Tumor Targeting Research Articles

The unexpected PD-L1 suppression function of celery-derived extracellular vesicles improves lung cancer chemotherapy efficacy

Aim: The article explores celery-derived extracellular vesicles (CDEVs), characterized by high cellular uptake, low immunogenicity, and high stability, as a therapeutic strategy for antitumor nanomedicines. Methods: The methods employed in this study include in vitro cell experiments such as co-culture, Western Blot, and flow cytometry. In vivo experiments were conducted in C57BL/6 tumor-bearing mice subcutaneously injected with Lewis lung carcinoma (LLC) cells. The experiments encompassed parameters such as survival rate, body weight, tumor size, flow cytometry, immunohistochemistry, and spectral live imaging system. Results: Our study revealed that CDEVs could be used as drugs to effectively downregulate the phosphorylated signal transducer and activator of transcription 3(p-STAT3)/programmed cell death ligand 1 (PD-L1) axis in lung cancer cells. In co-culture experiments, CDEVs were observed to impede the expression of PD-L1, thereby interfering with the interaction between PD-L1 and programmed death 1 (PD-1) and subsequently preventing the suppression of T cells. In in vivo distribution experiments, CDEVs loaded with paclitaxel (PTX) demonstrated better tumor targeting capabilities. Remarkably, following CDEVs-PTX treatment, CD8+ T cell levels in mice were increased, presumably leading to improved antitumor effects. Conclusion: CDEVs not only serve as drug carriers but also function as drugs themselves; as such, through a single administration of CDEVs, it is possible to combine immunotherapy and chemotherapy to achieve better effects between the two, providing a more comprehensive and effective cancer treatment strategy that promises to improve treatment outcomes and reduce the adverse effects of therapy.

Recombinant PASylated Nanobody Probes with Improved Blood Circulation and Tumor Targeting

Recombinant PASylated Nanobody Probes with Improved Blood Circulation and Tumor Targeting

Magnetic resonance imaging-guided single-fraction preoperative radiotherapy for early-stage breast cancer (the RICE trial): feasibility study

BackgroundOver the past decade, the adoption of screening programs, digital mammography, and magnetic resonance imaging (MRI) has increased early-stage breast cancer diagnosis rates. Mortality rates have decreased due to early detection and improved treatments, including personalized therapies. Accelerated partial-breast irradiation (APBI) is emerging as a convenient and effective treatment for some patients, with studies exploring its preoperative use. Preoperative APBI, especially with MRI guidance, offers improved tumor targeting and potentially reduced side effects. Magnetic Resonance Imaging-Guided Single-Fraction Pre-Operative Radiotherapy for Early-Stage Breast Cancer (RICE trial) aims to assess the feasibility and efficacy of MRI-guided single-dose radiotherapy (RT) for early-stage breast cancer.MethodsThe RICE study is a prospective, single-arm study evaluating single-fraction preoperative, APBI treatment for patients with early-stage breast cancer using a magnetic resonance imaging linear accelerator (MRI linac). Eligible patients enrolled in this study will have a core biopsy to confirm estrogen receptor-positive and HER2-negative sub-type. RT planning will use a planning computed tomography (CT) co-registered with a MRI with the patient in either the supine or prone position. For the diagnostic workup, [18F] fluorodeoxyglucose positron emission tomography/CT ([18F] FDG PET/CT) and [18F] fluoroestradiol positron emission tomography/CT ([18F] FES PET/CT) will be performed prior to treatment. Thirty patients will receive a single ablative RT dose of 21 Gray to the tumor. Pre-treatment and post-treatment MRI scans will be acquired at baseline and 5 weeks post-RT respectively. Breast-conserving surgery will be scheduled for 6 weeks after APBI treatment using the MRI linac.The primary study endpoint is the successful administration of a single fraction of preoperative breast RT under the guidance of an MRI linac. Secondary endpoints include evaluating the utility of MRI, [18F] FDG PET/CT, and [18F] FES PET/CT as a non-invasive method for assessing treatment response in patients undergoing single-fraction preoperative APBI.ConclusionThe RICE trial represents a significant step in breast cancer treatment, offering insights that could lead to treatment protocols with minimized RT appointments and enhanced patient outcomes.Trial registrationThis trial is registered with the Australian New Zealand Clinical Trials Registry (ANZCTR). Registered 31st of May 2021. Registration number: ACTRN12621000659808.

