Tumor Site Research Articles

A highly permeable nanoplatform based on functionalized carbon dots for synergistic reactive oxygen/nitrogen species tumor therapy

Reactive oxygen species (ROS)-based antitumor strategies, particularly chemodynamic therapy, have garnered considerable attention. However, challenges such as difficulties in achieving deep penetration, relatively low H2O2 levels in the tumor microenvironment, the requirement for low pH by the Fenton reaction, and their short lifespan have impeded satisfactory therapeutic outcomes. Hence, we have developed a nanoplatform with enhanced permeability that not only generates significant amounts of ROS but also converts them into longer-lasting reactive nitrogen species (RNS), thereby improving tumor therapy efficacy. In our study, carbon dots were functionalized by doping with gold atoms and grafting nitrosoglutathione (GSNO) to form ACN, which exhibits glucose oxidase-like properties and enables laser-responsive NO release. ACN and indocyanine green (ICG) were then loaded onto MnO2 nanoflowers to form MnO2@AI. Upon arrival at the tumor site, MnO2 reacts with H2O2 and GSH, leading to its degradation and the subsequent release of ACN, which is characterized by three permeation-promoting properties: ultra-small size, positive charge, and NO content. In addition, ACN promotes H2O2 production through glucose metabolism and reduces pH, both of which enhance the Fenton-like reaction of MnO2, thereby amplifying ROS generation. The ICG in MnO2@AI enhances its photothermal properties, leading to the responsive release of NO from GSNO grafted onto ACN, which then reacts with the increased ROS to generate more toxic RNS. Collectively, the approach described herein offers substantial potential for advancing the treatment of malignant tumors.

Endoscopic surgery for squamous cell carcinoma in the nasal cavity and ethmoid sinus: A retrospective observational study

ObjectiveReports of endoscopic surgery for squamous cell carcinoma of the nasal cavity and ethmoid sinus are limited. Herein, we present a comprehensive account of the results obtained from performing endoscopic surgery based on the concept of en bloc resection. MethodsThis was a retrospective observational study of patients who underwent nasal endoscopic surgery for squamous cell carcinoma of the nasal cavity and ethmoid sinus at a hospital between July 2018 and December 2021. Primary endpoints were overall survival, relapse-free survival, and local recurrence-free survival. Data on tumor stage, tumor site of origin, postoperative treatment, and papilloma-related status were reviewed. Statistical analyses included the Kaplan–Meier method, Cox regression analysis, and Fisher's exact test. ResultsTwenty-two patients with a median age of 62 (range 27–84) years, comprising 15 male and 7 female, were included in this study, and the median duration of observation was 2.1 (range 0.6–4.3) years. The 2-year overall survival, relapse-free survival, and recurrence-free survival rates were 91.0%, 69.9%, and 79.0%, respectively. Cancer of the nasal cavity was significantly superior to that of the ethmoid sinus in terms of local recurrence-free survival (p = 0.03). The patients who underwent postoperative treatment had significantly worse recurrence-free survival rates than those who did not receive postoperative treatment (p = 0.03). ConclusionsThis study examined the results of the endoscopic treatment for squamous cell carcinoma of the nasal cavity and ethmoid sinus with the concept of en bloc resection. Patients with ethmoid sinus carcinoma had a greater risk for local recurrence, and the prognosis for patients requiring postoperative treatment was poor.

High-frequency shear wave MR elastography of parotid glands: custom driver design and preliminary results.

Parotid glands are one of the most common sites for salivary gland tumors. Conventional imaging techniques have limited usefulness in the quantitative assessment of the parotid glands, making it difficult to differentiate between healthy tissue and tumors, as well as between benign and malignant tumors. Magnetic resonance elastography (MRE) is a non-invasive technique that may potentially overcome these limitations. Nevertheless, due to the size of the parotid gland, increased elastographic resolution is required. This may be achieved by applying shear waves at higher frequencies. However, it also results in stronger attenuation, making the illumination of the parotid challenging. Here, we describe a novel passive driver tailored to the anatomy of the human face, which minimizes the distance shear waves need to travel from the source to the area of interest and thus decreases shear wave attenuation, making high-frequency shear wave MRE feasible.

