Strategy For Treatment Of Tumors Research Articles

Ionizing radiation-induced mitophagy promotes ferroptosis by increasing intracellular free fatty acids.

Ferroptosis is a type of cell death characterized by the accumulation of intracellular iron and an increase in hazardous lipid peroxides. Ferroptosis and autophagy are closely related. Ionizing radiation is a frequently used cancer therapy to kill malignancies. We found that ionizing radiation induces both ferroptosis and autophagy and that there is a form of mutualism between the two processes. Ionizing radiation also causes lipid droplets to form in proximity to damaged mitochondria, which, through the action of mitophagy, results in the degradation of the peridroplet mitochondria by lysosomes and the consequent release of free fatty acids and a significant increase in lipid peroxidation, thus promoting ferroptosis. Ionizing radiation has a stronger, fatal effect on cells with a high level of mitophagy, and this observation suggests a novel strategy for tumor treatment.

Sulfonated vitamin K3 mediated bimetallic metal-organic framework for multistage augmented cancer therapy

Chemodynamic therapy (CDT) relying on Fenton reaction has emerged as a promising strategy for tumor treatment. However, its clinical efficacy is hindered by the inadequate reactive oxygen species (ROS) and the potential cytotoxicity towards normal cells. To address these challenges, we have successfully developed a multistage augmented cancer therapy system based on bimetallic metal-organic framework (BMOF) that amplifies ROS and facilitates tumor-specific therapeutic effects. By employing a simple one-pot self-assembly approach, we synthesized SVK3@ZnCo-ZIF in which sulfonated vitamin K3 (SVK3) was encapsulated within ZnCo-ZIF BMOF. The results revealed that the incorporation of Zn atoms significantly diluted the Fenton activity of Co atoms towards normal cells. Notably, SVK3@ZnCo-ZIF underwent pH-controlled decomposition triggered by the tumor microenvironment (TME), thus releasing SVK3, Co2+ and Zn2+. Specifically, the H2O2 levels in tumors was effectively elevated by the interaction of SVK3 with NAD(P)H quinone oxidoreductase-1 (NQO-1). It thus enhanced the Fenton activity of Co2+. Moreover, the release of Zn2+ ions can induce cellular dysfunction and mitochondrial damage, thereby promoting the generation of ROS and subsequent cell death. The synergistic combination of CDT, SVK3 chemotherapy, and Zn2+-interfered therapy greatly facilitated apoptosis of tumor cells. Collectively, our investigations demonstrate the efficacy of such system in selectively inducing toxicity in cancer cells while minimizing detrimental effects on normal cells.

THU503 An Unusual Case Of Ectopic ACTH Syndrome Secondary To Non-small Cell Lung Cancer