CD38 as theranostic target in oncology.

CD38 is a multifunctional transmembrane glycoprotein found in multiple tissues and overexpressed in many cancer cells, notably in hematological malignancies such as leukemia and multiple myeloma (MM). Therefore, targeting CD38 remains an attractive strategy for cancer treatment in hematological malignancies as well as in solid tumors. It plays a critical role in the progression of these diseases through its ADP-ribosyl cyclase and cADPR-hydrolase activities. Its importance has led to the development of various anti-CD38 monoclonal antibodies (mAbs), including daratumumab and isatuximab, approved for MM treatment. These mAbs exert their anti-tumor effects through Fc-dependent immune mechanisms and immunomodulation, enhancing T-cell and NK-cell-mediated responses. However, resistance mechanisms arise during the treatment with daratumumab, creating the necessity for new therapies. This review explains current knowledge about the role of CD38 as a target in oncology and aims to delineate the use of single domain antibodies (sdAbs) as innovative theranostic tools in nuclear medicine. For diagnostic purposes, PET radionuclides like 68Ga, 64Cu, and SPECT radionuclides like 99mTc and 111In, are commonly used. Significant progress has been made in anti-CD38 radioligand therapy (RLT), with anti-CD38 antibodies providing insights into tumor biology and treatment efficacy. In terms of therapy, RLT is a promising approach that offers precise targeting of malignant cells while minimizing exposure to healthy tissue. This involves the use of radionuclides emitting α particles, like 225Ac, 212Pb or 211At, and β--particles like 90Y, 131I, or 177Lu, to exert cytotoxic effects. Derived from Camelidae heavy chain antibodies, sdAbs offer advantages over conventional mAbs such as small size, high stability, specificity, and ability to recognize hidden epitopes. CD38-specific sdAbs, such as sdAb 2F8, characterized by our laboratory, showing excellent tumor targeting and their engineered constructs, such as biparatopic antibodies and chimeric antibodies, represent a new generation of theranostic agents for diagnosis and treatment CD38-expressing malignancies.

Axl and EGFR Dual-Specific Binding Affibody for Targeted Therapy in Nasopharyngeal Carcinoma

Nasopharyngeal carcinoma (NPC) is a tumor of the head and neck, with a higher incidence in southern China and Southeast Asia. Radiotherapy and chemotherapy are the main treatments; however, metastasis and recurrence remain the main causes of treatment failure. Further, the majority of patients are diagnosed in the late stage due to lack of tumor-specific biomarker for early diagnosis. Therefore, an effective treatment and early detection can improve the outcome of patient with NPC. Axl and EGFR are co-expressed in NPC tissues and play key roles in tumor proliferation, migration, and invasion, which are often correlated with poor prognosis and therapy resistance. In this study, we generated a novel bispecific affibody (Z239-1907) for the dual targeting and inhibition of Axl and EGFR expression in NPC-positive cells both in vitro and in vivo. The in vitro experiments demonstrated that Z239-1907 had more pronounced antitumor effects than either modality alone (ZAXL239 or ZEGFR1907) in NPC-positive cells. Further, mice bearing NPC-positive tumors showed significant inhibition in tumor growth after treatment with Z239-1907 compared to ZAXL239 and ZEGFR1907. The in vivo tumor targeting ability and imaging also showed that Z239-1907 specifically and selectively targeted NPC xenograft mice models and accumulate at tumor site as early as 30 min and disappeared within 24 h post-injection. Collectively, these results suggest that Z239-1907 dual-target affibody is a promising therapeutic agent and a molecular imaging probe for early diagnosis in NPC.

