Strategy For Cancer Treatment Research Articles

Anti-4-1BB×PDL1 Bispecific Antibody Reinvigorates Tumor-Specific Exhausted CD8+ T Cells and Enhances the Efficacy of Anti-PD1 Blockade.

To overcome the limited efficacy of immune checkpoint blockade, there is a need to find novel cancer immunotherapeutic strategies for the optimal treatment of cancer. The novel anti-4-1BB×PDL1 bispecific antibody-ABL503 (also known as TJ-L14B)-was designed to simultaneously target PDL1 and 4-1BB and demonstrated strong antitumor T-cell responses without considerable toxicity. In this study, we investigated the mechanisms by which the combination of ABL503 and anti-PD1 blockade affected the reinvigoration of exhausted tumor-infiltrating CD8+ T cells (CD8+ TIL) and antitumor efficacy. Single-cell suspensions of hepatocellular carcinoma and ovarian cancer tissues from treatment-naïve patients were used for immunophenotyping of CD8+ TILs and in vitro functional assays. Humanized hPD1/hPDL1/h4-1BB triple-knock-in mice were used to evaluate the effects of ABL503 and anti-PD1 blockade in vivo. We observed that ABL503 successfully restored the functions of 4-1BB+ exhausted CD8+ TILs, which were enriched for tumor-specific T cells but unresponsive to anti-PD1 blockade. Importantly, compared with anti-PD1 blockade alone, the combination of ABL503 and anti-PD1 blockade further enhanced the functional restoration of human CD8+ TILs in vitro. Consistently, the combination of ABL503 with anti-PD1 in vivo significantly alleviated tumor growth and induced enhanced infiltration and activation of CD8+ TILs. ABL503, a PDL1 and 4-1BB dual-targeting bispecific antibody, elicits pronounced additive tumor growth inhibition, with increased infiltration and functionality of exhausted CD8+ T cells, which in turn enhances the anticancer effects of anti-PD1 blockade. These promising findings suggest that ABL503 (TJ-L14B) in combination with PD1 inhibitors will likely further enhance therapeutic benefit in clinical trials. See related commentary by Molero-Glez et al., p. 3971.

Synergistic chemotherapy and photothermal therapy of lung cancer using MoS2 nanosheets co-loaded with silybin and doxorubicin

The active ingredient in traditional Chinese medicine, silybin (SBN), is known to inhibit the proliferation of cancer cells and synergistically enhance the anticancer effects of the chemotherapy drug doxorubicin (DOX). However, the combination of SBN and DOX faces challenges such as a lack of targeting, short half-lives, different administration routes, and pharmacokinetic processes, which prevent the drug combination from effectively targeting tumors and diminish their synergistic potential, thereby limiting their in vivo antitumor effects. In response, this study proposes the development of a novel nanocarrier system based on molybdenum disulfide (MoS₂) modified with polyethylene glycol (PEG) and sialic acid (SA) to co-deliver SBN and DOX. This system is designed to trigger the release of the drugs in response to dual stimuli of pH and near-infrared light, increasing the intracellular concentration of the drugs and enhancing their synergistic interaction. The MoS₂-LPN-SBN/DOX nanosystem circulates within the body and specifically accumulates at tumor sites due to the enhanced permeability and retention (EPR) effect and SA-mediated active targeting. Upon exposure to near-infrared light, the system provides combined chemo- and photothermal therapy, leading to significant tumor suppression. This research offers a new approach and strategy for the clinical treatment of lung cancer, suggesting a promising pathway for enhancing the efficacy of traditional therapies.

C-Myc, AKT, Hsc70, and the T-Box Transcription Factor TBX3 Form an Important Oncogenic Signaling Axis in Breast Cancer.

