Treatment Of Solid Tumors Research Articles

Supramolecular Combination Chemotherapy: Directly Inducing Immunogenic Cell Death To Inhibit Tumor Metastasis via Host-Guest Interactions.

Tumor metastasis is a difficult clinical problem to solve due to tumor heterogeneity and the emergence of antiapoptotic clones driven by tumor evolution. Clinical combination chemotherapy remains a standard treatment for solid metastasis tumors but with worse treatment efficiency. It is worth exploring a high-efficiency and low-side-effect therapeutic method to solve solid metastases. Herein, we fabricate a supramolecular combination chemotherapeutic system based on host-guest interactions using a cucurbit[8]uril complex (CB[8]-lobaplatin-oxaliplatin, CLO). We explored whether CLO can induce colorectal cancer cell death by activating immunogenic cell death (ICD) to inhibit cancer cell migration in a safe and effective manner. CLO inhibits the viability of human colorectal cancer cells (HCT116) at only 10 μM and alleviates the cytotoxicity induced by lobaplatin-oxaliplatin (LO) in normal colorectal cells (NCM460). Interestingly, CLO can trigger ICD in colorectal tumor cells, and our results verified the upregulations of high mobility group box 1 (HMGB1) and adenosine triphosphate (ATP) release and cell surface calreticulin (CRT) exposure. Besides, we found that CLO can inhibit tumor migration both in vivo and in vitro, and bio-AFM characterization of tumor cellular surface also confirmed this phenomenon. To further investigate the underlying mechanisms of the antitumor effects of CLO, quantitative proteomics was employed, and the results indicated that the citrate cycle (TCA cycle), protein processing in the endoplasmic reticulum, cGMP-PKG signaling pathway, p53 signaling pathway, chemical carcinogenesis, and necroptosis signaling pathway might contribute to CLO-induced antitumor effects. Collectively, our study suggests that the supramolecular combination chemotherapeutic system based on CB[8] host-guest complex can activate ICD to inhibit metastasis in antitumor strategy and exhibits a remarkable potential for supramolecular immunotherapy.

The chiisanoside derivatives present in the leaves of Acanthopanax sessiliflorus activate autophagy through the LRP6/GSK3β axis and thereafter inhibit oxidative stress, thereby counteracting cisplatin-induced ototoxicity

IntroductionCisplatin is extensively employed in the treatment of multiple solid malignant tumors. Nevertheless, side effects such as cisplatin-induced ototoxicity (CIO) pose obstacles to tumor therapy.The important natural product chiisanoside from Acanthopanax sessiliflorus has abundant activity against CIO.MethodsIn this study, 26 chiisanoside derivatives were screened, and compound 19 demonstrated significant protective activity against CIO damage. A cisplatin—induced HEI—OC1 cell injury model and a mouse ototoxicity model were established. The regulatory effects were revealed through transcriptome sequencing, and the protein expression levels were analyzed by molecular docking, ELISA, Western blotting, and immunofluorescence.ResultsIt was found that compound 19 inhibited cell apoptosis, alleviated abnormal hearing and spiral ganglion damage. Transcriptome sequencing revealed its regulatory effects. Compound 19 treatment increased autophagy levels, thereby alleviating mitochondrial dysfunction and reducing the accumulation of reactive oxygen species (ROS).In-depth studies have found that the autophagy inhibitor 3-methyladenine (3-MA) weakens the regulatory effect of compound 19 on autophagy and inhibits the clearance of damaged cells, resulting in oxidative stress damage, apoptosis and necrosis. By knocking down LRP6, it was found that the protective effect of compound 19 was eliminated, the autophagy level was significantly reduced, oxidative stress and ROS production were induced, and apoptosis after cisplatin exposure was promoted. Finally, the inhibitor LiCl was used to suppress the expression of GSK3β. It was found that inhibiting GSK3β could protect cells from cisplatin-induced damage by activating autophagy.DiscussionThese findings suggest that compound 19 is capable of preventing ototoxicity by activating autophagy via the LRP6/GSK3β axis and consequently inhibiting oxidative stress, offering a new approach for treating CIO and sensorineural hearing loss.

Recent Advances in Nanocarrier-mediated Combination Drug Therapy for Tackling Solid-resistant Tumors.