The prognostic value of tumor-infiltrating lymphocytes in head and neck squamous cell carcinoma: A systematic review and meta-analysis

Head and neck squamous cell carcinoma (HNSCC) is experiencing a rising incidence and mortality worldwide, emphasizing the need for reliable prognostic markers. Tumor-infiltrating lymphocytes (TILs) have emerged as a promising biomarker for predicting HNSCC prognosis, yet no systematic reviews have exclusively focused on hematoxylin and eosin (H&E)–stained formalin-fixed paraffin-embedded (FFPE) samples, which are routinely used in clinical practice. This systematic review and meta-analysis followed the PRISMA guidelines to examine the prognostic value of TILs in HNSCC using H&E-stained FFPE samples. Data were pooled from 43 studies, including 26 studies in a meta-analysis, analyzing 5037 HNSCC samples. We found that a high TIL count associated with a significantly improved overall survival (OS) (HR 0.47, 95 % CI 0.41–0.55, p < 0.0001), disease-free survival (DFS) (HR 0.55, 95 % CI 0.41–0.55, p < 0.0001), and disease-specific survival (DSS) (HR 0.58, 95 % CI 0.46–0.73, p < 0.0001). The heterogeneity was moderate for the pooled analysis (OS: I² = 40 %; DFS: I² = 39 %; DSS: I² = 51 %), but low for the subgroup analysis based on tumor site in oral, oropharyngeal, laryngeal, and nasopharyngeal cancer (OS and DFS: I² = 0–14 %). This review is the first to systematically evaluate TILs in HNSCC using H&E-stained samples, confirming their prognostic value. A high TIL count is associated with improved survival outcomes, suggesting their potential as prognostic biomarkers in clinical settings.

An Intelligent Triple Assisted Gold Cluster‐Based Nanosystem for Enhanced Tumor Photodynamic Therapy

Comprehensive SummaryPhotodynamic therapy (PDT) has been attracted a surge of research interest. However, there are several obstacles to limit the efficacy of PDT, such as hypoxic tumor microenvironment (TME), overexpressed glutathione (GSH), inefficient reactive oxygen species (ROS) generation, and so on. Herein, a smart responsive nanosystem was constructed, which was composed of Au25 modified with triphenylphosphine (Au25‐TPP), catalase (CAT) and GSH‐responsive diselenide‐bridged mesoporous silica nanoparticles (Se‐MSN). When the nanosystem arrived at tumor site, Se‐MSN was degraded by the intracellular overexpressed GSH to release Au25‐TPP and CAT. The Au25‐TPP was targeted to mitochondria and generated ROS under the 808 nm NIR laser irradiation to kill tumor cells. Simultaneously, CAT could catalyze hydrogen peroxide to provide oxygen for relieving the hypoxia of TME. Besides, GSH was consumed by the diselenide bond to diminish the ROS loss. The above tactics (mitochondria targeting, hypoxia relieving and GSH consuming) jointly enhanced the PDT efficacy. The nanosystem showed distinct in vitro anticancer effect significantly stronger than other groups containing one or two assistance. Moreover, the in vivo results suggested that the tumors could be restrained obviously. The current study provides a new inspiration for constructing novel inorganic nanomedicines with multiple enhancement effect of PDT efficacy.

