Extracellular vesicles in anti-tumor drug resistance: Mechanisms and therapeutic prospects.

Drug resistance presents a significant challenge to achieving positive clinical outcomes in anti-tumor therapy. Prior research has illuminated reasons behind drug resistance, including increased drug efflux, alterations in drug targets, and abnormal activation of oncogenic pathways. However, there's a need for deeper investigation into the impact of drug-resistant cells on parental tumor cells and intricate crosstalk between tumor cells and the malignant tumor microenvironment (TME). Recent studies on extracellular vesicles (EVs) have provided valuable insights. EVs are membrane-bound particles secreted by all cells, mediating cell-to-cell communication. They contain functional cargoes like DNA, RNA, lipids, proteins, and metabolites from mother cells, delivered to other cells. Notably, EVs are increasingly recognized as regulators in the resistance to anti-cancer drugs. This review aims to summarize the mechanisms of EV-mediated anti-tumor drug resistance, covering therapeutic approaches like chemotherapy, targeted therapy, immunotherapy and even radiotherapy. Detecting EV-based biomarkers to predict drug resistance assists in bypassing anti-tumor drug resistance. Additionally, targeted inhibition of EV biogenesis and secretion emerges as a promising approach to counter drug resistance. We highlight the importance of conducting in-depth mechanistic research on EVs, their cargoes, and functional approaches specifically focusing on EV subpopulations. These efforts will significantly advance the development of strategies to overcome drug resistance in anti-tumor therapy.

Effect of the presence of berberine/curcumin on the binding of limonin to human serum albumin and antitumor activity in vitro.

The competition among drugs for binding to plasma proteins is regarded as a pharmacokinetic drug interaction. Competition between antitumor agents and other drugs for plasma protein binding can alter the free concentration of the drug, potentially impacting its efficacy and increasing the risk of toxic side effects. Through a range of spectroscopic techniques, this study examined the interaction between limonin and human serum albumin (HSA) in the context of berberine (Ber) and curcumin (Cur) under physiological conditions to clarify the binding mechanisms of binary and ternary systems at the molecular level. As demonstrated by fluorescence quenching experiments, Static quenching was identified as the mechanism of interaction between HSA and limonin. The results of site competition experiments indicated that the binding site between limonin and HSA was site I, a result further supported by molecular docking simulations. Through the use of thermodynamic data calculations, it was determined that limonin forms a stable complex with HSA by establishing hydrogen bonds and van der Waals forces. Circular dichroism (CD) spectroscopy, three-dimensional (3D) fluorescence spectroscopy, and synchronous fluorescence spectroscopy (SFS) employed to validate the notion that limonin perturbed the microenvironment of amino acids and induced conformational changes in HSA. What's more, the presence of Ber or Cur was found to have further modified the alterations observed in the interaction between the original HSA-limonin binary system. In vitro cellular experiments showed that interaction with HSA reduced the antitumor activity of limonin. In contrast, adding Ber or Cur increased the inhibition rate of tumor cells. The coexistence of both Ber and Cur significantly diminished limonin's binding affinity to HSA. The current investigation enhances comprehension regarding the binding characteristics and interaction mechanisms involving limonin, Ber, Cur, and HSA. It explores the potential of HSA as a versatile drug carrier and furnishes theoretical underpinnings for co-administrative strategies.

LAG-3 and PD-1 synergize on CD8+ T cells to drive T cell exhaustion and hinder autocrine IFN-γ-dependent anti-tumor immunity.