Breast cancer is the second leading cause of death in women globally, and it remains a health burden due to poor therapy response, cancer cell drug resistance, and the debilitating side effects associated with most therapies. One approach to addressing the need to improve breast cancer therapies has been to elucidate the mechanism(s) underpinning this disease to identify key drivers that can be targeted in molecular therapies. The T-box transcription factor, TBX3, is upregulated in breast cancer, in which it contributes to important oncogenic processes, and it has been validated as a potential therapeutic target. Here, we investigated the molecular mechanisms that upregulate TBX3 in breast cancer, and we show that it involves transcriptional activation by c-Myc, post-translational modification by AKT1 and AKT3, and interaction with the molecular chaperone Hsc70. Together, the results from this study provide evidence that c-Myc, AKT, Hsc70, and TBX3 form part of an important oncogenic pathway in breast cancer and thus reveal versatile ways of interfering with the oncogenic activity of TBX3 for the treatment of this neoplasm. Implications: Targeting the c-Myc/AKT/TBX3/Hsc70 signaling axis may be an effective treatment strategy for TBX3-driven breast cancer.

Ferroptosis-induced Cardiotoxicity and Antitumor Drugs.

The induction of regulated cell death ferroptosis in tumors is emerging as an intriguing strategy for cancer treatment. Numerous antitumor drugs (e.g., doxorubicin, etoposide, tyrosine kinase inhibitors, trastuzumab, arsenic trioxide, 5-fluorouracil) induce ferroptosis. Although this mechanism of action is interesting for fighting tumors, the clinical use of drugs that induce ferroptosis is hampered by cardiotoxicity. Besides in cancer cells, ferroptosis induced by chemotherapeutics can occur in cardiomyocytes, and this feature represents an important drawback of antitumor therapy. This inconvenience has been tackled by developing less or no cardiotoxic antitumor drugs or by discovering cardioprotective agents (e.g., berberine, propofol, fisetin, salidroside, melatonin, epigallocatechin- 3gallate, resveratrol) to use in combination with conventional chemotherapeutics. This review briefly summarizes the molecular mechanisms of ferroptosis and describes the ferroptosis dependent mechanisms responsible for cardiac toxicity developed by cancer- suffering patients following the administration of some chemotherapeutics. Additionally, the pharmacological strategies very recently proposed for potentially preventing this inconvenience are considered.

Versatile hydrogel drug carrier loading with peptide-carbon dots conjugates for efficient targeting and synergistic suppression of breast cancer cell

Breast cancer become the most prevalent malignancy and is rising up to the first leading cause of cancer-related mortality among the female people globally. Approaches for safe, specific targeting and efficient inhibition of breast cancer cells, are urgently demanded for lifting the survival rate of breast tumor-bearing patients. Herein, a versatile hydrogel drug carrier consisting of doxorubicin (DOX)-loaded hydrogel microsphere and carbon dots (CDs)-loaded peptide nanowires (DOX@PEG/PNFs-CDs) was constructed, presenting specific targeting and synergistic anti-cancer cell potencies. The hydrogel PEG microspheres with a rich porous structure benefited the drug loading efficiency, demonstrating good biodegradability and higher drug release efficiency at acidic environment. Benefiting from the RGD group of the peptide nanowires, the drug-loaded system specific targeted onto the MDA-MB-231 cells, subsequently promoting the synergistic inhibition of the cancer cell growth by DOX and metformin derived CDs. This all-in-one smart drug carrier post a promising strategy for breast cancer treatment.

Investigation of the α9-nicotinic receptor single nucleotide polymorphisms induced oncogenic properties and molecular mechanisms in breast cancer.

α9-nAChR, a subtype of nicotinic acetylcholine receptor, is significantly overexpressed in female breast cancer tumor tissues compared to normal tissues. Previous studies have proposed that specific single nucleotide polymorphisms (SNPs) in the CHRNA9 (α9-nAChR) gene are associated with an increased risk of breast cancer in interaction with smoking. The study conducted a breast cancer risk assessment of the α9-nAChR SNP rs10009228 (NM_017581.4:c.1325A > G) in the Taiwanese female population, including 308 breast cancer patients and 198 healthy controls revealed that individuals with the heterozygous A/G or A/A wild genotype have an increased susceptibility to developing breast cancer in the presence of smoking compared to carriers of the G/G variant genotype. Our investigation confirmed the presence of this missense variation, resulting in an alteration of the amino acid sequence from asparagine (N442) to serine (S442) to facilitate phosphorylation within the α9-nAchR protein. Additionally, overexpression of N442 (A/A) in breast cancer cells significantly enhanced cell survival, migration, and cancer stemness compared to S442 (G/G). Four-line triple-negative breast cancer patient-derived xenograft (TNBC-PDX) models with distinct α9-nAChR rs10009228 SNP genotypes (A/A, A/G, G/G) further demonstrated that chronic nicotine exposure accelerated tumor growth through sustained activation of the α9-nAChR downstream oncogenic AKT/ERK/STAT3 pathway, particularly in individuals with the A/G or A/A genotype. Collectively, our study established the links between genetic variations in α9-nAChR and smoking exposure in promoting breast tumor development. This emphasizes the need to consider gene-environment interactions carefully while developing effective breast cancer prevention and treatment strategies.

