled release strategies represents a promising direction in cancer therapy. These systems offer the potential for improved patient outcomes by enhancing drug targeting and minimizing adverse effects. Further research is needed to optimize nanogel design, evaluate their safety and efficacy in clinical trials, and explore their potential for personalized medicine.

Cytokine Therapy Combined with Nanomaterials Participates in Cancer Immunotherapy.

Immunotherapy has gradually become an emerging treatment modality for tumors after surgery, radiotherapy, and chemotherapy. Cytokine therapy is a promising treatment for cancer immunotherapy. Currently, there are many preclinical theoretical bases to support this treatment strategy and a variety of cytokines in clinical trials. When cytokines were applied to tumor immunotherapy, it was found that the efficacy was not satisfactory. As research on tumor immunity has deepened, the role of cytokines in the tumor microenvironment has been further explored. Meanwhile, the study of nanomaterials in drug delivery has been fully developed in the past 20 years. Researchers have begun to think about the possibility of combining cytokine therapy with nanomaterials. Herein, we briefly review various nano-delivery systems that can directly deliver cytokines or regulate the expression of cytokines in tumor cells for cancer immunotherapy. We further discussed the feasibility of the combination of various therapies. We looked forward to the main challenges, opportunities, and prospects of tumor immunotherapy with multiple cytokines and a nano-delivery system.

Multi-omics analysis identifies osteosarcoma subtypes with distinct prognosis indicating stratified treatment.

Osteosarcoma (OS) is a primary malignant bone tumor that most commonly affects children, adolescents, and young adults. Here, we comprehensively analyze genomic, epigenomic and transcriptomic data from 121 OS patients. Somatic mutations are diverse within the cohort, and only TP53 is significantly mutated. Through unsupervised integrative clustering of the multi-omics data, we classify OS into four subtypes with distinct molecular features and clinical prognosis: (1) Immune activated (S-IA), (2) Immune suppressed (S-IS), (3) Homologous recombination deficiency dominant (S-HRD), and (4) MYC driven (S-MD). MYC amplification with HR proficiency tumors is identified with a high oxidative phosphorylation signature resulting in resistance to neoadjuvant chemotherapy. Potential therapeutic targets are identified for each subtype, including platinum-based chemotherapy, immune checkpoint inhibitors, anti-VEGFR, anti-MYC and PARPi-based synthetic lethal strategies. Our comprehensive integrated characterization provides a valuable resource that deepens our understanding of the disease, and may guide future clinical strategies for the precision treatment of OS.

Inhibition of sphingolipid metabolism in osteosarcoma protects against CD151-mediated tumorigenicity.

Osteosarcoma is the most common primary bone tumor, with a poor prognosis owing to the lack of efficient molecular-based targeted therapies. Previous studies have suggested an association between CD151 and distinct consequences in osteosarcoma tumorigenicity. However, the potential of CD151 as a therapeutic target has not yet been sufficiently explored. Here, we performed integrated transcriptomic and metabolomic analyses of osteosarcoma and identified sphingolipid metabolism as the top CD151-regulated pathway. CD151 regulates sphingolipid metabolism primarily through SPTCL1, the first rate-limiting enzyme in sphingolipid biosynthesis. Mechanistically, depletion of CD151 enhanced c-myc polyubiquitination and subsequent degradation. c-myc is vital for the transcriptional activation of SPTLC1. Functionally, sphingolipid synthesis and the SPTLC1 inhibitor, myriocin, significantly suppressed the clonogenic growth of CD151-overexpression cells. Importantly, myriocin selectively restrained CD151-high expression tumor growth in preclinical patient-derived xenograft models. Collectively, these data establish that CD151 is a key mediator of sphingolipid metabolism and provide a new approach to developing novel CD151-based targeted therapies for osteosarcoma.

Applications of Nano/Micromotors for Treatment and Diagnosis in Biological Lumens.

Natural biological lumens in the human body, such as blood vessels and the gastrointestinal tract, are important to the delivery of materials. Depending on the anatomic features of these biological lumens, the invention of nano/micromotors could automatically locomote targeted sites for disease treatment and diagnosis. These nano/micromotors are designed to utilize chemical, physical, or even hybrid power in self-propulsion or propulsion by external forces. In this review, the research progress of nano/micromotors is summarized with regard to treatment and diagnosis in different biological lumens. Challenges to the development of nano/micromotors more suitable for specific biological lumens are discussed, and the overlooked biological lumens are indicated for further studies.