Overcoming immune-mediated resistance to PD-1 blockade remains a major clinical challenge. Enhanced efficacy has been demonstrated in melanoma patients with combined nivolumab (anti-PD-1) and relatlimab (anti-LAG-3) treatment, the first in its class to be FDA approved. However, how these two inhibitory receptors synergize to hinder anti-tumor immunity remains unknown. Here, we show that CD8+ T cells deficient in both PD-1 and LAG-3, in contrast to CD8+ T cells lacking either receptor, mediate enhanced tumor clearance and long-term survival in mouse models of melanoma. PD-1- and LAG-3-deficient CD8+ T cells were transcriptionally distinct, with broad TCR clonality and enrichment of effector-like and interferon-responsive genes, resulting in enhanced IFN-γ release indicative of functionality. LAG-3 and PD-1 combined to drive T cell exhaustion, playing a dominant role in modulating TOX expression. Mechanistically, autocrine, cell-intrinsic IFN-γ signaling was required for PD-1- and LAG-3-deficient CD8+ T cells to enhance anti-tumor immunity, providing insight into how combinatorial targeting of LAG-3 and PD-1 enhances efficacy.

Synthesis of Isatin-derived Heterocycles with Promising Anticancer Activities.

Isatin or 1H-indole-2,3-dione skeleton has been playing a significant role in drug de-sign and development. Isatin itself and many of its derivatives are widely distributed in naturally occurring bioactive compounds. Various synthetic isatin derivatives were found to possess a broad range of significant pharmacological efficacies especially anti-cancer activity against a wide variety of cancer cell lines. Interestingly, on a few occasions, some isatin-derived scaffolds were reported as more potent than the tested reputed drug molecules. As a result, isatin-derived compounds have been gaining significant attention in cancer-based drug developments. In this re-view, we have summarized literature reported during the last two decades related to the synthesis of structurally diverse isatin-derived scaffolds with promising anti-cancer activities.

A ß-1,3/1,6-glucan enhances anti-tumor effects of PD1 antibody by reprogramming tumor microenvironment.

Checkpoint blockades have emerged as a frontline approach in cancer management, designed to enhance the adaptive immune response against tumors. However, its clinical efficacy is limited to a narrow range of tumor types, which necessitates the exploration of novel strategies that target another main branch of the immune system. One such potential strategy is the therapeutic modulation of pattern recognition receptors (PRRs) pathways in innate immune cells, which have shown promise in tumor eradication. Previously, a ß-1,3/1,6-glucan with high purity from Durvillaea antarctica (BG136) was reported by our group to exhibit pan-antitumor effects. In the current study, we systemically studied the antitumor activity of BG136 in combination with anti-PD1 antibody in MC38 syngeneic tumor model in vivo. Integrated transcriptomic and metabolomic analyses suggested that BG136 enhances the antitumor immunity of anti-PD1 antibody by reprogramming the tumor microenvironment to become more proinflammatory. In addition, an increase in innate and adaptive immune cell infiltration and activation, enhanced lipid metabolism, and a decreased in ascorbate and aldarate metabolism were also found. These findings provide mechanistic insights that support the potent antitumor efficacy of BG136 when combined with immune checkpoint inhibitor antibodies.

Study on the sensitizing effect of SM-1 combined with irradiation on head and neck squamous cell carcinoma.

PURPOSE: Head and neck squamous cell carcinoma (HNSCC) is globally prevalent with high recurrence, low survival rate, and poor quality of life for patients. Derived from PAC-1, SM-1 can activate procaspase-3 and induce apoptosis in cancer cells to exert anti-tumor effects. However, the inhibitory effect of SM-1 on HNSCC after combination with radiation are unclear. This study aims to investigate the radiosensitizing effect of SM-1 on HNSCC in vitro and in vivo. METHODS: MTT method was used to detect the effect of SM-1 on the viability of HNSCC cell lines (HONE1, HSC-2, and CAL27). The effects of SM-1 combined with radiation on the survival index of HONE1, HSC-2, and CAL27 cell lines were determined by colony formation assay. Flow cytometry was used to investigate the effects of SM-1 and radiation combination on cell apoptosis and cell cycle, and western blot experiments were performed to detect the expression of apoptosis and cell cycle-related proteins. Finally, a xenograft tumor model of CAL27 was established to evaluate the anti-tumor effect of SM-1 combined with radiation in vivo. RESULTS: In vitro, SM-1 effectively inhibited the activity of HNSCC cell lines HONE1, HSC-2, and CAL27 cells, and synergistically showed anti-proliferation activity during combined irradiation. Meanwhile, anti-tumor effect of SM-1 on HNSCC was higher than that of Debio1143, and the radiosensitivity of cells was greatly increased. Flow cytometry and western blot analysis showed that SM-1 induced G2/M phase arrest of head and neck squamous cell carcinoma cells via inhibiting the expression of CyclinB1 and CDC2. Moreover, SM-1 activated caspase-3 activity and up-regulated the cleaved form of PARP1 to induce cell apoptosis. In vivo, SM-1 combined irradiation showed a good anti-tumor effect. CONCLUSION: SM-1 enhances HNSCC cell radiation sensitivity in vitro and in vivo, supporting its potential as a radiosensitizer for clinical trials in combination with radiotherapy.