Cancer is a group of dynamic diseases characterized by uncontrollable growth and spread of cells. The heterogenic nature of cancer hinders the abolishment of cancer resulting in a narrow therapeutic index, the capacity of drug efflux, multidrug resistance, and unacceptable side effects. The major challenge in the treatment of malignancies is multidrug resistance (MDR). A novel platform, nanoscale delivery system, concluding desirable applications for the treatment of cancer with targeted and controlled release of drugs, reducing the number of side effects and systemic toxicity. Recent studies emphasize that combining 2 or more nanocarrier-mediated therapies may produce complementary therapeutic effects, perhaps resulting in improved outcomes of cancer current therapies like deterioration of drug resistance. Therefore, in this article, we scrutinize the recent advancement addressing combination therapy by combining nanoparticles with anticancer drugs. It briefly concludes a thorough overview of cancer, tumor or solid resistant tumors, the mechanism of resistant tumors, current therapies for the treatment of solid tumors, and their challenges. It also covers various types of nanoparticles used in cancer treatment, the usage of nanocarriers in resistant tumors, and nanocarrier-based combinatorial therapy for the treatment of resistant tumors as well as its benefits. However, this approach still needs to be improved for clinical applications.

Zinc nanoparticles from oral supplements accumulate in renal tumours and stimulate antitumour immune responses.

A successful therapeutic outcome in the treatment of solid tumours requires efficient intratumoural drug accumulation and retention. Here we demonstrate that zinc gluconate in oral supplements assembles with plasma proteins to form ZnO nanoparticles that selectively accumulate into papillary Caki-2 renal tumours and promote the recruitment of dendritic cells and cytotoxic CD8+ T cells to tumour tissues. Renal tumour targeting is mediated by the preferential binding of zinc ions to metallothionein-1X proteins, which are constitutively overexpressed in Caki-2 renal tumour cells. This binding event further upregulates intracellular metallothionein-1X expression to induce additional nanoparticle binding and retention. In both tumour animal models and human renal tumour samples, we show that ZnO nanoparticles actively cross the vascular wall to achieve high intratumoural accumulation. We further explore this feature of ZnO nanoparticles for the delivery of chemotherapeutics to mouse and rabbit cancer models. Our findings demonstrate that ZnO nanoparticles derived from supplements can serve as a multifunctional drug delivery and cancer immunotherapy platform.

IPSC Technology Revolutionizes CAR-T Cell Therapy for Cancer Treatment

Chimeric Antigen Receptor (CAR)-engineered T (CAR-T) cell therapy represents a highly promising modality within the domain of cancer treatment. CAR-T cell therapy has demonstrated notable efficacy in the treatment of hematological malignancies, solid tumors, and various infectious diseases. However, current CAR-T cell therapy is autologous, which presents challenges related to high costs, time-consuming manufacturing processes, and the necessity for careful patient selection. A potential resolution to this restriction could be found by synergizing CAR-T technology with the induced pluripotent stem cell (iPSC) technology. iPSC technology has the inherent capability to furnish an inexhaustible reservoir of T cell resources. Experimental evidence has demonstrated the successful generation of various human CAR-T cells using iPSC technology, showcasing high yield, purity, robustness, and promising tumor-killing efficacy. Importantly, this technology enables the production of clinical-grade CAR-T cells, significantly reducing manufacturing costs and time, and facilitating their use as allogeneic cell therapies to treat multiple cancer patients simultaneously. In this review, we aim to elucidate essential facets of current cancer therapy, delineate its utility, enumerate its advantages and drawbacks, and offer an in-depth evaluation of a novel and pragmatic approach to cancer treatment.