Detection and surveillance of circulating tumor cells in osteosarcoma for predicting therapy response and prognosis.

OBJECTIVE: Osteosarcoma (OS) is an aggressive, highly metastatic, relatively drug-resistant bone tumor with poor long-term survival rates. The presence and persistence of circulating tumor cells (CTCs) in the peripheral blood are believed to be associated with treatment inefficiency and distant metastases. A blood-based CTC test is thus greatly needed for monitoring disease progression and predicting clinical outcomes. However, traditional methods cannot detect CTCs from tumors of mesenchymal origin such as OS, and research on CTC detection in mesenchymal tumors has been hindered for years. METHODS: In this study, we developed a CTC test based on hexokinase 2, a metabolic function-associated marker, for the detection and surveillance of OS CTCs, and subsequently explored its clinical value. Twelve patients with OS were enrolled as the training cohort for serial CTC tests. Dynamic CTC counting, in combination with therapy evaluation and post-treatment follow-up, was used to establish a model for predicting post-chemotherapy evaluation and disease-free survival, and the model was further validated with a cohort of 8 patients with OS. RESULTS: Two dynamic CTC number patterns were identified, and the resulting predictive model exhibited 92% consistency with the clinical outcomes. This model suggested that a single CTC test has similar predictive power to serial CTC analysis. In the validation cohort, the single CTC test exhibited 100% and 87.5% consistency with therapy response and disease-free survival, respectively. CONCLUSIONS: Our non-invasive test for detection and surveillance of CTCs enables accurate prediction of therapy efficiency and prognosis, and may be clinically valuable for avoiding inefficient therapy and prolonging survival.

CDK7/GRP78 signaling axis contributes to tumor growth and metastasis in osteosarcoma.

Osteosarcoma derives from primitive bone-forming mesenchymal cells and is the most common primary bone malignancy. Therapeutic targeting of osteosarcoma has been unsuccessful; therefore, identifying novel osteosarcoma pathogenesis could offer new therapeutic options. CDK7 is a subunit within the general transcription factor TFIIH. We aim to explore the new mechanism by which CDK7 regulates osteosarcoma and our studies may provide new theoretical support for the use of CDK7 inhibitors in the treatment of osteosarcoma. Here, we investigate the molecular mechanism underlying the association between CDK7 and GRP78 in osteosarcoma. Specifically, we find that an E3 ubiquitin ligase TRIM21 binds and targets GRP78 for ubiquitination and degradation, whereas CDK7 phosphorylates GRP78 at T69 to inhibit TRIM21 recruitment, leading to GRP78 stabilization. Notably, a CDK7-specific inhibitor, THZ1, blunts osteosarcoma growth and metastasis. Combination treatment with CDK7 and GRP78 inhibitors yield additive effects on osteosarcoma growth and progression inhibition. Thus, simultaneous suppression of CDK7 and GRP78 activity represents a potential new approach for the treatment of osteosarcoma. In conclusion, the discovery of this previously unknown CDK7/GRP78 signaling axis provides the molecular basis and the rationale to target human osteosarcoma.

Magnetic-Driven Hydrogel Microrobots Selectively Enhance Synthetic Lethality in MTAP-Deleted Osteosarcoma.

Background: Drugs based on synthetic lethality have advantages such as inhibiting tumor growth and affecting normal tissue in vivo. However, specific targets for osteosarcoma have not been acknowledged yet. In this study, a non-targeted but controllable drug delivery system has been applied to selectively enhance synthetic lethality in osteosarcoma in vitro, using the magnetic-driven hydrogel microrobots. Methods: In this study, EPZ015666, a PRMT5 inhibitor, was selected as the synthetic lethality drug. Then, the drug was carried by hydrogel microrobots containing Fe3O4. Morphological characteristics of the microrobots were detected using electron microscopy. In vitro drug effect was detected by the CCK-8 assay kit, Western blotting, etc. Swimming of microrobots was observed by a timing microscope. Selective inhibition was verified by cultured tumors in an increasing magnetic field. Results: Genomic mutation of MTAP deletion occurred commonly in pan-cancer in the TCGA database (nearly 10.00%) and in osteosarcoma in the TARGET database (23.86%). HOS and its derivatives, 143B and HOS/MNNG, were detected by MTAP deletion according to the CCLE database and RT-PCR. EPZ015666, the PRMT5 inhibitor, could reduce the SDMA modification and inhibition of tumor growth of 143B and HOS/MNNG. The hydrogel microrobot drug delivery system was synthesized, and the drug was stained by rhodamine. The microrobots were powered actively by a magnetic field. A simulation of the selected inhibition of microrobots was performed and lower cell viability of tumor cells was detected by adding a high dose of microrobots. Conclusion: Our magnetic-driven drug delivery system could carry synthetic lethality drugs. Meanwhile, the selective inhibition of this system could be easily controlled by programming the strength of the magnetic field.