A simulation framework for preclinical proton irradiation workflow

Objective.The integration of proton beamlines with x-ray imaging/irradiation platforms has opened up possibilities for image-guided Bragg peak irradiations in small animals. Such irradiations allow selective targeting of normal tissue substructures and tumours. However, their small size and location pose challenges in designing experiments. This work presents a simulation framework useful for optimizing beamlines, imaging protocols, and design of animal experiments. The usage of the framework is demonstrated, mainly focusing on the imaging part.Approach.The fastCAT toolkit was modified with Monte Carlo (MC)-calculated primary and scatter data of a small animal imager for the simulation of micro-CT scans. The simulated CT of a mini-calibration phantom from fastCAT was validated against a full MC TOPAS CT simulation. A realistic beam model of a preclinical proton facility was obtained from beam transport simulations to create irradiation plans in matRad. Simulated CT images of a digital mouse phantom were generated using single-energy CT (SECT) and dual-energy CT (DECT) protocols and their accuracy in proton stopping power ratio (SPR) estimation and their impact on calculated proton dose distributions in a mouse were evaluated.Main results.The CT numbers from fastCAT agree within 11 HU with TOPAS except for materials at the centre of the phantom. Discrepancies for central inserts are caused by beam hardening issues. The root mean square deviation in the SPR for the best SECT (90 kV/Cu) and DECT (50 kV/Al-90 kV/Al) protocols are 3.7% and 1.0%, respectively. Dose distributions calculated for SECT and DECT datasets revealed range shifts <0.1 mm, gamma pass rates (3%/0.1 mm) greater than 99%, and no substantial dosimetric differences for all structures. The outcomes suggest that SECT is sufficient for proton treatment planning in animals.Significance.The framework is a useful tool for the development of an optimized experimental configuration without using animals and beam time.

Injectable nanocomposite hydrogel with cascade drug release for treatment of uveal melanoma

Uveal melanoma (UM) is the most common malignant intraocular tumor with the trait of distant metastases. Currently, the standard clinical therapy results in suboptimal outcomes due to ineffective inhibition of tumor metastasis. Thus, developing novel therapeutic modalities for UM remains a critical priority. Herein, we have developed an injectable nanocomposite hydrogel (HA-DOX/LAP gel) through integrating hyaluronic acid-based drug-loaded nanoparticles into an alginate-dopamine gel, delivering the chemotherapeutic drugs, lapatinib and doxorubicin for combinational treatment of UM. HA-DOX/LAP gel is fabricated in situ by a simple injection of the mixed precursor solution into tumor sites and maintains in vivo for more than 21 days. The entrapped drug-loaded nanoparticles can gradually release from HA-DOX/LAP gel, enhancing tumor targeting and penetration, and synchronously releasing lapatinib and doxorubicin into the acidic intracellular environment to synergistically destroy UM cells. In vivo anti-tumor studies conducted in MuM-2B tumor models demonstrated that HA-DOX/LAP gel significantly impedes tumor growth, diminishes postoperative recurrence, and prolongs overall survivals of UM tumor-bearing mice through only single injection. Remarkably, the escaped drug-loaded nanoparticles effectively reduce the risk of tumor metastases. Our findings provide new insights for the development of multifunctional nanocomposite-incorporating combination therapy against UM by targeting tumor recurrence and metastases.

Advancing Photodynamic Therapy with Nano-Conjugated Hypocrellin: Mechanisms and Clinical Applications.