Squalene-Conjugated Drugs Exploit Endogenous Low-Density Lipoproteins for Enhanced Targeting for Cancer Therapy

Cancer is a major global health threat and a leading cause of mortality worldwide. Nucleotide analog chemodrugs are commonly used in the treatment of various solid tumors, but their clinical efficacy is often limited by rapid blood metabolization, poor intracellular diffusion and significant side effects due to non-selectivity targeting. To address these challenges, this study investigates the potential of conjugating squalenea natural triterpene and cholesterol biosynthesis precursorto two model chemodrugs to enhance the drug's incorporation into endogenous low-density lipoproteins (LDLs) for targeted cancer delivery. By leveraging the natural affinity of lipoproteins for cancer cells with overexpressed lipoprotein receptors, this approach can potentially improve the drugs specificity to cancer cells and accumulation at tumor sites. Using molecular dynamics (MD) simulations, we found that squalene-conjugated drugs have favorable partitioning into LDL interior with a deep negative free energy well. It confirms that squalene-drug conjugates possess the significantly higher affinity to LDL and the potential to exploit LDL for targeting cancer cells. The improved drug behaviors are expected to improve drug circulation and tumor accumulation. The findings provide valuable insights into the potential of squalene-conjugated chemodrugs as a novel strategy for improving the therapeutic efficacy of nucleoside analogs in cancer treatment

TBK1 Targeting Is Identified as a Therapeutic Strategy to Enhance CAR T-Cell Efficacy Using Patient-Derived Organotypic Tumor Spheroids.

Novel therapeutic strategies are needed to improve the efficacy of chimeric antigen receptor (CAR) T cells as a treatment of solid tumors. Multiple tumor microenvironmental factors are thought to contribute to resistance to CAR T-cell therapy in solid tumors, and appropriate model systems to identify and examine these factors using clinically relevant biospecimens are limited. In this study, we examined the activity of B7-H3-directed CAR T cells (B7-H3.CAR-T) using 3D microfluidic cultures of patient-derived organotypic tumor spheroids (PDOTS) and then confirmed the activity of B7-H3.CAR T cells in PDOTS. Although B7-H3 expression in PDOTS was associated with B7-H3.CAR-T sensitivity, mechanistic studies revealed dynamic upregulation of co-inhibitory receptors on CAR T-cells following target cell encounter that led to CAR T-cell dysfunction and limited efficacy against B7-H3-expressing tumors. PD-1 blockade restored CAR T-cell activity in monotypic and organotypic tumor spheroids with improved tumor control and upregulation of effector cytokines. Given the emerging role of TANK-binding kinase 1 (TBK1) as an immune evasion gene, we examined the effect of TBK1 inhibition on CAR T-cell efficacy. Similar to PD-1 blockade, TBK1 inhibition restored CAR T-cell activity in monotypic and organotypic tumor spheroids, prevented CAR T-cell dysfunction, and enhanced CAR T-cell proliferation. Inhibition or deletion of TBK1 also enhanced the sensitivity of cancer cells to immune-mediated killing. Taken together, our results demonstrate the feasibility and utility of ex vivo profiling of CAR T cells using PDOTS and suggest that targeting TBK1 could be used to enhance CAR T-cell efficacy by overcoming tumor-intrinsic and -extrinsic resistance mechanisms.

HDAC6: Tumor Progression and Beyond.

Histone Deacetylase 6 (HDAC6) is an intriguing therapeutic target in cancer re-search, distinguished as the only HDAC family member predominantly located in the cyto-plasm. HDAC6 features two catalytic domains and a unique ubiquitin-binding domain, which sets it apart from other HDACs. Beyond its role in histone deacetylation, HDAC6 targets vari-ous nonhistone substrates, such as α-tubulin, cortactin, Heat Shock Protein 90 (HSP90), and Heat Shock Factor 1 (HSF1). Its involvement spans critical aspects of tumor progression, in-cluding invasion, metastasis, angiogenesis, drug resistance, stemness, and the reduction of tu-mor cell immunogenicity. Given these functions, HDAC6 inhibitors are emerging as valuable tools in the treatment of both solid and hematological tumors. Recent advancements have seen several HDAC6 inhibitors to enter clinical trials, with promising outcomes reported. This re-view covers the structural features of HDAC6, its biological roles, and its impact on tumor development, particularly focusing on progression-related events. Additionally, a detailed dis-cussion of preclinical and clinical trials involving selective HDAC6 inhibitors is provided.