The cytokine Meteorin-like inhibits anti-tumor CD8+ T cell responses by disrupting mitochondrial function.

Tumor-infiltrating lymphocyte (TIL) hypofunction contributes to the progression of advanced cancers and is a frequent target of immunotherapy. Emerging evidence indicates that metabolic insufficiency drives T cell hypofunction during tonic stimulation, but the signals that initiate metabolic reprogramming in this context are largely unknown. Here, we found that Meteorin-like (METRNL), a metabolically active cytokine secreted by immune cells in the tumor microenvironment (TME), induced bioenergetic failure of CD8+ T cells. METRNL was secreted by CD8+ T cells during repeated stimulation and acted via both autocrine and paracrine signaling. Mechanistically, METRNL increased E2F-peroxisome proliferator-activated receptor delta (PPARδ) activity, causing mitochondrial depolarization and decreased oxidative phosphorylation, which triggered a compensatory bioenergetic shift to glycolysis. Metrnl ablation or downregulation improved the metabolic fitness of CD8+ T cells and enhanced tumor control in several tumor models, demonstrating the translational potential of targeting the METRNL-E2F-PPARδ pathway to support bioenergetic fitness of CD8+ TILs.

Loss of histone deubiquitinase Bap1 triggers anti-tumor immunity.

PURPOSE: Immunotherapy using PD-L1 blockade is effective in only a small group of cancer patients, and resistance is common. This emphasizes the importance of understanding the mechanisms of cancer immune evasion and resistance. METHODS: A genome-scale CRISPR-Cas9 screen identified Bap1 as a regulator of PD-L1 expression. To measure tumor size and survival, tumor cells were subcutaneously injected into both syngeneic WT mice and immunocompromised mice. The phenotypic and transcriptional characteristics of Bap1-deleted tumors were examined using flow cytometry, RNA-seq, and CUT&Tag-seq analysis. RESULTS: We found that loss of histone deubiquitinase Bap1 in cancer cells activates a cDC1-CD8+ T cell-dependent anti-tumor immunity. The absence of Bap1 leads to an increase in genes associated with anti-tumor immune response and a decrease in genes related to immune evasion. As a result, the tumor microenvironment becomes inflamed, with more cDC1 cells and effector CD8+ T cells, but fewer neutrophils and regulatory T cells. We also found that the elimination of Bap1-deleted tumors depends on the tumor MHCI molecule and Fas-mediated CD8+ T cell cytotoxicity. Our analysis of TCGA data further supports these findings, showing a reverse correlation between BAP1 expression and mRNA signatures of activated DCs and T-cell cytotoxicity in various human cancers. CONCLUSION: The histone deubiquitinase Bap1 could be used as a biomarker for tumor stratification and as a potential therapeutic target for cancer immunotherapies.

Anti-tumor effect of antibody-drug conjugate targeting cell adhesion molecule 1 on GIST cells representing small intestinal GIST.