Exosome-mediated transfer of lncRNA RP3-340B19.3 promotes the progression of breast cancer by sponging miR-4510/MORC4 axis

BackgroundThis study aims to explore the molecular mechanism of lncRNA RP3-340B19.3 on breast cancer cell proliferation and metastasis and clinical significance of lncRNA RP3-340B19.3 for breast cancer.MethodsThe subcellular localization of lncRNA RP3-340B19.3 was identified using RNA fluorescence in situ hybridization (FISH). The expression of lncRNA RP3-340B19.3 in breast cancer cells, breast cancer tissues, as well as the serum and serum exosomes of breast cancer patients, was measured through quantitative RT-PCR. In the in vitro setting, we conducted experiments to observe the effects of RP3-340B19.3 on both cell migration and proliferation. This was achieved through the utilization of transwell migration assays as well as clone formation assays. Meanwhile, transwell migration assays and clone formation assays were used to observe the effects of MDA-MB-231-exosomes enriched in RP3-340B19.3 on breast cancer microenvironment cells MCF7 and BMMSCs. Additionally, western blotting techniques were used to assess the expression levels of proteins associated with essential cellular processes such as proliferation, apoptosis, and metastasis. In vivo, the impact of RP3-340B19.3 knockdown on tumour weight and volume was observed within a nude mice model. We aimed to delve into the intricate molecular mechanisms involving RP3-340B19.3 by using bioinformatics analysis, dual luciferase reporter gene experiments and western blotting. Moreover, the potential correlations between RP3-340B19.3 expression and various clinical pathological characteristics were analyzed.ResultsOur investigation revealed that RP3-340B19.3 was expressed in both the cytoplasm and nucleus, with a noteworthy increase in breast cancer cells. Notably, we found that RP3-340B19.3 exerted a promoting influence on the proliferation and migration of breast cancer cells, both in vitro and in vivo. MDA-MB-231-exosomes enriched in RP3-340B19.3 promoted the proliferation and migration of MCF7 and BMMSCs in vitro. Mechanistically, RP3-340B19.3 demonstrated the capability to modulate the expression of MORC4 by forming a complex with miR-4510. This interaction subsequently triggered the activation of the NF-κB and Wnt-β-catenin signaling pathways. Furthermore, our study highlighted the potential diagnostic utility of RP3-340B19.3. We discovered its presence in the serum and exosomes of breast cancer patients, showing promising efficacy as a diagnostic marker. Notably, the diagnostic potential of RP3-340B19.3 was particularly significant in relation to distinguishing between different pathological types of breast cancer and correlating with tumour diameter.ConclusionOur findings establish that RP3-340B19.3 plays a pivotal role in driving the proliferation and metastasis of breast cancer. Additionally, exosomes enriched in RP3-340B19.3 could influence MCF7 and BMMSCs in tumour microenvironment, promoting the progression of breast cancer. This discovery positions RP3-340B19.3 as a prospective novel candidate for a tumour marker, offering substantial potential in the realms of breast cancer diagnosis and treatment strategies.

Polyamine Derived Photosensitizer: A Novel Approach for Photodynamic Therapy of Cancer.

Polyamines play a pivotal role in cancer cell proliferation. The excessive polyamine requirement of these malignancies is satisfied through heightened biosynthesis and augmented extracellular uptake via the polyamine transport system (PTS) present on the cell membrane. Meanwhile, photodynamic therapy (PDT) emerges as an effective anti-cancer treatment devoid of drug resistance. Recognizing these intricacies, our study devised a novel polyamine-derived photosensitizer (PS) for targeted photodynamic treatment, focusing predominantly on pancreatic cancer cells. We synthesized and evaluated novel spermine-derived fluorescent probes (N2) and PS (N3), exhibiting selectivity towards pancreatic cancer cells via PTS. N3 showed minimal dark toxicity but significant phototoxicity upon irradiation, effectively causing cell death in vitro. A significant reduction in tumor volume was observed post-treatment with no pronounced dark toxicity using the pancreatic cancer CDX mouse model, affirming the therapeutic potential of N3. Overall, our findings introduce a promising new strategy for cancer treatment, highlighting the potential of polyamine-derived PSs in PDT.