Assessment of targets of antibody drug conjugates in SCLC

Antibody-drug conjugate (ADC) therapy has transformed treatment for several solid tumors, including small cell lung cancer (SCLC). However, significant challenges remain, including systemic toxicity, acquired resistance, and the lack of reliable biomarkers for patient selection. To enhance the effectiveness of ADC therapies in SCLC, we focused on target selection in this study by investigating the expression of ADC targets - SEZ6, DLL3, CD276, and TACSTD2 - in cell lines and patient samples. SEZ6 expression was significantly elevated in various SCLC transcriptional subtypes, particularly ASCL1, and exhibited gender-specific differences, being lower in women. DLL3 was primarily observed in the ASCL1 subtype, while CD276 showed high expression in non-neuroendocrine subtypes. TACSTD2 levels were generally low and attenuated in lymph nodes and brain metastases compared to primary tumors. Our findings underscore the importance of understanding target expression patterns to optimize ADC therapy and advance precision medicine in SCLC treatment.

Squaric acid derivatives with cytotoxic activity-a review.

3,4-Dihydroxycyclobut-3-ene-1,2-dione (squaric acid, SQ) is the most important representative of the oxocarbon acids family. Squaric acid derivatives can be promising pharmaceutical agents, due to their unique structural properties, from which novel drugs benefit: a planar aromatic ring, the ability to form hydrogen bonds, good reactivity and similarity with carboxylate, phosphate and amide groups. These properties make it suitable for three major applications in cancer treatment. Firstly, due to their excellent ion binding ability, the halogenated squaramides can be used as artificial ion transporters or mobile carriers to disrupt Na+/Cl- gradients in cancer cells, thus hindering lysosomal function and inducing apoptosis. Another advantage of this class is their bioisosteric properties. Such molecules have been reported to be selective inhibitors of HDACs, FAK, SNM1A, MMP and kinases, involved in tumor growth and metastasis. Finally, the cyclobutenedione moiety proves to be a great linker in complex radiopharmaceuticals, used in theranostics. Its aromaticity and good reactivity make the generation and stability of these drugs easy and efficient. Multiple derivatives containing the squamide motif have been the subject of in-vitro investigations and have demonstrated anti-cancer activity in the nanomolar range against tumor cell lines, including colorectal adenocarcinoma, breast cancer, gastric carcinoma and cervical cancer. On the other hand, squaric acid derivative-Navarixin, has already been evaluated in Phase II clinical trials for its potential efficacy in the treatment of solid tumors. In this context this review is the first looking into the potential applications of squaric acid derivatives as anticancer therapies. It analyzes experimental studies presented in articles published between 2000 and 2024.

Hsa-miR-214-3p inhibits breast cancer cell growth and improves the tumor immune microenvironment by downregulating B7H3.

Immune checkpoint inhibitors play an important role in the treatment of solid tumors, but the currently used immune checkpoint inhibitors targeting programmed cell death-1 (PD-1), programmed cell death ligand-1 (PD-L1), and cytotoxic T-lymphocyte antigen-4 (CTLA-4) show limited clinical efficacy in many breast cancers. B7H3 has been widely reported as an immunosuppressive molecule, but its immunological function in breast cancer patients remains unclear. We analyzed the expression of B7H3 in breast cancer samples using data from the Cancer Genome Atlas Program (TCGA) and the Gene Expression Omnibus (GEO) databases. MicroRNAs were selected using the TarBase, miRTarBase, and miRBase databases. The regulatory role of the microRNA hsa-miR-214-3p on B7H3 was investigated through dual-luciferase reporter assays, which identified the specific action sites of interaction. The expression levels of B7H3 and hsa-miR-214-3p in human breast cancer tissues and adjacent normal tissues were quantified using Western blotting and quantitative PCR (qPCR). In vitro experiments were performed to observe the effects of modulating the expression of B7H3 or hsa-miR-214-3p on breast cancer cell proliferation and apoptosis. Additionally, the regulatory impact of hsa-miR-214-3p on B7H3 was examined. Enzyme-linked immunosorbent assays (ELISA) and flow cytometry were employed to assess the effects of co-cultured breast cancer cells and normal human peripheral blood mononuclear cells (PBMCs) on immune cells and associated cytokines. In breast cancer tissues, the expression level of B7H3 is inversely correlated with that of hsa-miR-214-3p, as well as with the regulatory effects on breast cancercell behavior. Hsa-miR-214-3p was found to inhibit breast cancer cell growth by downregulating B7H3. Importantly, our research identified, for the first time, two binding sites for hsa-miR-214-3p on the 3' UTR of B7H3, both of which exert similar effects independently. Co-culture experiments revealed that hsa-miR-214-3p obstructs the suppressive function of B7H3 on CD8+ T cells and natural killer cells. This study confirms the existence of two hsa-miR-214-3p binding sites on the 3' UTR of B7H3, reinforcing the role of hsa-miR-214-3p as a regulatory factor for B7H3. In breast cancer, hsa-miR-214-3p reduces tumor cell proliferation and enhances the tumor immune microenvironment by downregulating B7H3. These findings suggest new potential targets for the clinical treatment of breast cancer.