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the alimentary tract. The prognosis depends on the primary site, and small intestinal GISTs have a worse prognosis than gastric GISTs. Molecularly targeted drugs to inhibit tyrosine kinase activity of KIT were used for unresectable or recurrent GISTs. However, secondary resistance to the drugs is often acquired, and treatments based on other mechanisms are needed. Previously, we reported that cell adhesion molecule 1 (CADM1) was highly expressed in most of small intestinal GISTs but not in most of gastric GISTs. In the present study, we examined whether the antibody-drug conjugate (ADC) with anti-CADM1 antibody and monomethyl auristatin E (anti-CAD-ADC) shows anti-tumor effect on CADM1-expressing human GIST cells. The ADC adhibited in this study was previously used for CADM1-expressing human mesothelioma cells and showed anti-tumor effect for them in vitro. GIST-T1 cell line of gastric origin which scarcely expresses CADM1 and GIST-T1 cells transfected with CADM1 cDNA (GIST-T1-CAD cells) which highly expresses CADM1 and represents small intestinal GIST were used. In vitro, anti-CAD-ADC showed remarkable cytotoxic activity on GIST-T1-CAD cells, but control ADC did not. Both anti-CAD-ADC and control ADC did not show anti-tumor effect on original GIST-T1 cells. When GIST-T1-CAD cells were subcutaneously injected to the nude mice, intravenous administration of anti-CAD-ADC showed inhibitory effect for tumor enlargement. Tumor of GIST-T1 cells grew even after anti-CAD-ADC injection. When GIST-T1-CAD cells were injected into peritoneal cavity of the SCID mice, intraperitoneal administration of anti-CAD-ADC showed reduction of the peritoneal tumor. On the other hand, peritoneal tumor grew after control ADC administration. Tissue and organ damage due to administration of anti-CAD-ADC was not apparent by macroscopic and histological examinations in mice. These results indicate that anti-CAD-ADC could have apparent anti-tumor effect on CADM1-expressing human GIST cells both in in vitro and in vivo mouse models.

Unlocking the Intricacies: Exploring the Complex Interplay Between Platelets and Ovarian Cancer.

Ovarian cancer, an aggressive malignancy of the female reproductive tract, is frequently linked to an elevated risk of thrombotic events. This association is manifested by a pronounced rise in platelet counts and activation levels. Current research firmly supports the pivotal role of platelets in the oncogenic processes of ovarian cancer, influencing tumor cell proliferation and metastasis. Platelets influence these processes through direct interactions with tumor cells or by secreting cytokines and growth factors that enhance tumor growth, angiogenesis, and metastasis. This review aims to thoroughly dissect the interactions between platelets and ovarian cancer cells, emphasizing their combined role in tumor progression and associated thrombotic events. Additionally, it summarizes therapeutic strategies targeting platelet-cancer interface which show significant promise. Such approaches could not only be effective in managing the primary ovarian tumor but also play a pivotal role in preventing metastasis and attenuating thrombotic complications associated with ovarian cancer.

Impact of high-salt diet in health and diseases and its role in pursuit of cancer immunotherapy by modulating gut microbiome.

Cancer chemotherapy remains an area of concern, as many of the therapies are uncomfortable involving side effects and unpleasant experiences. These factors could further reduce patient's quality of life, and even endanger their life. Many therapeutic strategies have been tried to reduce the unpleasant side effects and increase the treatment effectiveness; however, none have shown to have promising effects. One of the main hindrances to cancer therapy is the escape strategies by tumor cells to the immune attack. Promoting inflammation in the tumor microenvironment is the cornerstone and key therapeutic target in cancer chemotherapy. High-salt diet (HSD) intake, though it has deleterious effects on human health by promoting chronic inflammation, is found to be advantageous in the tumor microenvironment. Studies identified HSD favors an increased abundance of Bifidobacterium species in the tumor environment due to gut barrier alteration, which, in turn, promotes inflammation and favors improved response to cancer chemotherapy. A review of the literature was carried out to find out the effects of an HSD on health and diseases, with special mention of its effect on cancer chemotherapy. Studies emphasized HSD would block the myeloid-derived suppressor cells which will enhance the tumor immunity. Exploration of the precise mechanism of simple HSD regime/ingestion of specific bacterial species as probiotics will be effective and essential to formulate the game-changing cancer chemotherapy. With the modern era of healthcare moving toward precision medicine where the physician can choose the treatment option suitable for the individual, HSD regime/ingestion of specific bacterial species can be considered.