Hypocrellin-based photodynamic therapy (PDT) is developing as a viable cancer therapeutic option, especially when enhanced by nanoconjugation. This review investigates the methods by which nano-conjugated hypocrellin enhances therapeutic efficacy and precision when targeting cancer cells. These nanoconjugates encapsulate or covalently bind hypocrellin photosensitizers (PSs), allowing them to accumulate preferentially in malignancies. When activated by light, the nanoconjugates produce singlet oxygen and other reactive oxygen species (ROS), resulting in oxidative stress that selectively destroys cancer cells while protecting healthy tissues. We look at how they can be used to treat a variety of cancers. Clinical and preclinical studies show that they have advantages such as increased water solubility, improved tumor penetration, longer circulation times, and tailored delivery, all of which contribute to fewer off-target effects and overall toxicity. Ongoing research focuses on improving these nanoconjugates for better tumor targeting, drug release kinetics, and overcoming biological obstacles. Furthermore, the incorporation of developing technologies such as stimuli-responsive nanocarriers and combination therapies opens exciting opportunities for enhancing hypocrellin-based PDT. In conclusion, the combination of hypocrellin and nanotechnology constitutes a significant approach to cancer treatment, increasing the efficacy and safety of PDT. Future research will seek to create conjugates including hypocrellin, herceptin, and gold nanoparticles to induce apoptosis in human breast cancer cells in vitro, opening possibilities for therapeutic applications.

5-Fluorouracil/curcumin loaded silk fibroin hydrogel for the adjuvant therapy in colorectal cancer

This study employed silk fibroin (SF) as a carrier material to encapsulate curcumin (CUR) and 5-fluorouracil (5-FU), forming a highly effective drug-loaded hydrogel. The process involved mixing SF solution containing 5-FU with curcumin solution dissolved in acetone (AC), leading to the formation of composite drug-loaded nanospheres with particle sizes ranging from 77.87 nm to 299.22 nm, demonstrated enhanced permeability and retention (EPR) effects, enabling passive targeting of solid tumors. After the formation of the nanospheres, they were dispersed into a solution containing SF and polyethylene glycol (PEG). Following gelation and PEG removal, a SF hydrogel loaded with 5-FU and CUR (5-FU/CUR@SF hydrogel) was obtained. Results indicated that the 5-FU/CUR@SF hydrogel exhibited excellent drug release properties, with 5-FU and CUR achieving sustained release of 59.66 ± 3.76 % and 47.94 ± 5.03 %, respectively, over a 400-h of sustainable releasing period. Human colorectal cancer cell line (HT-29) and normal human colon epithelial cell line (NCM-460) were cultured with the 5-FU/CUR@SF hydrogel, resulting an apoptosis rate of only 17.38 ± 1.98 % for NCM-460 cells, whereas the apoptosis rate for HT-29 cells significantly increased to 72.31 ± 2.18 %, and its cell viability dropped to 59.77 ± 0.55 %. These findings suggest that the 5-FU/CUR@SF hydrogel exhibits low cytotoxicity toward normal NCM-460 cells, while exerting significant and sustained inhibitory effects on HT-29 cancer cells. In conclusion, the SF-based drug-loaded composite hydrogel holds great potential as a novel adjuvant therapeutic strategy for the treatment of CRC.

Application of Nanoparticles in the Diagnosis and Treatment of Colorectal Cancer.

Colorectal cancer is a common malignant tumor with high morbidity and mortality rates, imposing a huge burden on both patients and the healthcare system. Traditional treatments such as surgery, chemotherapy and radiotherapy have limitations, so finding more effective diagnostic and therapeutic tools is critical to improving the survival and quality of life of colorectal cancer patients. While current tumor targeting research mainly focuses on exploring the function and mechanism of molecular targets and screening for excellent drug targets, it is crucial to test the efficacy and mechanism of tumor cell therapy that targets these molecular targets. Selecting the appropriate drug carrier is a key step in effectively targeting tumor cells. In recent years, nanoparticles have gained significant interest as gene carriers in the field of colorectal cancer diagnosis and treatment due to their low toxicity and high protective properties. Nanoparticles, synthesized from natural or polymeric materials, are NM-sized particles that offer advantages such as low toxicity, slow release, and protection of target genes during delivery. By modifying nanoparticles, they can be targeted towards specific cells for efficient and safe targeting of tumor cells. Numerous studies have demonstrated the safety, efficiency, and specificity of nanoparticles in targeting tumor cells, making them a promising gene carrier for experimental and clinical studies. This paper aims to review the current application of nanoparticles in colorectal cancer diagnosis and treatment to provide insights for targeted therapy for colorectal cancer while also highlighting future prospects for nanoparticle development.