Smart release injectable hydrogel co-loaded with liposomal combretastatin A4 and doxorubicin nanogel for local combinational drug delivery: A preclinical study.

Surgical resection and postoperative adjuvant chemotherapy have enhanced the outlook for breast cancer patients. However, tumor relapse and serious side effects of chemotherapy continue to impact patients' quality of life. Designing injectable composite hydrogel made of biodegradable polymers providing sustained release of antiangiogenic and chemotherapeutic agents might play a vital role in elimination of cancer cells. In this regard, we developed dextran based composite hydrogel incorporating doxorubicin-loaded dual-sensitive pH-redox nanogels (DOX-DSNG) and combretastatin A4 (CA4) loaded liposomes which undergo rapid disassembly in cancer cells. CA4 prevents tubulin polymerization and thus inhibits angiogenesis by binding to vascular endothelial tubulin. The results showed that DOX-DSNGs were negatively charged and 144.8±0.85nm in size. Besides, the size of CA4 loaded liposomes were 102.35±4.22nm and were negatively charged. Encapsulation efficiency of DOX-DSNGs and CA4 loaded liposomes were 100% and 89%, respectively. After loading into the hydrogel structure, doxorubicin and CA4 were gradually released from the composite hydrogel for up to 21days. DOX-DSNGs and CA4 loaded liposomes showed a dose-dependent cytotoxic effect against 4T1 breast cancer cells. Thereafter, the anti-neoplastic effect and survival study of the composite hydrogel was evaluated in vivo in tumor-bearing mice. The composite hydrogel significantly reduced tumor volume (from 116mm3 to 38mm3) with negligible organ damage, while showed lower cardiotoxicity in 28days. In conclusion, our results revealed that injectable composite dextran-based hydrogel incorporated with DOX-DSNG and CA4 loaded liposomes could be used as an efficient delivery platform for combination therapies in treatment of solid tumors.

Unveiling FDA-approved Drugs and Formulations in the Management of Bladder Cancer: A Review.

Urological cancers are one of the most prevalent malignancies around the globe. Specifically, bladder cancer severely threatens the health of humans because of its heterogeneous and aggressive nature. Extensive studies have been conducted for many years in order to address the limitations associated with the treatment of solid tumors with selective substances. This article aims to provide a summary of the therapeutic drugs that have received FDA approval or are presently in the testing phase for use in the prevention or treatment of bladder cancer. In this review, FDA-approved drugs for bladder cancer treatment have been listed along with their dose protocols, current status, pharmacokinetics, action mechanisms, and marketed products. The article also emphasizes the novel preparations of these drugs that are presently under clinical trials or are in the approval stage. Thus, this review will serve as a single point of reference for scientists involved in the formulation development of these drugs.

Deep Learning and Multidisciplinary Imaging in Pediatric Surgical Oncology: A Scoping Review.

Medical images play an important role in diagnosis and treatment of pediatric solid tumors. The field of radiology, pathology, and other image-based diagnostics are getting increasingly important and advanced. This indicates a need for advanced image processing technology such as Deep Learning (DL). Our review focused on the use of DL in multidisciplinary imaging in pediatric surgical oncology. A search was conducted within three databases (Pubmed, Embase, and Scopus), and 2056 articles were identified. Three separate screenings were performed for each identified subfield. In total, we identified 36 articles, divided between radiology (n = 22), pathology (n = 9), and other image-based diagnostics (n = 5). Four types of tasks were identified in our review: classification, prediction, segmentation, and synthesis. General statements about the studies'' performance could not be made due to the inhomogeneity of the included studies. To implement DL in pediatric clinical practice, both technical validation and clinical validation are of uttermost importance. In conclusion, our review provided an overview of all DL research in the field of pediatric surgical oncology. The more advanced status of DL in adults should be used as guide to move the field of DL in pediatric oncology further, to keep improving the outcomes of children with cancer.