Abstract Disclosure: N. Hernandez: None. E. Askar: None. J.R. Fredrick: None. R.C. Schulman-Rosenbaum: None. Background: Cushing syndrome (CS) is a clinical entity characterized by HTN, DM, peripheral edema, hypokalemia, metabolic alkalosis, and myopathy. CS can be clinically classified into Corticotropin-dependent vs Corticotropin-independent processes. Those categorized as corticotropin dependent can further be subclassified into Eutopic CS (i.e. from the pituitary) vs Ectopic CS (i.e. extra-pituitary). The extra-pituitary source of ACTH most often comes from intra-thoracic neoplasms, of which small cell lung cancer (SCLC) is the most prevalent. However, here we present a case of a patient with Ectopic ACHT Syndrome (EAS) due to non-small cell lung cancer. Clinical Case: 87-year-old woman with pmhx of RA and HTN was admitted for 2-week history of constipation and lower abdominal pain. Physical exam was notable for hypertension and tachycardia, along with lower abdominal tenderness. Laboratory results showed WBCs of 32,000 (3,800-10,500), K of 2.7 mmol/L (3.5-5.5 mmol/L) and HCO3 was 38 mmol/L (22-29 mmol/L). CT chest and abdomen showed a left perihilar necrotic mass 6.6 X 6.0cm, with loco-regional lymphadenopathy with destructive osseous lesion on the right pedicle of L1 and metastatic disease to the liver and adrenal glands. Paraneoplastic ACTH production was suspected in the setting of metastatic lung cancer. Serum ACTH level was 105 pg/mL (7.2-63.6 pg/mL). Initial 8AM cortisol was 41 ug/dL (6.8-18.4 ug/dL) and 24 hr urine cortisol was 2327 mcg/24 h (3.5-45 mcg/24 h) which proved the diagnosis of ACTH-dependent hypercortisolemia. The AM cortisol was 62.3 ug/dL (6.0-18.4 ug/dL) after the 1mg dexamethasone test consistent with hypercortisolemia secondary to ectopic ACTH. IR biopsy of the right axillary LN showed poorly differentiated non-small cell carcinoma with squamous differentiation. The patient was started on chemotherapy, as well as, mifepristone 300 mg daily and ketoconazole 200 TID for hypercortisolism. She was also considered for Metyrapone. However, cortisol levels did not improve despite optimized therapy due to the aggressive nature of the cancer. Later chemotherapy was discontinued and was discharged on hospice with ketoconazole and mifepristone. Conclusion: EAS is associated with neuroendocrine tumors of which up to 50% are caused by SCLC and rarely with adenocarcinoma. However, our case is novel as the source of ACTH was a lung tumor of squamous cell origin. Treatment strategies for ACTH secreting tumors combine chemotherapy as well as medications that target the hormonal imbalance such as steroidogenesis inhibitors and cortisol receptor blockers. Unfortunately, patients with ACTH producing tumors tend to have low median survival rates which limits our ability as clinicians to determine the effectiveness of such interventions. Given the uniqueness of her case, it would be even harder to predict the type of clinical response obtained from such treatment. Presentation: Thursday, June 15, 2023

STAT5 promotes PD-L1 expression by facilitating histone lactylation to drive immunosuppression in acute myeloid leukemia

sImmunotherapy is a revolutionized therapeutic strategy for tumor treatment attributing to the rapid development of genomics and immunology, and immune checkpoint inhibitors have successfully achieved responses in numbers of tumor types, including hematopoietic malignancy. However, acute myeloid leukemia (AML) is a heterogeneous disease and there is still a lack of systematic demonstration to apply immunotherapy in AML based on PD-1/PD-L1 blockage. Thus, the identification of molecules that drive tumor immunosuppression and stratify patients according to the benefit from immune checkpoint inhibitors is urgently needed. Here, we reported that STAT5 was highly expressed in the AML cohort and activated the promoter of glycolytic genes to promote glycolysis in AML cells. As a result, the increased-lactate accumulation promoted E3BP nuclear translocation and facilitated histone lactylation, ultimately inducing PD-L1 transcription. Immune checkpoint inhibitor could block the interaction of PD-1/PD-L1 and reactive CD8+ T cells in the microenvironment when co-culture with STAT5 constitutively activated AML cells. Clinically, lactate accumulation in bone marrow was positively correlated with STAT5 as well as PD-L1 expression in newly diagnosed AML patients. Therefore, we have illustrated a STAT5-lactate-PD-L1 network in AML progression, which demonstrates that AML patients with STAT5 induced-exuberant glycolysis and lactate accumulation may be benefited from PD-1/PD-L-1-based immunotherapy.

The Ferroptosis Induced by Palmitic Acid via CD36 Activating ER Stress to Break Calcium-Iron Balance in Colon Cancer Cells