Dual-emission carbon dots-based biosensor for polarity/targeting bimodal recognition and mild photothermal therapy of tumor

It is essential to develop a multifunctional nanoplatform for biosensing, tumor diagnosis and treatment simultaneously. Herein, dual-emission fluorescent carbon dots (HA-CDs) were fabricated via a one-pot solvothermal method using spinach powder as carbon source and hyaluronic acid (HA) as targeting agent. The obtained HA-CDs exhibited outstanding optical properties, good targeted tumor and excellent photothermal conversion performance. Interestingly, HA-CDs can sensitively perceive the changes in polar environments attributed to the inherent ratiometric fluorescence characteristics, and combined with the intrinsic targeting tumor ability achieved tumor cell recognition. More importantly, the HA-CDs possess good photothermal conversion efficiency of 21.2 % to be beneficial for photothermal therapy of tumors. The survival rate of HeLa cells incubated with HA-CDs dramatically decreased to 14 % after 660 nm laser irradiation, revealing the significant tumor inhibition of HA-CDs in vitro. Notably, through individual intraperitoneal and intratumoral injection, it was found that HA-CDs demonstrated a similar tumor suppressed effect on 4T1 tumor-bearing mice exposed to laser irradiation, fully uncovering that HA-CDs can efficiently accumulate at tumor site by intraperitoneal injection. Besides, the histopathological analysis of major organs ex vivo revealed a good biosafety profile. Collectively, this strategy of designed HA-CDs provides a new multifunctional nanoplatform for potential clinical application.

Expression of human epidermal growth factor receptor 2 (HER2) in colorectal cancer and its correlation with clinicopathological characteristic among Jordanian patients

Abstract Introduction/Objective Human epidermal growth factor receptor 2 (HER2/neu) is a well-established therapeutic target in breast and gastric cancers. Currently HER2 expression is being considered in other solid tumors including colorectal cancer (CRC). We aimed to investigate HER2 expression in CRC among Jordanians and its association with clinicopathological variables. Methods/Case Report Formalin-fixed, paraffin-embedded tissue blocks of 69 CRC cases were retrieved with their clinicopathological data. Tissue microarray (TMA) were constructed and immunostained using anti-HER2/neu 4B5 monoclonal antibody (Ventana, Tucson, AZ). HER2 scoring was performed by two experienced pathologists using the HERACLES criteria (HER2 positivity: cases of (3+) in ≥10% of cells and FISH-positive equivocal cases). Fisher’s exact/Chi-square test was used to investigate the association between HER2 s and clinicopathological data such as age, gender, histological differentiation, node and metastasis (NM) stage, and tumor site. Survival analysis was evaluated using Kaplan–Meier curves. Results (if a Case Study enter NA) Any degree (score) of HER2/neu expression was seen in 43.5 % of the cases. In 25 (36.2%), 4 (5.8%) and 1 (1.5%) the HER2 score was 1+, 2+ and 3+ respectively. The rest of the cases, 39 (56.5%) were scored as 0. Two of the four cases with a score (2+) required ISH testing to confirm amplification which was not performed. No significant association was found between HER2/neu expression and clinicopathological parameters or with survival. However, survival analysis showed that combined 2+/ 3+ group tend to have worse overall (OS) and event -free survival than the (0/1+) group. Conclusion The prevalence of HER2 overexpression in CRC is low among Jordanian patients, with only 1.5% of the study sample exhibiting definite HER2 overexpression. This rate is lower than the 3-5% rate reported in general, however the small sample size and lack of FISH confirmation might have contributed to this low rate. There was a trend towards worse OS and EFS in HER2 positive cases

Programmable Circular Multivalent Nanobody‐Targeting Chimeras (mNbTACs) for Multireceptor‐Mediated Protein Degradation and Targeted Drug Delivery