Immune Microenvironment in Osteosarcoma: Components, Therapeutic Strategies and Clinical Applications.

Osteosarcoma is a primary malignant tumor that tends to threaten children and adolescents, and the 5-year event-free survival rate has not improved significantly in the past three decades, bringing grief and economic burden to patients and society. To date, the genetic background and oncogenesis mechanisms of osteosarcoma remain unclear, impeding further research. The tumor immune microenvironment has become a recent research hot spot, providing novel but valuable insight into tumor heterogeneity and multifaceted mechanisms of tumor progression and metastasis. However, the immune microenvironment in osteosarcoma has been vigorously discussed, and the landscape of immune and non-immune component infiltration has been intensively investigated. Here, we summarize the current knowledge of the classification, features, and functions of the main infiltrating cells, complement system, and exosomes in the osteosarcoma immune microenvironment. In each section, we also highlight the complex crosstalk network among them and the corresponding potential therapeutic strategies and clinical applications to deepen our understanding of osteosarcoma and provide a reference for imminent effective therapies with reduced adverse effects.

Pectolinarigenin acts as a potential anti-osteosarcoma agent via mediating SHP-1/JAK2/STAT3 signaling.

Signal transducer and activator of transcription 3 (STAT3) plays essential roles in cancer progression and has been considered as a promising target for cancer therapy. Here, we used a dual luciferase assay to identify that pectolinarigenin inhibited STAT3 transcriptional activity. Further, results showed pectolinarigenin inhibited constitutive and IL6 induced STAT3 signaling, diminished the accumulation of STAT3 in the nucleus, dimerization and blocked STAT3 DNA binding activity. Mechanism investigations indicated that pectolinarigenin disturbed the STAT3/DNMT1/HDAC1 complex formation in the promoter region of SHP-1, which reversely mediates STAT3 signaling, leading to the upregulation of SHP-1 expression in osteosarcoma. We also found pectolinarigenin significantly suppressed osteosarcoma growth, induced apoptosis. In addition, pectolinarigenin blocked tumor cells migration, invasion and reserved EMT phenotype. In spontaneous tibial injection and patient-derived xenograft models of osteosarcoma, we identified administration (i.p.) of pectolinarigenin (20 mg/kg/2 days and 50 mg/kg/2 days) blocked STAT3 activation and disturbed tumor growth and metastasis with superior pharmacodynamic properties. Taken together, our findings demonstrate that pectolinarigenin may be a candidate for osteosarcoma intervention linked to its STAT3 signaling inhibitory activity.

Correlation between Patient-Derived Xenograft Modeling and Prognosis in Osteosarcoma.