Pulmonary Delivery of Dual-Targeted Nanoparticles Improves Tumor Accumulation and Cancer Cell Targeting by Restricting Macrophage Interception in Orthotopic Lung Tumors

Despite the recognized potential of inhaled nanomedicines to enhance and sustain local drug concentrations for lung cancer treatment, the influence of macrophage uptake on targeted nanoparticle delivery to and within tumors remains unclear. Here, we developed three ligand-coated nanoparticles for pulmonary delivery in lung cancer therapy: phenylboronic acid-modified nanoparticles (PBA-NPs), PBA combined with folic acid (FA-PBA-NPs), and PBA with mannose (MAN-PBA-NPs). In vitro, MAN-PBA-NPs were preferentially internalized by macrophages, whereas FA-PBA-NPs exhibited superior uptake by cancer cells compared to macrophages. Following intratracheal instillation into mice with orthotopic Lewis lung carcinoma tumors, all three nanoparticles showed similar lung retention. However, MAN-PBA-NPs were more prone to interception by lung macrophages, which limited their accumulation in tumor tissues. In contrast, both PBA-NPs and FA-PBA-NPs achieved comparable high tumor accumulation (∼11.3% of the dose). Furthermore, FA-PBA-NPs were internalized by ∼30% of cancer cells, significantly more than the 10-18% seen with PBA-NPs or MAN-PBA-NPs. Additionally, FA-PBA-NPs loaded with icaritin effectively inhibited the Wnt/β-catenin pathway, resulting in superior anti-tumor efficacy through targeted cancer cell delivery. Overall, FA-PBA-NPs demonstrated advantageous competitive uptake kinetics by cancer cells compared to macrophages, enhancing tumor targeting and therapeutic outcomes.

Diblock Copolymer Targeted Lipid Nanoparticles: Next-Generation Nucleic Acid Delivery System Produced by Confined Impinging Jet Mixers.

Despite the recent advances and clinical demonstration of lipid nanoparticles (LNPs) for therapeutic and prophylactic applications, the extrahepatic delivery of nucleic acids remains a significant challenge in the field. This limitation arises from the rapid desorption of lipid-PEG in the bloodstream and clearance to the liver, which hinders extrahepatic delivery. In response, we explore the substitution of lipid-PEG with biodegradable block copolymers (BCPs), specifically poly(ε-caprolactone)-block-poly(ethylene glycol) (PCL-b-PEG). BCPs offer strong anchoring for large macromolecules, potentially enhancing cell-specific targeting. To develop and optimize BCP-stabilized LNPs (BCP-LNPs), we employed a Design of Experiment (DOE) approach. Through a systematic exploration, we identified optimal formulations for BCP-LNPs, achieving desirable physicochemical properties and encapsulation efficiency. Notably, BCP-LNPs exhibit surprising trends in transfection efficiency, with certain formulations showing up to a 40-fold increase in transfection in Hela cells, while maintaining minimal cytotoxicity. The lipid compositions that optimized PCL-b-PEG LNP transfection were different from the compositions that optimized PEG-lipid LNP transfection. Furthermore, our study confirms the versatility of BCP-LNPs in encapsulating and delivering both mRNA and pDNA, demonstrating their cargo-agnostic nature. Lastly, we showcased the targeted BCP-LNPs using a Cetuximab-conjugated formulation. These targeted LNPs show significant promise in delivering cargo specific to EGFR-overexpressing cells (A549 cells), with up to 2.4 times higher transfection compared to nontargeted LNPs. This finding underscores the potential of BCP-LNPs in targeted gene therapy, especially in challenging scenarios such as tumor targeting. Overall, our study establishes the viability of BCP-LNPs as a versatile, efficient, and targeted delivery platform for nucleic acids, opening avenues for advanced therapeutic applications.