Multispecific therapeutics hold significant promise in drug delivery, protein degradation, and cell recruitment to address clinical issues of tumor heterogeneity, resistance, and immune evasion. However, their modular engineering remains challenging. We developed a targeted degradation platform, termed multivalent nanobody‐targeting chimeras (mNbTACs), by encoding diverse nanobody codons on a circular template using DNA printing technology. The homo‐ or hetero‐ mNbTACs specifically recognized membrane targets in a multivalent manner and simultaneously recruited scavenger receptors to favor clathrin‐/caveolae‐dependent endocytosis and lysosomal degradation of multiple proteins with high efficiency and selectivity. We demonstrated that a bispecific doxorubicin‐loaded mNbTAC, named Doxo‐mvNbsPPH, passively accumulated at tumor sites, specifically interacted with PD‐L1 and HER2 targets, and was rapidly transported into lysosome, inducing potent immunogenic cell death and alleviating immune checkpoint evasion. The synergistic boosting of innate and adaptive immunity promoted the infiltration and proliferation of CD8+ T cells in tumor microenvironment (an 11‐fold increase) with high toxicity and low exhaustion, eventually enhancing antitumor efficacy. Our mNbTAC platform provides multispecific therapeutics with variable valences and programmed species, whereas it induces targeted protein degradation through multireceptor‐mediated endocytosis and lysosomal degradation without the need for lysosome‐targeting receptors, representing a general and modular tool to harness extracellular proteome for disease treatment.

Programmable Circular Multivalent Nanobody-Targeting Chimeras (mNbTACs) for Multireceptor-Mediated Protein Degradation and Targeted Drug Delivery.

Multispecific therapeutics hold significant promise in drug delivery, protein degradation, and cell recruitment to address clinical issues of tumor heterogeneity, resistance, and immune evasion. However, their modular engineering remains challenging. We developed a targeted degradation platform, termed multivalent nanobody-targeting chimeras (mNbTACs), by encoding diverse nanobody codons on a circular template using DNA printing technology. The homo- or hetero- mNbTACs specifically recognized membrane targets in a multivalent manner and simultaneously recruited scavenger receptors to favor clathrin-/caveolae-dependent endocytosis and lysosomal degradation of multiple proteins with high efficiency and selectivity. We demonstrated that a bispecific doxorubicin-loaded mNbTAC, namedDoxo-mvNbsPPH, passively accumulated at tumor sites, specifically interacted with PD-L1and HER2targets, and was rapidly transported into lysosome, inducing potent immunogenic cell death and alleviating immune checkpoint evasion. The synergistic boosting of innate and adaptive immunity promoted the infiltration and proliferation of CD8+T cells in tumor microenvironment (an 11-fold increase) with high toxicity and low exhaustion, eventually enhancing antitumor efficacy. Our mNbTAC platform provides multispecific therapeutics with variable valences and programmed species, whereas it induces targeted protein degradation through multireceptor-mediated endocytosis and lysosomal degradation without the need for lysosome-targeting receptors, representing a general and modular tool to harness extracellular proteome for disease treatment.

The Weight of Nutrition on Post-Resection Oncologic Morbidity and Mortality: A Systematic Review and Meta-Analysis of Nutritional Indices

Abstract Context Nutritional status is a critical factor in the selection of patients for solid tumor resection. A variety of indices have been developed to quantify nutritional status, and they have differing degrees of predictive power for various postoperative outcomes. Objective This study aimed to comprehensively evaluate the predictive ability of commonly used nutritional indices in relation to postoperative complications (POCs), recurrence-free survival (RFS), and OS. Data Sources We performed a systematic review of 14 established nutritional indices from January 2015 to July 2022: Data Extraction The primary end point was OS, while the secondary end points were POCs and RFS. A subsequent meta-analysis was performed to further assess the predictive ability of these indices for OS based on general index type, primary tumor site, and the patient’s index status. Data Analysis In this evaluation, 38 articles reporting data on 23 970 patients were analyzed, focusing on 14 nutritional indices. The indices were categorized into phenotypic, metabolic, immunologic, and combined types. Patients within the cut-off range of any index were predicted to have lower OS (hazard ratio [HR] 2.14, 95% CI 1.84–2.49, P &amp;lt; .01). Lower gastrointestinal (GI) and “other” sites were less predictive than upper GI primary tumors (HR 1.63, HR 1.82, and HR 2.54, respectively; all with P &amp;lt; .01). Phenotypic indices were less predictive than combined indices (HR 1.73 vs HR 2.47, P &amp;lt; .01). Within the combined category, there was no significant difference in the predictive ability of Prognostic Nutritional Index (PNI) vs Geriatric Nutritional Risk Index (GNRI) vs Controlling Nutritional Index (CONUT) (HR 2.63 vs HR 2.42 vs HR 2.07, P = .07). Conclusion The predictive efficacy of a nutritional index was found to be highly dependent on the index type, the primary tumor site, and the outcome of interest. In the context of upper GI resections, nutritional status appeared to be more of a significant predictor of OS, compared with cases involving lower GI and hepatic malignancies. Indices that integrate phenotypic, metabolic, and immunologic patient factors potentially offer greater clinical utility in forecasting OS.