There have been numerous studies to date on the treatment of tumors by saturated fatty acids. But the role that ferroptosis plays in this is not clear. Palmitic acid (PA) is a common saturated fatty acid with huge application prospects for inducing tumor cell ferroptosis. In vivo and in vitro experiments were performed to verify changes in cell proliferation, apoptosis and ferroptosis after PA treatment of colon cancer cells. Changes in ROS, lipid peroxidation, ferric ions, calcium ions, endoplasmic reticulum (ER) stress, endocytosis recycling trafficking of transferrin after PA treatment of colon cancer cells were detected. Further using necrosis inhibitor (Necrostatin-1), apoptosis inhibitor (Z-VAD-FMK), autophagy inhibitor (CQ), iron death inhibitor (Fer-1), calcium / ferric ion chelator (BAPTA-AM / DFP), iron supplement (FAC), calcium ion agonist (thapsigargin) for positive and negative verification. The association of CD36 expression and patient prognosis in colon cancer patients was subsequently evaluated by bioinformatics analysis. Detect the difference of CD36 expression in different colon cancer cells induced by PA, and further knock down or over express CD36 to explore the change of sensitivity to PA induced ferroptosis. PA inhibited colon cancer cell viability in vitro and in vivo, in conjunction with an accumulation of ROS and lipid peroxidation. The ferroptosis inhibitor Ferrostatin-1 but not Z-VAD-FMK, Necrostatin-1, or CQ rescued the cell death induced by PA. Subsequently, we verified that PA-induced ferroptosis through excess iron as cell death was inhibited by iron chelator deferiprone (DFP) but exacerbated by a supplement of ferric ammonium citrate (FAC). Mechanistically, PA leads to endoplasmic reticulum calcium release by inducing ER stress, and the increase of cytosolic calcium level positively regulates the endocytosis recycling transport of transferrin to promote the increase of intracellular iron content. Furthermore, we observed that cells with high expression of CD36 were more vulnerable to PA-induced ferroptosis. Knocking down the expression of CD36 can inhibit the sensitivity of colon cancer cells to PA induced ferroptosis, and vice versa. In general, we report for the first time that PA can selectively induce ferroptosis in colon cancer cells with high expression of CD36 by activating ER stress/ER calcium release/transferrin-dependent ferroptosis. This provides a new strategy and basis for the precise treatment of tumors.

Lipid metabolism as a target for cancer drug resistance: progress and prospects.

Cancer is the world's leading cause of human death today, and the treatment process of cancer is highly complex. Chemotherapy and targeted therapy are commonly used in cancer treatment, and the emergence of drug resistance is a significant problem in cancer treatment. Therefore, the mechanism of drug resistance during cancer treatment has become a hot issue in current research. A series of studies have found that lipid metabolism is closely related to cancer drug resistance. This paper details the changes of lipid metabolism in drug resistance and how lipid metabolism affects drug resistance. More importantly, most studies have reported that combination therapy may lead to changes in lipid-related metabolic pathways, which may reverse the development of cancer drug resistance and enhance or rescue the sensitivity to therapeutic drugs. This paper summarizes the progress of drug design targeting lipid metabolism in improving drug resistance, and providing new ideas and strategies for future tumor treatment. Therefore, this paper reviews the issues of combining medications with lipid metabolism and drug resistance.

A SIRT6 Inhibitor, Marine-Derived Pyrrole-Pyridinimidazole Derivative 8a, Suppresses Angiogenesis.

Angiogenesis refers to the process of growing new blood vessels from pre-existing capillaries or post-capillary veins. This process plays a critical role in promoting tumorigenesis and metastasis. As a result, developing antiangiogenic agents has become an attractive strategy for tumor treatment. Sirtuin6 (SIRT6), a member of nicotinamide adenine (NAD+)-dependent histone deacetylases, regulates various biological processes, including metabolism, oxidative stress, angiogenesis, and DNA damage and repair. Some SIRT6 inhibitors have been identified, but the effects of SIRT6 inhibitors on anti-angiogenesis have not been reported. We have identified a pyrrole-pyridinimidazole derivative 8a as a highly effective inhibitor of SIRT6 and clarified its anti-pancreatic-cancer roles. This study investigated the antiangiogenic roles of 8a. We found that 8a was able to inhibit the migration and tube formation of HUVECs and downregulate the expression of angiogenesis-related proteins, including VEGF, HIF-1α, p-VEGFR2, and N-cadherin, and suppress the activation of AKT and ERK pathways. Additionally, 8a significantly blocked angiogenesis in intersegmental vessels in zebrafish embryos. Notably, in a pancreatic cancer xenograft mouse model, 8a down-regulated the expression of CD31, a marker protein of angiogenesis. These findings suggest that 8a could be a promising antiangiogenic and cancer therapeutic agent.

Perspectives for immunotherapy of EBV-associated GLELC: A relatively "hot" tumor microenvironment.