Self‐Oxygenated Biomimetic Nanozyme for Tumor Catalytic Immunotherapy

AbstractThe treatment of solid tumors remains a significant challenge due to the complex, immunosuppressive tumor microenvironment (TME). This manuscript introduces the self‐oxygenated biomimetic nanozyme system, SS‐MSN@Au‐BOM, which innovatively combines catalytic therapy with immunotherapy to modulate the TME for enhanced therapeutic efficacy. Employing mesoporous silicon nanoparticles doped with disulfide bonds, the system integrates gold nanozymes that exhibit glucose oxidase (GOx)‐like and peroxidase (POD)‐like activities, along with a catalase (CAT) function derived from bacterial outer membrane (BOM) coatings. SS‐MSN@Au‐BOM significantly disrupted tumor growth by catalyzing endogenous hydrogen peroxide to generate cytotoxic ROS and essential oxygen, enhancing intratumoral ROS levels while alleviating hypoxia. This catalytic action facilitates immunogenic cell death, enhances dendritic cell maturation, and T‐cell activation. Notably, the system shows excellent biocompatibility, effective tumor targeting, and prolonged systemic circulation. SS‐MSN@Au‐BOM offers a dual‐functional approach that effectively disrupts the TME and promotes robust antitumor immunity. This study paves the way for further clinical investigation and the development of enzyme‐based therapeutics, potentially transforming the landscape of cancer treatment.

The Dawning Era of Anticancer Nanomedicines: From First Principles to Application of Silk Nanoparticles

AbstractThis review introduces nanomedicines and medical silks by addressing seminal and recent research within these fields. First, the successes of nanoparticles in improving the safety profiles and pharmacokinetic–pharmacodynamic properties are explored but also the concepts of threshold dosing and targeting of tumor‐associated macrophages. Current barriers to systemic delivery of nanomedicines are detailed and methods to overcome these barriers and increase tumor targeting are evaluated, namely: tuning the nanomedicine size and surface charge for enhanced tumor accumulation and penetration; non‐spherical nanomedicine morphologies for macrophage evasion and targeted delivery to endothelial cells; and, surface functionalization for stealth coatings and targeting receptor‐mediated endocytosis. The advantages of using silk as a nanomedicine with reference to its structure, composition, biological performance, and formulation are discussed. While batch methods for silk processing enable the formation of nano to microparticles, continuous technology can overcome bottlenecks of the deployed engineering methods such as low throughput and poor reproducibility. Finally, the chemical modification of silk using homogeneous and heterogenous chemistries is assessed within the nanomedicine context. Overall, this review covers silk nanomedicines from first principles to carrier design and on to areas of future development.

Glycosylated AIE‐active Red Light‐triggered Photocage with Precisely Tumor Targeting Capability for Synergistic Type I Photodynamic Therapy and CPT Chemotherapy

AbstractPhotocaging is an emerging protocol for precisely manipulating spatial and temporal behaviors over biological activity. However, the red/near‐infrared light‐triggered photolysis process of current photocage is largely singlet oxygen (1O2)‐dependent and lack of compatibility with other reactive oxygen species (ROS)‐activated techniques, which has proven to be the major bottleneck in achieving efficient and precise treatment. Herein, we reported a lactosylated photocage BT‐LRC by covalently incorporating camptothecin (CPT) into hybrid BODIPY‐TPE fluorophore via the superoxide anion radical (O2−⋅)‐cleavable thioketal bond for type I photodynamic therapy (PDT) and anticancer drug release. Amphiphilic BT‐LRC could be self‐assembled into aggregation‐induced emission (AIE)‐active nanoparticles (BT‐LRCs) owing to the regulation of carbohydrate‐carbohydrate interactions (CCIs) among neighboring lactose units in the nanoaggregates. BT‐LRCs could simultaneously generate abundant O2−⋅ through the aggregation modulated by lactose interactions, and DNA‐damaging agent CPT was subsequently and effectively released. Notably, the type I PDT and CPT chemotherapy collaboratively amplified the therapeutic efficacy in HepG2 cells and tumor‐bearing mice. Furthermore, the inherent AIE property of BT‐LRCs endowed the photocaged prodrug with superior bioimaging capability, which provided a powerful tool for real‐time tracking and finely tuning the PDT and photoactivated drug release behavior in tumor therapy.