OBJECTIVE: To retrospectively analyze and compare the relationship between the success rate of patient-derived xenograft (PDX) modeling of osteosarcoma and prognosis (3-year overall survival rate and disease-free survival rate) and incidence of lung metastasis. METHODS: The sample group consisted of 57 osteosarcoma patients with definite pathological diagnoses from Shanghai General Hospital from 2015-2017. PDX models in 57 patients were analyzed by retrospective analyses. Among the patients currently inoculated, 20 were tumorigenic in the PDX model, and 37 were nontumorigenic. According to the tumorigenicity of PDXs, the corresponding osteosarcoma patients were divided into two groups. The effects of clinically related indicators on the model were retrospectively compared. The patients were followed, and the 3-year survival, 3-year disease-free survival (DFS), and lung metastasis rates were collected. The relationship between the modeling success and patient prognosis was investigated. RESULTS: In the chemotherapy-treated group, the PDX modeling success rate was 17.4%, and in the nonchemotherapy group, the success rate was 47.1%. The success of PDX modeling was related to whether patients received chemotherapy. The success rate of PDX modeling is significantly reduced after receiving chemotherapy. The 3-year overall survival rate of the PDX-grafted group was 49.23%, and that of the PDX-nongrafted group was 65.71%. There was a significant difference between the two groups, showing a strong negative correlation between the 3-year survival rate and the success rate of the PDX model. The 3-year disease-free survival rate of the PDX-grafted group was 29.54%. The 3-year DFS of the PDX-nongrafted group was 50.34%. There was a significant difference between the two groups. Lower grafted rates indicate a higher DFS rate. The incidence of lung metastasis in the PDX-grafted group was 32.4%, and that in the nongrafted group was 13.1%. There was a significant difference between the two groups. The successful establishment of the PDX model indicates that patients are more likely to have lung metastases. CONCLUSIONS: The success of PDX modeling often indicates poor prognosis (low 3-year overall survival rate and disease-free survival rate) and a greater possibility of lung metastasis. Therefore, PDX modeling in osteosarcoma patients can accurately predict the prognosis of patients and the risk of lung metastasis in advance to help us develop better therapeutic strategies.

Multicentre Study Using Machine Learning Methods in Clinical Diagnosis of Knee Osteoarthritis.

Knee osteoarthritis (OA) is one of the most common musculoskeletal disorders. OA diagnosis is currently conducted by assessing symptoms and evaluating plain radiographs, but this process suffers from the subjectivity of doctors. In this study, we retrospectively compared five commonly used machine learning methods, especially the CNN network, to predict the real-world X-ray imaging data of knee joints from two different hospitals using Kellgren-Lawrence (K-L) grade of knee OA to help doctors choose proper auxiliary tools. Furthermore, we present attention maps of CNN to highlight the radiological features affecting the network decision. Such information makes the decision process transparent for practitioners, which builds better trust towards such automatic methods and, moreover, reduces the workload of clinicians, especially for remote areas without enough medical staff.

Management of Apatinib-Related Adverse Events in Patients With Advanced Osteosarcoma From Four Prospective Trials: Chinese Sarcoma Study Group Experience.

Four prospective trials have reported apatinib-related efficacy in osteosarcoma, with a high response rate of 43.2%. Currently, Adverse Events (AEs) have increasingly gained attention, as treatment with multiple tyrosine kinase inhibitors (TKIs) is potentially lifelong. For this reason, a consensus meeting of the Chinese Sarcoma Study Group (CSSG), which is a multidisciplinary panel composed of pediatric, medical and surgical oncologists specializing in sarcoma, nurse specialists, oncological senior pharmacists and gastroenterologists, was held to develop comprehensive guidelines on AEs emerging due to apatinib treatment to better assist in the prevention, management, and understanding of AE development. We summarized all AEs that arose in ≥10% of the participants as well as rare AEs that required extra caution to prevent that were observed in these four published prospective trials and arranged these AEs into 14 disorder systems according to CTCAE 5.0. In this review, we discuss strategies for the management of AEs in patients with advanced osteosarcoma, with the aim of maximizing treatment benefits and minimizing the need for apatinib treatment discontinuation. We also focus on providing recommendations for the prophylaxis and treatment of advanced osteosarcoma using apatinib to achieve optimal outcomes.

Surgical Treatment of Sacral Metastatic Tumors.