Epstein-Barr virus (EBV)-associated gastric lymphoepithelioma-like carcinoma (EBVaGLELC) represents a small number of gastric cancer (GC), and research on tumor microenvironment (TME) and treatment strategy are still lacking. Here, we aim to elucidate the immune features of this rare disease and further help to develop more effective treatment options. A retrospective analysis was conducted between 2019 to 2022 in West China Hospital to reveal the immunological characteristics of EBV-positive GLELC. The difference of immune cell subset and tumor vascular structure between gastric denocarcinoma (GAC) and EBVaGLELC will be pointed out. 13 patients with GELEC and 8 patients with GAC were retrospectively studied. The heterogeneity of the immune cell profile was then confirmed through multiplexed immunofluorescence staining (mIF), which revealed a higher proportion of CD3+ T cells, CD8+ T cells, and Treg cells in the EBV-associated GLELC group. Such a distinct TME may provide therapeutic advantages, and patients with this rare subtype of GC could be good candidates for immune checkpoint inhibitors (ICIs). Angiogenesis in EBV-positive GLELC may be less intense than that in gastric adenocarcinoma (GAC), a feature that might decrease their susceptibility to antiangiogenic therapy. Furthermore, we reported a 52-year-old male with advanced EBV-positive GLELC who showed a favorable response to the combined therapy with . A repeat evaluation showed sustained partial response (PR), and the progression-free survival (PFS) was more than 34 months until now. Compared with GAC, EBVaGLELC revealed higher T cell infiltration and less intense of angiogenesis. It displays relatively "hot" TME that may provide the rationality to treat with immunotherapy in EBV-related GLELC.

The role of platelets in the regulation of tumor growth and metastasis: the mechanisms and targeted therapy.

Platelets are a class of pluripotent cells that, in addition to hemostasis and maintaining vascular endothelial integrity, are also involved in tumor growth and distant metastasis. The tumor microenvironment is a complex and comprehensive system composed of tumor cells and their surrounding immune and inflammatory cells, tumor-related fibroblasts, nearby interstitial tissues, microvessels, and various cytokines and chemokines. As an important member of the tumor microenvironment, platelets can promote tumor invasion and metastasis through various mechanisms. Understanding the role of platelets in tumor metastasis is important for diagnosing the risk of metastasis and prolonging survival. In this study, we more fully elucidate the underlying mechanisms by which platelets promote tumor growth and metastasis by modulating processes, such as immune escape, angiogenesis, tumor cell homing, and tumor cell exudation, and further summarize the effects of platelet-tumor cell interactions in the tumor microenvironment and possible tumor treatment strategies based on platelet studies. Our summary will more comprehensively and clearly demonstrate the role of platelets in tumor metastasis, so as to help clinical judgment of the potential risk of metastasis in cancer patients, with a view to improving the prognosis of patients.

A “biomimetic bone-magnet” with suitable mechanical properties concurrently performs accurate target collection of nanoparticles for magnetothermally driven osteosarcoma thermo-chemotherapy

Osteolytic lesions of bone tumors lead to stress-induced loss of load-bearing bones, making it difficult to treat tumors and repair bone tissue structures. Magnetic hyperthermia has become an effective minimally invasive treatment for malignant bone tumors without depth limitations. However, the effectiveness of magnetic heat therapy alone is not satisfactory, and if combined with chemotherapy, it can lead to significant systemic side effects. It is important to efficiently target chemotherapy substances to the correct area for combined therapy. We have developed a biomimetic bone magnet (BBM) that uses polymethyl methacrylate (PMMA) bone cement-loaded permanent magnet materials with good support performance to create an intrinsic tumor magnetic field. This magnetic field has magnetothermal properties and collects drug-loaded magnetic phase change nanoparticles (mCNPs) circulating in the blood for magnetothermally triggered chemotherapy. Moreover, PMMA has good mechanical properties, providing potential stress support for bone reconstruction after bone tumor treatment. Importantly, both in vivo and in vitro experimental results demonstrated the effectiveness of magnetic hyperthermia through minimally invasive injection of BBM phase transition. This new method achieves magnetic targeting by manufacturing tumor biomagnets to generate strong magnetic fields within the tumor, which opens up new avenues for treatment strategies for malignant bone tumors.