Bisphosphonate-mineralized nano-IFNγ suppresses residual tumor growth caused by incomplete radiofrequency ablation through metabolically remodeling tumor-associated macrophages.

Rationale: Radiofrequency ablation (RFA), as a minimally invasive surgery strategy based on local thermal-killing effect, is widely used in the clinical treatment of multiple solid tumors. Nevertheless, RFA cannot achieve the complete elimination of tumor lesions with larger burden or proximity to blood vessels. Incomplete RFA (iRFA) has even been validated to promote residual tumor growth due to the suppressive tumor immune microenvironment (TIME). Therefore, exploring strategies to remodel TIME is a key issue for the development of RFA therapy. Methods: The negative effect of iRFA on colorectal cancer therapy was firstly investigated. Then a zoledronate-mineralized nanoparticle loaded with IFNγ (Nano-IFNγ/Zole) was designed and its tumor suppressive efficacy was evaluated. Finally, the metabolic reprogramming mechanism of Nano-IFNγ/Zole on tumor-associated macrophages (TAMs) was studied in detail. Results: We found iRFA dynamically altered TIME and promoted TAM differentiation from M1 to M2. Nano-IFNγ/Zole was fabricated to metabolically remodel TAMs. IFNγ in Nano-IFNγ/Zole concentrated in the ablation site to play a long-term remodeling role. Acting on mevalonate pathway, Nano-IFNγ/Zole was discovered to reduce lysosomal acidification and activate transcription factor TFEB by inhibiting isoprene modification of the Rab protein family. These mechanisms, in conjunction with IFNγ-activated JAK/STAT1 signaling, accelerated the reprogramming of TAMs from M2 to M1, and suppressed tumor recurrence after iRFA. Conclusions: This study elaborates the synergistic mechanism of zoledronate and IFNγ in Nano-IFNγ/Zole to reshape suppressive TIME caused by iRFA by remodeling TAMs, and highlights the important value of metabolically induced cellular reprogramming. Since both zoledronate and IFNγ have already been approved in clinics, this integrative nano-drug delivery system establishes an effective strategy with great translational promise to overcome the poor prognosis after clinically incomplete RFA.

Peptide-based CAR-NK cells: A novel strategy for the treatment of solid tumors.

CAR-T cell therapy has been proven to be effective on hematological tumors, although graft-versus-host disease and cytokine release syndrome(CRS) limit its application to a certain extent. However, CAR-T therapy for solid tumors met challenges, among which the lack of tumor-specific antigens (TSA) and immunosuppressive tumor microenvironment (TME) are the most important factors. CAR-NK could be a good alternative to CAR-T in some ways since they can induce mild CRS and are independent of HLA-matching, but the efficacy of CAR-NKs remains limited in solid tumors. CAR cells armed with multiple tumor targeting molecules may obtain higher therapeutic efficacy against solid tumors. Due to large molecular weight, multivalent scFvs cannot be displayed efficiently on T cells and the high affinity of scFv to the target makes it easy to cause on-target, off-tumor(OTOT) toxicity. Peptides with low molecular weight and slightly lower affinity than scFvs allow immune cells to display multiple peptides to increase killing ability and reduce OTOT toxicity. In our study, peptide-based CAR-NK cells were designed to solve the dilemma of CAR-T in solid tumors. Firstly, the peptide-based CAR-NK92MI cells with A1 peptide were constructed and their inhibitory effects on the growth of A549 tumor cells were identified. Secondly, the tri-specific CAR-NK92MI cells with peptides that simultaneously targeted PD-L1, EGFR and VEGFR2 were developed for the combinatory therapy. Tri-specific CAR-NK92MI exhibited comparable killing activities to scFv-based CAR-NK92MI. Moreover, peptide-based CAR NK92MI mitigated OTOT toxicity. Our study implied that peptide-based CAR-NKs could behave as promising tools in solid tumor.

TEAD1 Prevents Necroptosis and Inflammation in Cisplatin-Induced Acute Kidney Injury Through Maintaining Mitochondrial Function.