[Clinical efficacy and safety of blinatumomab bridging CAR-T cell therapy in the treatment of patients with adult acute B-cell lymphoblastic leukemia].

Objective: Exploring the efficacy and safety of bridging blinatumomab (BiTE) in combination with chimeric antigen receptor T (CAR-T) cell therapy for the treatment of adult patients with acute B-cell lymphoblastic leukemia (B-ALL) . Methods: Clinical data from 36 adult B-ALL patients treated at the First Affiliated Hospital of Suzhou University from August 2018 to May 2023 were retrospectively analyzed. A total of 36 cases were included: 18 men and 18 women. The median age was 43.5 years (21-72 years). Moreover, 21 cases of Philadelphia chromosome-positive acute lymphoblastic leukemia were reported, and 16 of these cases were relapsed or refractory. Eighteen patients underwent blinatumomab bridging followed by CAR-T cell therapy, and 18 patients received CAR-T cell therapy. This study analyzed the efficacy and safety of treatment in two groups of patients. Results: In the BiTE bridge-to-CAR-T group, 16 patients achieved complete remission (CR) after BiTE immunotherapy, with a CR rate of 88.9%. One month after bridging CAR-T therapy, bone marrow examination showed a CR rate of 100.0%, and the minimal residual disease (MRD) negativity rate was higher than the nonbridging therapy group (94.4% vs. 61.1%, Fisher, P=0.041). The incidence of cytokine release syndrome and other adverse reactions in the BiTE bridge-to-CAR-T group was lower than that in the nonbridging therapy group (11.1% vs. 50.0%, Fisher, P=0.027). The follow-up reveals that 13 patients continued to maintain MRD negativity, and five patients experienced relapse 8.40 months (2.57-10.20 months) after treatment. Two of five patients with relapse achieved CR after receiving the second CAR-T cell therapy. In the nonbridging therapy group, 10 patients maintained continuous MRD negativity, 7 experienced relapse, and 6 died. The 1 year overall survival rate in the BiTE bridge-to-CAR-T group was higher than that in the nonbridging therapy group, with a statistically significant difference at the 0.1 level (88.9%±10.5% vs. 66.7%±10.9%, P=0.091) . Conclusion: BiTE bridging CAR-T cell therapy demonstrates excellent efficacy in adult B-ALL treatment, with a low recent recurrence rate and ongoing assessment of long-term efficacy during follow-up.

Hainanenin-1, an oncolytic peptide, triggers immunogenic cell death via STING activation in triple-negative breast cancer.

BACKGROUND: In triple-negative breast cancer (TNBC) therapy, insufficient tumor infiltration by lymphocytes significantly hinders the efficacy of immune checkpoint inhibitors. We have previously demonstrated that Hainanenin-1 (HN-1), a host defense peptide (HDP) identified from Hainan frog skin, induces breast cancer apoptosis and boots anti-tumor immunity via unknown mechanism. METHODS: We used in vitro experiments to observe immunogenic cell death (ICD) indicators in HN-1-treated TNBC cell lines, a mouse tumor model to verify HN-1 promotion of mice anti-tumor immune response, and an in vitro drug sensitivity test of patient-derived breast cancer cells to verify the inhibitory effect of HN-1. RESULTS: HN-1 induced ICD in TNBC in a process during which damage-associated molecular patterns (DAMPs) were released that could further increase the anti-tumor immune response. The secretion level of interleukin 2 (IL-2), IL-12, and interferon γ in the co-culture supernatant was increased, and dendritic cells (DCs) were activated via a co-culture with HN-1-pretreated TNBC cells. As a result, HN-1 increased the infiltration of anti-tumor immune cells (DCs and T lymphocytes) in the mouse model bearing both 4T1 and EMT6 tumors. Meanwhile, regulatory T cells and myeloid-derived suppressor cells were suppressed. In addition, HN-1 induced DNA damage, and double-strand DNA release in the cytosol was significantly enhanced, indicating that HN-1 might stimulate ICD via activation of STING pathway. The knockdown of STING inhibited HN-1-induced ICD. Of note, HN-1 exhibited inhibitory effects on patient-derived breast cancer cells under three-dimensional culture conditions. CONCLUSIONS: Collectively, our study demonstrated that HN-1 could be utilized as a potential compound that might augment immunotherapy effects in patients with TNBC.