Breast Cancer Cell Destruction Using Individually Encapsulated Cytotoxic T Lymphocytes in Polyelectrolyte Layer Coated with Dual Nanoparticles in Combination with Magnetic Exposure and Laser Irradiation

ABSTRACTCell encapsulation can protect cells from the host immune system. It is well‐known that cytotoxic T lymphocytes (CTLs) can destroy cancer cells. In this study, we individually encapsulated CTLs in a cationic polyelectrolyte in combination with two types of nanomaterials: magnetic nanoparticles (MNPs) and gold nanorods (GNRs) conjugated to anti‐human epidermal growth factor receptor‐2 (HER2) antibodies referred to as CTLs/mMNPs/PAH/GNRs@HER2. When MCF‐7 breast cancer cells were co‐cultured with CTLs/mMNPs/PAH/GNRs@HER2 and subjected to a magnetic field and laser irradiation, the viability of MCF‐7 cells was significantly decreased to 42.98 ± 0.57% in comparison to MCF‐7 cells without any treatment or MCF‐7 cells co‐cultured with CTLs (51.52 ± 0.57%). This can be a novel strategy for cancer treatment using encapsulated CTLs in polyelectrolytes and dual nanomaterials in combination with magnetic exposure and laser irradiation.

The ubiquitin-proteasome system in the tumor immune microenvironment: a key force in combination therapy.

The ubiquitin-proteasome system (UPS) plays a crucial role in modulating the proliferation, activation, and normal functioning of immune cells through the regulation of protein degradation and function. By influencing the expression of immune checkpoint-associated proteins, the UPS modulates T cell-mediated anti-tumor immune responses and can potentially facilitate the immune escape of tumor cells. Additionally, the UPS contributes to the remodeling of the tumor immunosuppressive microenvironment (TIME) by regulating B cells, dendritic cells (DCs), macrophages, and Treg cells. Targeting the UPS in conjunction with immune checkpoint-associated proteins, and combining these with other therapeutic approaches, may significantly enhance the efficacy of combination therapies and pave the way for novel cancer treatment strategies. In this review, we first summarize the composition and alterations of the TIME, with a particular emphasis on the role of the UPS in TIME and its interactions with various immune cell types. Finally, we explore the potential of combining UPS-targeted therapies with immunotherapy to substantially improve the effectiveness of immunotherapy and enhance patient survival outcomes.

Combined single cell and spatial transcriptome analysis reveals cellular heterogeneity of hedgehog pathway in gastric cancer.

Gastric cancer (GC) is one of the most common and deadly malignancies in the world. Abnormal activation of hedgehog pathway is closely related to tumor development and progression. However, potential therapeutic targets for GC based on the hedgehog pathway have not been clearly identified. In the present study, we combined single-cell sequencing data and spatial transcriptomics to deeply investigate the role of hedgehog pathway in GC. Based on a comprehensive scoring algorithm, we found that fibroblasts from GC tumor tissues were characterized by a highly enriched hedgehog pathway. By analyzing the development process of fibroblasts, we found that CCND1 plays an important role at the end stage of fibroblast development, which may be related to the formation of tumor-associated fibroblasts. Based on spatial transcriptome data, we deeply mined the role of CCND1 in fibroblasts. We found that CCND1-negative and -positive fibroblasts have distinct characteristics. Based on bulk transcriptome data, we verified that highly infiltrating CCND1 + fibroblasts are a risk factor for GC patients and can influence the immune and chemotherapeutic efficacy of GC patients. Our study provides unique insights into GC and hedgehog pathways and also new directions for cancer treatment strategies.