Targeted Positron Emission Tomography-Tracked Biomimetic Codelivery Synergistically Amplifies Ferroptosis and Pyroptosis for Inducing Lung Cancer Regression and Anti-PD-L1 Immunotherapy Efficacy.

The chemoresistance and systemic toxicity of cisplatin (CDDP) severely limit its application in the treatment of non-small cell lung cancer (NSCLC). Here, I-124 labeled cancer cell membrane biomimetic nanovesicles loading Polyphyllin VI (PPVI) and CDDP (termed 124I-P/C@CMLvs) were constructed to enhance the sensitivity and efficacy of CDDP. The radiochemical purity (RCP) of 124I-P/C@CMLvs reached more than 99% and maintained reliable stability in vitro. Micro-positron emission tomography (micro-PET) imaging of I-124 quantitatively revealed the distribution and specific homologous tumor targeting ability of 124I-P/C@CMLvs in vivo with superior diagnosis performance, beneficial for dynamically monitoring the efficacy against NSCLC. Loaded PPVI significantly strengthened the sensitivity of NSCLC to CDDP therapy and exerted synergistic anti-tumor effect in vitro and in vivo, which was achieved by PPVI promoting p53 deubiquitination and stimulating reactive oxygen species (ROS) production to trigger the crosstalk between the amplification of GPX4 signaling-mediated ferroptosis and NLRP3/GSDMD/Caspase-1 axis-mediated pyroptosis. 124I-P/C@CMLvs also significantly stimulated the infiltration of immune cells including dendritic cells, CD8+ T cells, and CD4+ T cells in tumor tissues (P < 0.05). The combination of 124I-P/C@CMLvs and anti-PD-L1 therapy further synergistically promoted NSCLC regression. Altogether, 124I-P/C@CMLvs provide a transformational solution to the challenge of improving CDDP sensitivity and realizing the integration of diagnosis, treatment, and monitoring of NSCLC.

BTN2A1: A Novel Target to Boost Tumor Killing Capacity of Human γδ T Cells.

γδ T cells have recently raised great interest as effector cells in cancer immunotherapy because of their HLA-independent mode of action and their broad tumor reactivity. To translate the application of γδ T cells into clinically effective immunotherapies, specific tumor targeting and/or boosting of γδ T-cell activation in vivo seem to be a critical step. In this issue, Le Floch and colleagues report a new strategy for enabling γδ T cells to be specifically activated to kill acute lymphoblastic leukemia cells and solid tumor cells using agonistic BTN2A1 antibodies. See related article by Le Floch et al., p. XX .

Accurate and Safe Tumor Targeting of Orally-administered Salmonella typhimurium A1-R Leads to Regression of an Aggressive Fibrosarcoma in Nude Mice.

Salmonella typhimurium A1-R has been shown to target and inhibit many types of cancers in mouse models without continuous infection of normal tissue. The objective of the present study was to determine the effective dose of orally-administered Salmonella typhimurium A1-R, expressing-green fluorescent protein (GFP), on an HT1080 human-fibrosarcoma nude-mouse model. The HT1080-human- fibrosarcoma nude-mouse models were randomized into the following three groups: G1: untreated control; G2: Oral Salmonella typhimurium A1-R (5×107 colony forming units [CFU]/body, twice a week, 2 weeks); G3: Oral Salmonella typhimurium A1-R (3.3×108 CFU/body, twice a week, 2 weeks). Each group comprised five mice. Body weight and tumor volume were measured twice a week. The number of colonies of Salmonella typhimurium A1-R-GFP in excised tumors and excised livers in groups G2 and G3 were determined on day 3, day 7 and 14 by growth on agar plates. Tukey-Kramer analysis was used to examine the relationships between variables. Statistically-significant results are defined as those with p≤0.05. Salmonella typhimurium A1-R was administered orally at a dose of 3.3×108 CFU, which successfully regressed the HT1080 tumor in nude mice. However, this effect was not observed at a lower dose of 5×107 CFU. After administering Salmonella typhimurium A1-R at 3.3×108 CFU, tumors and liver tissues were harvested, homogenized, and cultured on days 3, 7 and 14. Resulting GFP-expressing Salmonella typhimurium A1-R colonies were then counted. The number of GFP-bacterial colonies derived from excised tumors at intervals of 3, 7, and 14 days increased over time post-administration of oral GFP-Salmonella typhimurium. Conversely, the number of GFP-Salmonella typhimurium A1-R colonies that could be grown from excised livers decreased over time, following oral administration of GFP-Salmonella typhimurium. Additionally, the GFP-bacterial colonies grown from the excised tumors were significantly larger than those grown from the excised livers. The present study showed that an aggressive fibrosarcoma could be regressed by orally-administered Salmonella typhimurium A1-R which accurately targeted tumors without continuous growth in normal organs. The present results suggested the potential of orally-administered Salmonella typhimurium A1-R as a probiotic to treat aggressive soft-tissue sarcoma.