Remodeling tumor-associated macrophage for anti-cancer effects by rational design of irreversible inhibition of mitogen-activated protein kinase-activated protein kinase 2.

Mitogen-activated protein kinase-activated protein kinase 2 (MK2) emerges as a pivotal target in developing anti-cancer therapies. The limitations of ATP-competitive inhibitors, due to insufficient potency and selectivity, underscore the urgent need for a covalent irreversible MK2 inhibitor. Our initial analyses of The Cancer Genome Atlas database revealed MK2's overexpression across various cancer types, especially those characterized by inflammation, linking it to poor prognosis and highlighting its significance. Investigating MK2's kinase domain led to the identification of a unique cysteine residue, enabling the creation of targeted covalent inhibitors. Compound 11 was developed, demonstrating robust MK2 inhibition (IC50 = 2.3 nM) and high selectivity. It binds irreversibly to MK2, achieving prolonged signal suppression and reducing pathological inflammatory cytokines in macrophages. Furthermore, compound 11 or MK2 knockdown can inhibit the tumor-promoting macrophage M2 phenotype in vitro and in vivo. In macrophage-rich tumor model, compound 11 notably slowed growth in a dose-dependent manner. These findings support MK2 as a promising anticancer target, especially relevant in cancers fueled by inflammation or dominated by macrophages, and provide compound 11 serving as an invaluable chemical tool for exploring MK2's functions.

Critical Review on the Effect and Mechanism of Realgar Nanoparticles on Lymphoma: State of the Art on In-Vitro Biomedical Studies.

Lymphoma is a malignant tumor caused by abnormal proliferation of lymphocytes in the lymphatic system. Conventional treatments for lymphoma often have limitations, and new therapeutic strategies need to be explored. Realgar is an ancient Chinese medicine that has been used for centuries to treat a variety of ailments due to its therapeutic potential for various diseases, including cancer. However, it is a time-consuming waste and has a low absorption rate in the gastrointestinal tract, so it has the disadvantages of oral dose, potential toxicity, and low bioavailability. Recently, the development of nanotechnology has promoted the nanization of realgar particles, which have better physicochemical properties and higher bioavailability. The antitumor activity of Realgar nanoparticles against lymphoma has been demonstrated in preclinical studies. Realgar nanoparticles exhibit cytotoxic effects by inducing apoptosis and inhibiting the growth and proliferation of lymphoma cells. Moreover, these nanoparticles exert immunomodulatory effects by enhancing the activity of immune cells and promoting the cytotoxicity of T lymphocytes against lymphoma cells. Additionally, realgar nanoparticles have been shown to inhibit tumor angiogenesis, thereby restricting the blood supply and nutrient availability to lymphoma cells. Despite promising preclinical data, further research on the role and mechanism of realgar nanoparticles in the treatment of lymphoma remains to be studied. Moreover, the translation of these findings into clinical practice requires rigorous evaluation through well-designed clinical trials. Realgar nanoparticles hold great potential as a novel therapeutic approach for lymphoma, and their development may contribute to the advancement of precision medicine in the field of oncology.

Antibody MYH9 and Antibiotic Lidamycin Inhibit the Growth and Proliferation of Lung Cancer Cells and Induce Their Apoptosis.