Bimetallic Organic Frameworks of High Piezo-Voltage for Sono-Piezo Dynamic Therapy.

Piezoelectric materials produce charges to directly act on cancer medium or promote reactive oxygen species (ROS) generation for novel tumor therapy triggered by sonography. Currently, piezoelectric sonosensitizers are mainly used to catalyze ROS generation by band-tilting effect for sonodynamic therapy. However, it remains a challenge for piezoelectric sonosensitizers to produce high piezo-voltages to overcome the band-gap barrier for direct charge generation. Herein, the Mn-Ti bimetallic organic framework tetragonal nanosheets (MT-MOF TNS) are designed to produce high piezo-voltages for novel sono-piezo dynamic therapy (SPDT) with remarkable antitumor efficacy in vitro and in vivo. MT-MOF TNS content non-centrosymmetric secondary building units of Mn-Ti-oxo cyclic octamers with charge heterogeneous components for piezoelectricity. MT-MOF TNS promote strong sono-cavitation to insitu induce piezoelectric effect with a high sono-piezo (SP) voltage (2.9V) to directly excite charges, which is validated by sono-piezo-excited luminescence spectrometry. The SP voltage and charges depolarize the mitochondrial and plasma membrane potentials, and cause ROS overproduction and serious tumor cell damage. Importantly, MT-MOF TNS can be decorated with targeting molecules and chemotherapeutics for more severe tumor regression by combining SPDT with chemodynamic therapy and chemotherapy. This report develops a fascinating MT-MOF piezoelectric nano-semiconductor and provides an efficient SPDT strategy for tumor treatment. This article is protected by copyright. All rights reserved.

Comprehensive treatment strategies for head neck tumors

Comprehensive treatment strategies for head neck tumors

The SUMOylation and ubiquitination crosstalk in cancer.

The cancer occurrence and progression are largely affected by the post-translational modifications (PTMs) of proteins. Currently, it has been shown that the relationship between ubiquitination and SUMOylation is highly complex and interactive. SUMOylation affects the process of ubiquitination and degradation of substrates. Contrarily, SUMOylation-related proteins are also regulated by the ubiquitination process thus altering their protein levels or activity. Emerging evidence suggests that the abnormal regulation between this crosstalk may lead to tumorigenesis. In this review, we have discussed the study of the relationship between ubiquitination and SUMOylation, as well as the possibility of a corresponding application in tumor therapy. The relevant literatures from PubMed have been reviewed for this article. The interaction between ubiquitination and SUMOylation is crucial for the occurrence and development of cancer. A greater understanding of the crosstalk of SUMOylation and ubiquitination may be more conducive to the development of more selective and effective SUMOylation inhibitors, as well as a promotion of synergy with other tumor treatment strategies.

Roles of zinc in cancers: From altered metabolism to therapeutic applications.

Zinc (Zn) is a crucial trace element involved in various cellular processes, including oxidative stress, apoptosis and immune response, contributing to cellular homeostasis. Dysregulation of Zn homeostasis occurs in certain cancers. This review discusses the role of Zn in cancer and its associated components, such as Zn-related proteins, their potential as biomarkers and the use of Zn-based strategies for tumor treatment. ZIP and ZnT proteins regulate Zn metabolism under normal conditions, but their expression is aberrant in cancer. These Zn proteins can serve as prognostic or diagnostic biomarkers, aiding in early cancer detection and disease monitoring. Moreover, targeting Zn and its pathways offers potential therapeutic approaches for cancer treatment. Modulating Zn biodistribution within cells using metal-binding agents allows for the control of downstream signaling pathways. Direct utilization of zinc as a therapeutic agent, including Zn supplementation or Zn oxide nanoparticle administration, holds promise for improving the prognosis of cancer patients.