New treatment strategy for early hormone receptor-positive HER2-negative breast cancer: updated results of adjuvant abemaciclib trial in operable and locally advanced breast cancer

Abemaciclib is an oral inhibitor 4 and 6 (CDK4/6). Abemaciclib differs from other drugs in this group in suppression spectrum of cyclin-dependent kinases and is proven to improve survival rates in different treatment lines of metastatic breast cancer. In randomized clinical trials 3rd phase in patients with early hormone-dependent HR+ HER2 negative breast cancer high risk of progression abemaciclib in conjunction with hormone therapy significantly improves invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS). Long- term outcome studies monarchE with 5 – year follow – up of patients showed that abemaciclib adding to ET increases 5-year IDFS from 76 to 83.6% (HR0.680; 95% CI 0.599 to 0.772; p <0.001) and 5-year DRFS from 79.2% to 86.0% (HR0.675; 95% CI 0.588 to 0.774; p <0.001). Adverse events of 3rd degree and higher are registrated in 45.5% of patients in abemaciclib group and in 12,7% in control group and mainly presented by neutropenia (18.6 and 0.7%) and diarrhea (7,6 and 0.1%). Toxicity profile was expected and controlled. The reasonable dose reduction of abemaciclib did not lead to deterioration of long-term treatment result.

Intersecting evidence: Bibliometric analysis and clinical trials illuminate immunotherapy in KRAS-mutation cancer: A review.

KRAS mutations play a critical role in the development and progression of several cancers, including non-small cell lung cancer and pancreatic cancer. Despite advancements in targeted therapies, the management of KRAS-mutant tumors remains challenging. This study leverages bibliometric analysis and a comprehensive review of clinical trials to identify emerging immunotherapies and potential treatments for KRAS-related cancers. Using the Web of Science Core Collection and Citespace, we analyzed publications from January 2008 to March 2023 alongside 52 clinical trials from ClinicalTrials.gov and WHO's registry, concentrating on immune checkpoint blockades (ICBs) and novel therapies. Our study highlights an increased focus on the tumor immune microenvironment and precision therapy. Clinical trials reveal the effectiveness of ICBs and the promising potential of T-cell receptor T-cell therapy and vaccines in treating KRAS-mutant cancers. ICBs, particularly in combination therapies, stand out in managing KRAS-mutant tumors. Identifying the tumor microenvironment and gene co-mutation profiles as key research areas, our findings advocate for multidisciplinary approaches to advance personalized cancer treatment. Future research should integrate genetic, immunological, and computational studies to unveil new therapeutic targets and refine treatment strategies for KRAS-mutant cancers.

Perioperative immunotherapy in nonsmall cell lung cancer.

To evaluate and summarize the current clinical efficacy, safety, treatment patterns, and potential biomarkers, to guide future treatment strategies for nonsmall cell lung cancer (NSCLC), improve patient prognosis, and provide a scientific basis for personalized therapy. In recent years, the class of immune checkpoint inhibitors (ICIs), with programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors at the helm, has catalyzed groundbreaking advancements within the perioperative treatment milieu for NSCLC. With the positive results of several phase III clinical trials, perioperative immunotherapy has been confirmed to significantly reduce the risk of postoperative recurrence in resectable NSCLC, becoming the new standard for perioperative treatment of stages II to III NSCLC. With the advent of the perioperative immunotherapy era, clinical issues such as the selection of the treatment population, the choice of regimen, the duration of treatment, whether patients with pCR need further adjuvant therapy, and the comprehensive management of patients throughout the perioperative period have attracted widespread attention. The perioperative treatment of NSCLC has fully entered the era of immunotherapy. Multiple clinical studies have confirmed that perioperative immunotherapy can significantly improve the survival benefit of resectable stages II to III NSCLC, establishing a new standard for the perioperative treatment of stages II to III NSCLC.