PD-1 and CTLA-4 serve as major gatekeepers for effector and cytotoxic T-cell potentiation by limiting a CXCL9/10-CXCR3-IFNγ positive feedback loop.

CXCR3 is a chemokine receptor with three ligands: CXCL9, CXCL10 and CXCL11. We report that in addition to attracting CXCR3+ T cells to tumor sites a key role of CXCL9 and CXCL10 is in inducing a self-feeding feedback loop that accelerates effector/cytotoxic activities of both CD4+ and CD8+ T cells while downregulating immunoregulatory protein TIM3. CXCR3KO mice displayed a markedly reduced response to anti-PD-1 and anti-CTLA-4 therapy. Results from a panel of in vivo and ex vivo 3D tumor models imply that, beyond driving CD8+ T cells into T-cell exhaustion, a major role of PD-1 and CTLA-4 is in limiting the CXCR3-based self-feeding mechanism of T cell potentiation. This may explain why patients that are CXCL9/CXCL10high tend to respond well to anti-PD-1 therapy, as opposed to patients that are CXCL9/CXCL10low. It also suggests a therapeutic role for CXCL9-Fc or CXCL10-Fc therapy; herein we demonstrate significant anti-tumor activity in multiple murine tumor models with such agents.

Recent advances in Tumor Treating Fields (TTFields) therapy for glioblastoma.

Tumor Treating Fields (TTFields) therapy is a locoregional, anticancer treatment consisting of a noninvasive, portable device that delivers alternating electric fields to tumors through arrays placed on the skin. Based on efficacy and safety data from global pivotal (randomized phase III) clinical studies, TTFields therapy (Optune Gio) is US Food and Drug Administration-approved for newly diagnosed (nd) and recurrent glioblastoma (GBM) and Conformité Européenne-marked for grade 4 glioma. Here we review data on the multimodal TTFields mechanism of action that includes disruption of cancer cell mitosis, inhibition of DNA replication and damage response, interference with cell motility, and enhancement of systemic antitumor immunity (adaptive immunity). We describe new data showing that TTFields therapy has efficacy in a broad range of patients, with a tolerable safety profile extending to high-risk subpopulations. New analyses of clinical study data also confirmed that overall and progression-free survival positively correlated with increased usage of the device and dose of TTFields at the tumor site. Additionally, pilot/early phase clinical studies evaluating TTFields therapy in ndGBM concomitant with immunotherapy as well as radiotherapy have shown promise, and new pivotal studies will explore TTFields therapy in these settings. Finally, we review recent and ongoing studies in patients in pediatric care, other central nervous system tumors and brain metastases, as well as other advanced-stage solid tumors (ie, lung, ovarian, pancreatic, gastric, and hepatic cancers), that highlight the broad potential of TTFields therapy as an adjuvant treatment in oncology.