A pH-responsive polymer-coated CaO2 as oxygen-generating nanoparticle in situ for enhanced chemo-photodynamic synergistic therapy against tumors

Photodynamic therapy (PDT) has emerged as an efficient strategy for tumor treatment. However, Insufficient amounts of inherent hypoxia and intrinsic hydrogen peroxide (H2O2) in the tumor microenvironment severely constrained PDT, as oxygen is the critical substrate for photosensitivity reaction. Here, a pH-responsive H2O2 and O2 self-supplying hybrid nanoparticle was designed. Through, the calcium peroxide (CaO2) as carriers loading a chemotherapeutic drug a photosensitizer 5,10,15,20-tetrakis(4-aminophenyl) porphyrin (TAPP) and doxorubicin (DOX), was covered with polyacrylic acid (PAA) to build up a feature material DOX-TAPP-CaO2@OA@PAA (denoted as DTCOP) through the reverse microemulsion method. In the acidic tumor microenvironment conditions exposing the water-sensitive CaO2 nanocore to generate hydrogen peroxide (H2O2) and O2, the self-supplied O2 alleviates hypoxia to enhance the PDT, and releasing DOX and TAPP. Synthetic characterization shows that the succeeded synthesized Nanocarriers could effectively carry DOX and TAPP to the tumor site and release O2 at the low pH of TME. And the experimental results demonstrated that this interpose exogenous oxygen strategy is efficient at inhibition of tumor growth both in vitro and in vivo. The nanocomposite exhibits excellent biocompatibility and the ability to inhibit tumor growth and has significant potential for the treatment of hypoxic tumors.

A laser free self-luminous nanosystem for photodynamic therapy of cervical cancer cells

Photodynamic therapy is a tumor treatment strategy. However, most of the photodynamic therapies rely on laser irradiation triggering, which limits their application in deep tissues. This study designed a self-luminescent nano system, hybrid protein oxygen nanocarrier coated graphene quantum dots (GQDs@HPOC) and mesoporous silica nanoparticles coated Luminol (L@MSNs), which self-assembled into GQDs@HPOC/L@MSNs without laser irradiation. The system utilized the weak acidic environment of tumors to trigger the release of Luminol and the chemiluminescence was catalyzed by HPOC. Next CRET occurred between Luminol and GQDs, producing 1O2, which could generate photodynamic damage to cervical cancer cells without the need for external laser irradiation. The system achieved the peak uptake in primary cervical cancer cells in 3 h, and had good biosafety before self-assembly. The system could significantly kill cells at a concentration of 16 μg/ml. The system will be further applied in in vivo experiments to investigate its therapeutic ability, providing a new strategy for the clinical treatment of cervical cancer.

Diagnostic value of conventional endoscopic ultrasound for lymph node metastasis in upper gastrointestinal neoplasia: A meta-analysis.

Upper gastrointestinal neoplasia mainly includes esophageal cancer and gastric cancer, both of which have high morbidity and mortality. Lymph node metastasis (LNM), as the most common metastasis mode of both diseases, is an important factor affecting tumor stage, treatment strategy and clinical prognosis. As a new fusion technology, endoscopic ultrasound (EUS) is becoming increasingly used in the diagnosis and treatment of digestive system diseases, but its use in detecting LNM in clinical practice remains limited. To evaluate the diagnostic value of conventional EUS for LNM in upper gastrointestinal neoplasia. Using the search mode of "MeSH + Entry Terms" and according to the predetermined inclusion and exclusion criteria, we conducted a comprehensive search and screening of the PubMed, EMBASE and Cochrane Library databases from January 1, 2000 to October 1, 2022. Study data were extracted according to the predetermined data extraction form. The quality of the included studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies tool, and the results of the quality assessment were presented using Review Manager 5.3.5 software. Finally, Stata14.0 software was used for a series of statistical analyses. A total of 22 studies were included in our study, including 2986 patients. The pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic score and diagnostic odds ratio of conventional EUS in the diagnosis of upper gastrointestinal neoplasia LNM were 0.62 [95% confidence interval (CI): 0.50-0.73], 0.80 (95%CI: 0.73-0.86), 3.15 (95%CI: 2.46-4.03), 0.47 (95%CI: 0.36-0.61), 1.90 (95%CI: 1.51-2.29) and 6.67 (95%CI: 4.52-9.84), respectively. The area under the summary receiver operating characteristic curve was 0.80 (95%CI: 0.76-0.83). Sensitivity analysis indicated that the results of the meta-analysis were stable. There was considerable heterogeneity among the included studies, and the threshold effect was an important source of heterogeneity. Univariable meta-regression and subgroup analysis showed that tumor type, sample size and EUS diagnostic criteria were significant sources of heterogeneity in specificity (P < 0.05). No significant publication bias was found. Conventional EUS has certain clinical value and can assist in the detection of LNM in upper gastrointestinal neoplasia, but it cannot be used as a confirmatory or exclusionary test.