Emerging Frontiers in Cancer Immunotherapy: Recent Advances in CAR-NK Cell and CAR-Macrophage Therapies

Chimeric antigen receptor (CAR) cell therapies have revolutionized the field of cancer treatment with the breakthrough successes of CAR-T cell therapy in hematological malignancies. However, CAR-T cell efficacy in solid tumors has been limited by challenges such as the immunosuppressive tumor microenvironment (TME) and safety concerns like cytokine release syndrome (CRS) and graft-versus-host disease (GvHD). This review focuses on the latest advancements in CAR-NK cell and CAR-macrophage therapies, which offer potential solutions to these limitations. CAR-NK cells exhibit natural cytotoxicity and MHC-independent tumor targeting, providing a safer profile with lower risks of GvHD and CRS compared to CAR-T cells. Innovations in CAR-NK cell therapy includes structural optimizations, gene editing with CRISPR-Cas9, and the development of multispecific CARs, all contributing to enhanced anti-tumor efficacy, especially in solid tumors. Meanwhile, CAR-macrophages are effective in remodeling the TME through phagocytosis and immune activation, addressing the challenges of solid tumor infiltration. This review compares the mechanisms of action, clinical applications, and safety profiles of CAR-NK cells and CAR-macrophages, highlighting the synergistic potential of these therapies. Although clinical research on both therapies is still in its early stages, the promising preclinical and early clinical trial results underscore their potential as alternative immunotherapies for refractory cancers. Future research will focus on overcoming challenges in production scalability, improving in vivo persistence, and personalizing CAR therapies through precision medicine approaches. These two therapies will likely play pivotal roles in the next generation of cancer immunotherapies.

Polyvalent Aptamer Nanodrug Conjugates Enable Efficient Tumor Cuproptosis Therapy Through Copper Overload and Glutathione Depletion.

Cuproptosis, a recently identified form of copper-dependent cell death, shows promising tumor suppressive effects with minimal drug resistance. However, its therapeutic efficacy is hampered by its dependence on copper ions and the glutathione (GSH)-rich microenvironment in tumors. Here, we have developed polyvalent aptamer nanodrug conjugates (termed CuPEs@PApt) with a nucleosome-like structure to improve tumor cuproptosis therapy by exploiting mitochondrial copper overload and GSH depletion. Polyvalent aptamer (PApt), comprising polyvalent epithelial cell adhesion molecule aptamers for tumor targeting and repetitive PolyT sequences for copper chelation, facilitates efficient loading and targeted delivery of copper peroxide-Elesclomol nanodots (CuPEs). Upon internalization by tumor cells, Elesclomol released from CuPEs@PApt accumulates copper ions in mitochondria to initiate cuproptosis, while lysosomal degradation of CuP nanodots generates exogenous Cu2+ and H2O2, triggering a Fenton-like reaction for GSH depletion to enhance cuproptosis. In vitro and in vivo experiments confirm the efficacy of this strategy in inducing tumor cell cuproptosis and immunogenic cell death, the latter contributing to the activation of the antitumor immune response for synergistic tumor growth inhibition.