Novel ultrathin ferrous sulfide nanosheets: Towards replacing black phosphorus in anticancer nanotheranostics

Biodegradable two-dimensional nanomaterials could be a significant breakthrough in the field of oncology nanotheranostic agents, which are rapidly emerging as promising candidates for tumor theranostic applications. Herein, a novel biodegradable ferrous sulfide nanosheet (FeS NS) is developed. Compared to the traditional photothermal material, black phosphorus nanosheet (BP NS), FeS demonstrates superior degradability and enhanced photothermal performance, and making it ideal for efficient photothermal therapy (PTT) of tumors. In the acidic tumor microenvironment, FeS degrades and releases H2S, which inhibits mitochondrial respiration and ATP production. This process leads to a reduction in heat shock protein expression, lowering the resistance of tumor cells to photothermal stimulation, and improving the efficacy of PTT. The released Fe2+ exhibits efficient peroxidase activity, triggering ferroptosis in tumor cells. Furthermore, due to its superparamagnetic nature, FeS NSs could accumulate at the tumor site and provide a strong magnetic resonance imaging (MRI) signal for imaging-guided tumor therapy. Overall, as a promising alternative to BP, the FeS NSs are a potentially innovative nanotheranostic agent of tumors, offering a synergistic approach to ferroptosis−PTT with MRI guidance.

Aptamer-drug conjugates-loaded bacteria for pancreatic cancer synergistic therapy

Pancreatic cancer is one of the most malignant tumors with the highest mortality rates, and it currently lacks effective drugs. Aptamer-drug conjugates (ApDC), as a form of nucleic acid drug, show great potential in cancer therapy. However, the instability of nucleic acid-based drugs in vivo and the avascularity of pancreatic cancer with dense stroma have limited their application. Fortunately, VNP20009, a genetically modified strain of Salmonella typhimurium, which has a preference for anaerobic environments, but is toxic and lacks specificity, can potentially serve as a delivery vehicle for ApDC. Here, we propose a synergistic therapy approach that combines the penetrative capability of bacteria with the targeting and toxic effects of ApDC by conjugating ApDC to VNP20009 through straightforward, one-step click chemistry. With this strategy, bacteria specifically target pancreatic cancer through anaerobic chemotaxis and subsequently adhere to tumor cells driven by the aptamer’s specific binding. Results indicate that this method prolongs the serum stability of ApDC up to 48 h and resulted in increased drug concentration at tumor sites compared to the free drugs group. Moreover, the aptamer’s targeted binding to cancer cells tripled bacterial colonization at the tumor site, leading to increased death of tumor cells and T cell infiltration. Notably, by integrating chemotherapy and immunotherapy, the effectiveness of the treatment is significantly enhanced, showing consistent results across various animal models. Overall, this strategy takes advantage of bacteria and ApDC and thus presents an effective synergistic strategy for pancreatic cancer treatment.

Alleviation of Tumor Invasion by the Development of Natural Polymerbased Low-risk Chemotherapeutic Systems - review on the Malignant Carcinoma Treatments.

The spread of tumors (48% in men and 51% in women), as well as the protection of malignant tumors by stromal cells and complex blood vessels, pose significant challenges to drug delivery to tumors. Modern chemotherapy, on the other hand, addresses tumor growth suppression by at least 60% through versatile formulation systems and numerous modifications to drug delivery systems. The renewable and naturally occurring polymers present invariably in all living cells form the fundamental foundation for most anticancer drug development. The review aims to discuss in detail the preparations of polysaccharide, lipid, and protein-based drug-loading vehicles for the targeted delivery of prominent anticancer drugs. It also provides an explanation of drug distribution in blood (cumulative releases of nearly 80% drug) and drug accumulation at tumor sites (1-5 mg/kg) due to enhanced permeability and retention (EPR). Specific delivery examples for treating colorectal and breast carcinomas have been presented to distinguish the varied drug administration, bioavailability, and tumor internalization mechanisms between sugar, fatty acid, and amino acid polymers. Current therapy possibilities based on cutting-edge literature are provided, along with drug delivery systems tailored to tumor location and invasive properties. The unique combinations of the three natural polymers provide unparalleled solutions to minimize the toxicity (<20% drug release) of the chemotherapeutic drugs on normal tissues. Moreover, the development of a consolidated drug delivery system has contributed to a substantial reduction (dose reduction from 10.43 μM to 1.9 μM) in the undesirable consequences of higher dosages of chemotherapeutic drugs. The review extensively covers safe chemotherapeutic systems with significant advantages (tumor volume shrinkage of 4T1 cells from 1000 mm3 to 200 mm3) in clinical applications of carcinoma treatments using natural polymers.