An organic free radical generator independent on hydrogen peroxide for chemodynamic and immunotherapy in vivo

It is desirable to develop a free radical generator that is neither dependent on hydrogen peroxide nor external stimuli-triggered to achieve effective tumor treatment. Herein, the free radical generator MNPs-mCPBA was constructed with Zn0.4Co0.6Fe2O4@Zn0.4Mn0.6Fe2O4 nanoparticles (MNPs) and 3-chloroperbenzoic acid (mCPBA). We believe that the iron (II) on the surface of MNPs-mCPBA maybe represent high reactive activity and promote the generation of a large number of organic free radicals (C6H4ClCOOO⋅) in an acidic tumor microenvironment, which realizes the acid-dependent tumor treatment strategy independent on the H2O2 level in tumors. In addition, the generated organic free radicals (C6H4ClCOOO⋅) effectively induced immunogenic cell death (ICD) and increased T cell infiltration. Under the synergetic treatment with an anti-PD-L1 antibody (α-PD-L1), a favorable anti-tumor effect was achieved.

CRISPR/Cas9: A Powerful Strategy to Improve CAR-T Cell Persistence.

As an emerging treatment strategy for malignant tumors, chimeric antigen receptor T (CAR-T) cell therapy has been widely used in clinical practice, and its efficacy has been markedly improved in the past decade. However, the clinical effect of CAR-T therapy is not so satisfying, especially in solid tumors. Even in hematologic malignancies, a proportion of patients eventually relapse after receiving CAR-T cell infusions, owing to the poor expansion and persistence of CAR-T cells. Recently, CRISPR/Cas9 technology has provided an effective approach to promoting the proliferation and persistence of CAR-T cells in the body. This technology has been utilized in CAR-T cells to generate a memory phenotype, reduce exhaustion, and screen new targets to improve the anti-tumor potential. In this review, we aim to describe the major causes limiting the persistence of CAR-T cells in patients and discuss the application of CRISPR/Cas9 in promoting CAR-T cell persistence and its anti-tumor function. Finally, we investigate clinical trials for CRISPR/Cas9-engineered CAR-T cells for the treatment of cancer.

Integration of Tumor Elimination And Tissue Regeneration via Selective Manipulation of Physiological Microenvironments Based on Intelligent Nanocomposite Hydrogel for Postoperative Treatment of Malignant Melanoma

AbstractTumor residue and tissue damage normally occurred after surgical treatment of malignant melanoma, and the effective postoperative therapy is still a challenge because the treatment requests simultaneous but opposite manipulation of tumor cells and healthy cells. Herein, MBGP‐Gel, a thermosensitive and biodegradable hydrogel incorporating S‐nitrosoglutathione (GSNO) loaded and N‐aminoethyl‐N’‐benzoyl thiourea (BTU) modified MSNs (MBGP NPs), was designed to utilize the significant difference of copper content between tumor cells and healthy cells to regulate various physiological microenvironments for integrative therapy of tumor elimination, metastasis inhibition and tissue regeneration. The MBGP‐Gel underwent sol‐gel transformation at body temperature after injection, and continuously released MBGP nanoparticles. In tumor cells, these nanoparticles would chelate the excess copper to inhibit the tumor migration. Meanwhile, copper was reduced to cuprous, which further catalyzed the abundant H2O2 and GSNO to produce oxygen species (ROS) and nitric oxide (NO), respectively. The ROS and the reaction product of ROS and NO (ONOO) would significantly damage the tumor tissue. In contrast, MBGP nanoparticles entered healthy cells only generate appropriate amount of NO to accelerate tissue healing. Both in vitro and in vivo results showed that the nanocomposite hydrogel could inhibit the growth and metastasis of malignant melanoma and promote the skin regeneration, which offered an promising strategy for postoperative treatment of various tumors.