The aim of this study was to investigate the impact of the antibiotic lidamycin (LDM) and the targeted therapy with the antibody Myosin heavy chain 9 (MYH9) on cancer cells, aiming to provide insights for cancer treatment. In this study, antibiotics and targeted antibodies were used in cancer cells, and then their effects on cell growth, proliferation, apoptosis regulation, and related proteins were measured, and comparative analysis was conducted on the effects of different drug concentrations on the growth of cancer cells. In H460, the apoptotic effect of 2 nM LDM on cells reached 70%. LDM had a downward trend on the levels of B-cell lymphoma-2 (Bcl-2) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in cells. The inhibitory effects of LDM at different concentrations on human large cell lung cancer H460 transplanted tumor in nude mice reached 53.20% and 69.80%, and the inhibitory effects on the growth of lung adenocarcinoma transplanted tumor in nude mice reached 40.20% and 58.30%. The expression of MYH9 (myosin, heavy polypeptide 9, non-muscle) in human lung cancer tissues and adjacent tissues reached more than 80%. At the concentration of 300 µM, antibody MYH9 inhibited cell growth by 30%, and the migration rate was also reduced by 25%. The inhibitory effect of siRNA after knocking out the MYH9 gene on cancer cells reached 70%. Antibiotic LDM and targeted antibody MYH9 can inhibit the growth, proliferation, and migration of cancer cells, promote cancer cell apoptosis, and have certain clinical significance for the treatment of cancer patients.

CBX4 suppresses CD8+ T cell antitumor immunity by reprogramming glycolytic metabolism.

Rationale: CD8+ T cells undergo a series of metabolic reprogramming processes during their activation and proliferation, including increased glycolysis, decreased aerobic oxidation of sugars, increased amino acid metabolism and increased protein synthesis. However, it is still unclear what factors regulate these metabolic reprogramming processes in CD8+ T cells in the tumor immune microenvironment. Methods: T cell chromobox protein 4 (CBX4) knock-out mice models were used to determine the role of CBX4 in CD8+ T cells on the tumor immune microenvironment and tumor progression. Flow cytometry, Cut-Tag qPCR, Chip-seq, immunoprecipitation, metabolite detection, lentivirus infection and adoptive T cells transfer were performed to explore the underlying mechanisms of CBX4 knock-out in promoting CD8+ T cell activation and inhibiting tumor growth. Results: We found that CBX4 expression was induced in tumor-infiltrating CD8+ T cells and inhibited CD8+ T cell function by regulating glucose metabolism in tumor tissue. Mechanistically, CBX4 increases the expression of the metabolism-associated molecule aldolase B (Aldob) through sumoylation of trans-acting transcription factor 1 (SP1) and Krüppel-like factor 3 (KLF3). In addition, Aldob inhibits glycolysis and ATP synthesis in T cells by reducing the phosphorylation of the serine/threonine protein kinase (Akt) and ultimately suppresses CD8+ T cell function. Significantly, knocking out CBX4 may improve the efficacy of anti-PD-1 therapy by enhancing the function of CD8+ T cells in the tumor microenvironment. Conclusion: CBX4 is involved in CD8+ T cell metabolic reprogramming and functional persistence in tumor tissues, and serves as an inhibitor in CD8+ T cells' glycolysis and effector function.

A Diketopyrrolopyrrole-Based All-in-One Nanoplatform for Self-Reinforcing Mild Photothermal Therapy Cascade Immunotherapy for Tumors.