Cisplatin is widely used for the treatment of solid tumors and its antitumor effects are well established. However, a known complication of cisplatin administration is acute kidney injury (AKI). In this study, we examined the role of TEA domain family member 1 (TEAD1) in the pathogenesis of cisplatin-induced AKI. TEAD1 expression was upregulated in tubular epithelial cells of kidneys with cisplatin-induced AKI. TEAD1 floxed mice (TEAD1CON) mice treated with cisplatin developed tubular cell damage and impaired kidney function. In contrast, proximal tubule specific TEAD1 knockout (TEAD1PKO) mice treated with cisplatin had enhanced tubular cell damage and kidney dysfunction. Additionally, TEAD1PKO mice treated with cisplatin had augmented necroptotic cell death and inflammatory response compared to TEAD1CON mice with cisplatin. Knockdown of TEAD1 in mouse tubular epithelial cells showed increased intracellular ROS levels, reduced ATP production and impaired mitochondrial bioenergetics compared to control cells treated with cisplatin. Mechanistically, TEAD1 interacts with peroxisomal proliferator-γ coactivator-1α (PGC-1α), a master regulator of mitochondrial biogenesis, to promote mitochondrial function. Taken together, our results indicate TEAD1 plays an important role in the pathogenesis of cisplatin-induced AKI through regulation of necroptosis and inflammation, which is associated with mitochondrial metabolism. Therefore, TEAD1 may represent a novel therapeutic target for cisplatin-induced AKI.

A novel ROR1-targeting antibody-PROTAC conjugate promotes BRD4 degradation for solid tumor treatment

A novel ROR1-targeting antibody-PROTAC conjugate promotes BRD4 degradation for solid tumor treatment

Cationizable transcytosis manganese nano-oxygenator for enhanced chemo-dynamic immunotherapy in deep tumour tissue.

Effective delivery of therapeutic agents for solid tumour treatment is impeded by multiple obstacles, such as aberrant interstitial fluid pressure and high density of the extracellular matrix, which causes impaired penetration to deep avascular tumour tissue that exists in a hypoxic immune cold environment. Only limited tumoricidal effects have been achieved with traditional nanomedicine due to its inefficient penetration and the multiple resistant effects that exist in the tumour microenvironment. Herein, a new chemo-dynamic immunotherapy (CDIT) is proposed based on a transcytosis tumour oxygenator (MnPO2/MC3) with effective chemo-dynamic effects. As a CDIT agent, MnPO2/MC3 is designed and synthesized to enhance deep tumour tissue penetration as well as provide relief of hypoxia to decrease immunosuppression. MnPO2/MC3 is orchestrated by an inner manganese core and double lipid outer layer. The outer layer is constructed by a tumour pH-cationizable outer lipid (D-Lin-MC3-DMA, MC3) layer and O2-loading inner layer. The MC3 lipid endows MnPO2/MC3 with tumour-responsive transcytosis potential, which instead delivers oxygen and Mn deep into tumour tissues. MnPO2/MC3 catalyses hydrogen peroxide to hydroxyl radicals by Mn2+ and increases CD8+ T cell infiltration. The oxygenation and ROS burst by MnPO2/MC3 effectively altered the tumour cold immune microenvironment so that adaptive anti-tumoral immunity was enhanced. MnPO2/MC3-mediated CDIT serving as an effective tumour oxygenator and ROS initiator, effectively suppressed tumour growth while enhancing adaptive anti-tumour immunity.

Application of Immunotherapy in the Treatment of Solid Tumors

Cancer is one of the major diseases that seriously threaten human life and health at present, and the number of deaths due to cancer every year ranks in the top 2 of all diseases. In recent years, the malignant tumor is increasing year by year, so it is necessary to explore new therapeutic methods. Immunotherapy of tumor cells is one of the hot topics in tumor therapy, which aims to destroy tumor cells by activating or regulating the immune system of patients. More and more tumor immunotherapy drugs have been successfully developed and marketed, bringing the hope of long-term survival to patients. However, like other tumor drug therapy, tumor immunotherapy has brought huge benefits to some tumor patients and made people full of expectations, but it also faces many difficulties and challenges in pre-clinical research and clinical application. This article summarizes the application and challenge of immunotherapy in solid tumors.