Investigation of the radiosensitive properties of curcumin and temozolomide

Radiotherapy, one of the cancer treatment strategies, uses ionizing radiation to destroy cancer cells. It is very important to know the photon interaction parameters of curcumin, which has both anti-cancer and cancer-protective properties, to determine the penetration and energy accumulation in the interaction of radiation with tissue. In this work, the linear attenuation coefficient (LAC, μ), mass attenuation coefficient (MAC, μ/ρ), mean free path (MFP), half value layer (HVL), effective atomic number (Zeff), and electron density (Nel) of curcumin and temozolomide have been determined experimentally at 53.16 keV, 80.99 keV, 276.39 keV, 302.85 keV, 356.61 keV and 383.84 keV photon energies emitted from Ba133 point source by using the ULEGe detector. Besides, the radiation interaction parameters were calculated theoretically using the EpiXS software program. Also, the exposure buildup factors (EBF and EABF) of these compounds were determined up to 40 mfp in the energy range 0.015–15 MeV. The experimental and theoretical mass attenuation coefficients have been found to agree. The gamma-ray absorption efficiency of curcumin is approximately 3.89% higher than that of temozolomide. Temozolomide has approximately 25.6% higher fast neutron removal cross-section than curcumin.

The Role of circHIPK3 in Tumorigenesis and Its Potential as a Biomarker in Lung Cancer.

Lung cancer treatment and detection can be improved by the identification of new biomarkers. Novel approaches in investigating circular RNAs (circRNAs) as biomarkers have yielded promising results. A circRNA molecule circHIPK3 was found to be widely expressed in non-small-cell lung cancer (NSCLC) cells, where it plays a crucial role in lung cancer tumorigenesis. CircHIPK3 promotes lung cancer progression by sponging oncosuppressive miRNAs such as miR-124, miR-381-3p, miR-149, and miR-107, which results in increased cell proliferation, migration, and resistance to therapies. Inhibiting circHIPK3 has been demonstrated to suppress tumour growth and induce apoptosis, which suggests its potential use in the development of new lung cancer treatment strategies targeting circHIPK3-related pathways. As a biomarker, circHIPK3 shows promise for early detection and monitoring of lung cancer. CircHIPK3 increased expression levels in lung cancer cells, and its potential link to metastasis risk highlights its clinical relevance. Given the promising preliminary findings, more clinical trials are needed to validate circHIPK3 efficacy as a biomarker. Moreover, future research should determine if the mechanisms discovered in NSCLC apply to small cell lung cancer (SCLC) to investigate circHIPK3-targeted therapies for SCLC.

Citrus aurantifolia-derived carbon quantum dots with red fluorescence emission for codelivery with curcumin as theranostic liposomes for lung cancer

BackgroundCarbon dots (CDs) derived from Citrus aurantifolia represent a promising platform for advanced cancer therapy and diagnostics (theranostics). These CDs are synthesized through a sustainable and cost-effective hydrothermal method, utilizing fruit juice as a green carbon source. Despite the potential, research on the synthesis of citrus-based CDs, especially regarding their red fluorescence emission, which is crucial for enhanced tissue penetration and biomedical efficacy, remains limited.ResultsIn this study, CDs were successfully synthesized from C. aurantifolia fruit, yielding nanoparticles below 5 nm in size (PDI 0.231 ± 0.04). Characterization revealed favorable optical properties, including excitation-dependent fluorescent behavior with prominent red emission under higher excitation wavelengths, a quantum yield of 8.17%, and stable photoluminescence. Chemical composition analysis using XPS, FTIR, and XRD confirmed the purity and structure of the CDs.To explore their biomedical application, CDs were co-loaded with curcumin into liposomes. The formulations had a mean size of 177.2 ± 3.6 nm (PDI 0.270 ± 0.012), demonstrated efficient drug entrapment (60.32 ± 2.24%), and exhibited rapid release kinetics, with 90.21 ± 2.16% of the drug release within 8 h. In vitro studies using A549 lung cancer cells demonstrated superior cellular uptake and cytotoxicity of Cur-CD-loaded liposomes compared to curcumin alone (Cur-Suspension), achieving IC50 values of 0.093 ± 0.011 µg/ml and 0.016 ± 0.006 µg/ml, respectively.ConclusionThis research underscores C. aurantifolia as a viable natural source for green CD synthesis. The obtained CDs with red fluorescence emission, optimized through reaction conditions and excitation wavelengths, hold promise for enhanced biological applications, particularly in the realm of lung cancer therapy. The findings advocate for further exploration and refinement of citrus-based CDs as versatile theranostic agents, capitalizing on their sustainable origins and potent biomedical properties. The combination of citrus-derived CDs with curcumin loaded into liposomal formulations represents a potent theranostic strategy for lung cancer treatment, leveraging the unique properties of CDs and their potential for targeted and effective therapy.Graphical abstract