Mild photothermal therapy (PTT) has attracted attention for effectively avoiding the severe side effects associated with high-temperature tumor ablation. However, its progress is hindered by the limited availability of high-performance photothermal agents (PTAs) and the thermoresistance of cancer cells induced by heat shock reactions. Herein, this work proposes a new strategy to expand the library of high-performance organic small-molecule PTAs and utilize it to construct a multifunctional nano-theranostic platform. By incorporating additional acceptors and appropriate π-bridges, a diketopyrrolopyrrole-based dye BDB is developed, which exhibits strong absorption and bright fluorescence emission in the near-infrared (NIR) region. Subsequently, BDB is co-coated with the heat shock protein (HSP) inhibitor tanespimycin (17-AAG) using the functional amphiphilic polymers DSPE-Hyd-PEG2000-cRGD to form an all-in-one nanoplatform BAG NPs. As a result, BAG NPs can precisely target tumor tissue, guide the treatment process in real-time through NIR-II fluorescence/photoacoustic/photothermal imaging, and release 17-AAG on demand to enhance mild PTT. Additionally, the mild PTT has been demonstrated to induce immunogenic cell death (ICD) and activate a systemic anti-tumor immune response, thereby suppressing both primary and distant tumors. Overall, this study presents a multifunctional nanoplatform designed for precise mild PTT combined with immunotherapy for effective tumor treatment.

A multifaceted role of bisphosphonates from palliative care to anti-cancer therapy in solid tumors.

INTRODUCTION: Bisphosphonates (P-C-Ps) also called diphosphonates are the structural analogs of naturally occurring pyrophosphates. Bisphosphonates are traditionally used and shown to provide long-term success in the treatment and prevention of osteoporosis and other bone loss pathologies. Furthermore, bisphosphonates are gaining popularity in the present era of cancer therapeutics and prevention. The usage of bisphosphonates as adjuvant or neoadjuvant therapy, either as a single agent or combined with other chemotherapy, has been studied in different solid tumors. This review aims to present the various roles of bisphosphonates in solid tumors. DATA SOURCES: Articles in MEDLINE/PubMed and the National Institutes of Health Clinical Trials Registry (http://www. Clinicaltrials.gov) between 1 January 2011 and 1 February 2022 were extracted using MeSH terms "bisphosphonates/diphosphosphonates and mechanism," "bisphosphonates and breast cancer," "bisphosphonates and prostate cancer," "bisphosphonates and lung cancer," "bisphosphonates and cancer risk," and "bisphosphonates and adverse events." Manual searches of some major oncology journals were also conducted. DISCUSSION: This review article focuses on the antitumor activity of bisphosphonates, safety profile, and the role of bisphosphonates as preventive, neoadjuvant, and adjuvant chemotherapy. A significant improvement in overall survival and cancer-specific survival and recurrence-free survival with the usage of bisphosphonates is noted in breast cancer patients, particularly in post-menopausal women. Though great progress has been achieved in over 20 years, further research is needed to identify the subgroup of patients that are most likely to benefit from adjuvant bisphosphonate therapy and to determine regimens with greater efficacy and better safety profile.

An Overview of Nanoparticle-Based Delivery Platforms for mRNA Vaccines for Treating Cancer.

With its unique properties and potential applications, nanoparticle-based delivery platforms for messenger RNA (mRNA) vaccines have gained significant attention in recent years. Nanoparticles have the advantages of enhancing immunogenicity, targeting delivery, and improving stability, providing a new solution for drug and vaccine delivery. In some clinical studies, a variety of nanoparticle delivery platforms have been gradually applied to a wide range of vaccine applications. Current research priorities are exploring various types of nanoparticles as vaccine delivery systems to enhance vaccine stability and immunogenicity. Lipid nanoparticles (LNPs) have shown promising potential in preclinical and clinical studies on the efficient delivery of antigens to immune cells. Moreover, lipid nanoparticles and other nanoparticles for nucleic acids, especially for mRNA delivery systems, have shown vast potential for vaccine development. In this review, we present various vaccine platforms with an emphasis on nanoparticles as mRNA vaccine delivery vehicles. We describe several novel nanoparticle delivery platforms for mRNA vaccines, such as lipid-, polymer-, and protein-based nanoparticles. In addition, we provide an overview of the anti-tumor immunity of nanovaccines against different tumors in cancer immunotherapy. Finally, we outline future perspectives and remaining challenges for this promising technology of nanoparticle-based delivery platforms for vaccines.