OBJECTIVE: This study intends to retrospectively analyze the data of patients with sacral metastases in our center, and analyze the treatment methods and therapeutic effects of sacral metastases. METHODS: 73 patients with sacral metastases treated in our hospital from June 2013 to June 2019 were retrospectively analyzed. There were 54 cases of neurological symptoms, 42 cases of sacroiliac joint instability, 24 cases of lower limb muscle weakness and 19 cases of abnormal urination and defecation. Four patients with tumors below S3 underwent complete tumor resection, 23 patients with tumors above S3 and without sacroiliac joint instability underwent tumor curettage and nerve root lysis, 34 patients with tumors above S3 and sacroiliac joint instability underwent tumor curettage, nerve root release and screw rod reconstruction. 12 patients with multiple metastases underwent percutaneous radiofrequency ablation and sacroplasty. VAS was used to evaluate the preoperative and postoperative pain scores, and the postoperative pain relief, neurological function, bowel function, wound healing and complications were evaluated. RESULTS: There were no perioperative death, 8 cases of poor wound healing, 5 cases of nerve injury, postoperative sensory and motor loss of lower limbs. Cerebrospinal fluid (CSF) leak in 7 cases. The patients were followed up for 6-25 months (mean 12 months). The VAS scores of patients with pain symptoms were 7 points before operation and 1.44 points after operation, In 19 patients with abnormal urination and defecation function, 12 patients recovered to normal 3-6 months after operation, 5 cases had no significant change compared with preoperative, and 2 cases had aggravated symptoms; 17 cases of patients with lower limb muscle strength were significantly recovered after operation, and the average muscle strength was increased by 2 grades; 30 cases of patients with unstable sacroiliac joint got internal fixation had significantly pain relief. Pain symptoms of 9 patients were significantly relieved after percutaneous radiofrequency ablation. CONCLUSION: the operation of sacral metastases mainly adopts a relatively conservative surgical method, which can effectively improve the quality of life of patients with sacral metastases by retaining the nerve function and relieving the pain of patients, combining with radiofrequency ablation, sacroplasty and targeted drugs.

Bromodomain Inhibition Attenuates the Progression and Sensitizes the Chemosensitivity of Osteosarcoma by Repressing GP130/STAT3 Signaling.

Osteosarcoma is the most common primary malignant bone tumor, and there are few ideal clinically available drugs. The bromodomain and extraterminal domain (BET) protein is an emerging target for aggressive cancer, but therapies targeting the BET in osteosarcoma have been unsuccessful in clinical trials to date, and further exploration of specific BET inhibitors is of great significance. In our study, we demonstrated that NHWD-870, a potent BET inhibitor in a phase I clinical trial, significantly inhibited tumor proliferation and promoted cell apoptosis by reversing the oncogenic signature in osteosarcoma. More importantly, we identified NHWD-870 impeded binding of BRD4 to the promoter of GP130 leading to diminished activation of JAK/STAT3 signaling pathway. Furthermore, GP130 knockdown significantly sensitizes the chemosensitivity in vitro. In OS cell-derived xenografts, NHWD-870 effectively inhibited the growth of osteosarcoma. Beyond that, NHWD-870 effectively inhibited the differentiation and maturation of precursor osteoclasts in vitro and attenuated osteoclast-mediated bone loss in vivo. Finally, we confirmed the efficacy of synthetic lethal effects of NHWD-870 and cisplatin in antagonizing osteosarcoma in a preclinical PDX model. Taken together, these findings demonstrate that NHWD-870, as an effective BET inhibitor, may be a potential candidate for osteosarcoma intervention linked to its STAT3 signaling inhibitory activity. In addition, NHWD-870 appears to be a promising therapeutic strategy for bone-associated tumors, as it interferes with the vicious cycle of tumor progression and bone destruction.

Identification of two immune subtypes in osteosarcoma based on immune gene sets.

Osteosarcoma (OS) is a highly aggressive cancer with poor prognosis, which mainly occurs in teenagers. Recent studies have shown that tumor-infiltrating immune cells play an important role in the progression of OS. In the present study, we identified two immune subtypes of OS (referred to as high and low immune cell infiltration subtypes, respectively) based on immune-related gene sets using TARGET and GEO cohort datasets. Elevated immune scores, increased stromal scores, decreased tumor purities, and higher infiltration of CD8 + T cells and M1 macrophages were observed for the high immune cell infiltration subtype. Moreover, the high immune cell infiltration subtype was characterized by high expression of immune checkpoint molecules. Gene set enrichment analysis showed that "B cell receptor signaling pathway" and "T cell receptor signaling pathway" gene sets were enriched in the high immune cell infiltration subtype. In addition, patients in the high immune cell infiltration subtype had better prognosis than patients in the low immune cell infiltration subtype. Furthermore, differentially expressed genes were screened according to the two OS subtypes and a risk model was generated by multivariate Cox regression analysis to predict the prognosis of OS patients. These results in this study showed that OS patients could be divided into two immune subtypes and offered a novel two-gene risk signature to predict the prognosis of patients with OS.