Cu0-based nanoparticles boost anti-tumor efficacy via synergy of cuproptosis and ferroptosis enhanced by cuproptosis-induced glutathione synthesis disorder

Apoptotic resistance of tumor often leads to poor efficacy from mono-therapy based on apoptosis. Cuproptosis, a new type of non-apoptotic cell death related to mitochondrial dysfunction, can alter metabolism and enhance ferroptosis, providing a promising strategy for effective synergistic cancer treatment. In this work, Cu0-based nanoparticles (denoted as HA-ZCu) were successfully developed to improve anti-tumor efficacy by combining cuproptosis with enhanced ferroptosis, which was achieved by cuproptosis-induced glutathione synthesis disorder. In vitro studies revealed that HA-ZCu effectively induced cuproptosis and ferroptosis in HepG2 cells. Moreover, HA-ZCu induced mitochondrial dysfunction and decreased intracellular adenosine triphosphate (ATP), glutamate, and glutathione, demonstrating the effective synergy. In vivo studies further approved the synergistic therapeutic efficacy of HA-ZCu, where the inhibition rate of tumor growth reached 83.2 %. This work represents the first example of enhanced anti-tumor efficacy via cuproptosis and ferroptosis synergy through cuproptosis-induced glutathione synthesis disorder.

STING-Activating Small Molecular Therapeutics for Cancer Immunotherapy.

Immuno-oncology has become a revolutionary strategy for cancer treatment. Therapeutic interventions based on adaptive immunity through immune checkpoint therapy or chimeric antigen receptor (CAR) T cells have received clinical approval for monotherapy and combination treatment in various cancers. Although these treatments have achieved clinical successes, only a minority of cancer patients show a response, highlighting the urgent need to discover new therapeutic molecules that could be exploited to improve clinical outcomes and pave the way for the next generation of immunotherapy. Given the critical role of the innate immune system against infection and cancer, substantial efforts have been dedicated to developing novel anticancer therapeutics that target these pathways. Targeting the stimulator of interferon genes (STING) pathway is a powerful strategy to generate a durable antitumor response, and activation of the adaptor protein STING induces the initiation of transcriptional cascades, thereby producing type I interferons, pro-inflammatory cytokines and chemokines. Various STING agonists, including natural or synthetic cyclic dinucleotides (CDNs), have been developed as anticancer therapeutics. However, since most CDNs are confined to intratumoral administration, there has been a great interest in developing non-nucleotide agonists for systemic treatment. Here, we review the current development of STING-activating therapeutics in both preclinical and clinical stages.

Bcl-2 knockdown by multifunctional lipid nanoparticle and its influence in apoptosis pathway regarding cutaneous melanoma: in vitro and ex vivo studies.

Multifunctional therapies have emerged as innovative strategies in cancer treatment. In this research article, we proposed a nanostructured lipid carrier (NLC) designed for the topical treatment of cutaneous melanoma, which simultaneously delivers 5-FU and Bcl-2 siRNA. The characterized nanoparticles exhibited a diameter of 259 ± 9nm and a polydispersion index of 0.2, indicating a uniform size distribution. The NLCs were primarily localized in the epidermis, effectively minimizing the systemic release of 5-FU across skin layers. The ex vivo skin model revealed the formation of a protective lipid film, decreasing the desquamation process of the stratum corneum which can be associated to an effect of increasing permeation. In vitro assays demonstrated that A375 melanoma cells exhibited a higher sensitivity to the treatment compared to non-cancerous cells, reflecting the expected difference in their metabolic rates. The uptake of NLC by A375 cells reached approximately 90% within 4h. The efficacy of Bcl-2 knockdown was thoroughly assessed using ELISA, Western blot, and qRT-PCR analyses, revealing a significant knockdown and synergistic action of the NLC formulation containing 5-FU and Bcl-2 siRNA (at low concentration --100 pM). Notably, the silencing of Bcl-2 mRNA also impacted other members of the Bcl-2 protein family, including Mcl-1, Bcl-xl, BAX, and BAK. The observed modulation of these proteins strongly indicated the activation of the apoptosis pathway, suggesting a successful inhibition of melanoma growth and prevention of its in vitro spread.