G‐Quadruplex RNA Based PROTAC Enables Targeted Degradation of RNA Binding Protein FMRP for Tumor Immunotherapy

AbstractFragile X mental retardation protein (FMRP), an RNA binding protein (RBP), is aberrantly hyper‐expressed in human tumors and plays an essential role in tumor invasion, metastasis and immune evasion. However, there is no small‐molecule inhibitor for FMRP so far. In this study, we developed the first FMRP‐targeting degrader based on PROteolysis TArgeting Chimera (PROTAC) technology and constructed a heterobifunctional PROTAC through linking a FMRP‐targeting G‐quadruplex RNA (sc1) to a von Hippel‐Lindau (VHL)‐targeting ligand peptide (named as sc1‐VHLL). Sc1‐VHLL specifically degraded endogenous FMRP via ubiquitination pathway in both mouse and human cancer cells. The FMRP degradation significantly changed the secretion pattern of cancer cells, resulting in higher expression of pro‐inflammatory cytokine and smaller amounts of immunomodulatory contents. Furthermore, sc1‐VHLL, when encapsulated into ionizable liposome nanoparticles (LNP), efficiently targeted tumor site and degraded FMRP in cancer cells. In CT26 tumor‐bearing mouse model, FMRP degradation within tumors substantially promoted the infiltration of lymphocytes and CD8 T cells and reduced the proportion of Treg cells, reshaping the proinflammatory tumor microenvironment and accordingly transforming cold tumor into hot tumor. When combined with immune checkpoint blockade (ICB) therapy, sc1‐VHLL based treatment remarkably inhibited the tumor growth.

G-Quadruplex RNA Based PROTAC Enables Targeted Degradation of RNA Binding Protein FMRP for Tumor Immunotherapy.

Fragile X mental retardation protein (FMRP), an RNA binding protein (RBP), is aberrantly hyper-expressed in human tumors and plays an essential role in tumor invasion, metastasis and immune evasion. However, there is no small-molecule inhibitor for FMRP so far. In this study, we developed the first FMRP-targeting degrader based on PROteolysis TArgeting Chimera (PROTAC) technology and constructed a heterobifunctional PROTAC through linking a FMRP-targeting G-quadruplex RNA (sc1) to a von Hippel-Lindau (VHL)-targeting ligand peptide (named as sc1-VHLL). Sc1-VHLL specifically degraded endogenous FMRP via ubiquitination pathway in both mouse and human cancer cells. The FMRP degradation significantly changed the secretion pattern of cancer cells, resulting in higher expression of pro-inflammatory cytokine and smaller amounts of immunomodulatory contents. Furthermore, sc1-VHLL, when encapsulated into ionizable liposome nanoparticles (LNP), efficiently targeted tumor site and degraded FMRP in cancer cells. In CT26 tumor-bearing mouse model, FMRP degradation within tumors substantially promoted the infiltration of lymphocytes and CD8 T cells and reduced the proportion of Treg cells, reshaping the proinflammatory tumor microenvironment and accordingly transforming cold tumor into hot tumor. When combined with immune checkpoint blockade (ICB) therapy, sc1-VHLL based treatment remarkably inhibited the tumor growth.

Two‐Step Targeting‐Tunable Semiconducting Nanoswitches Amplify Mitochondrion Damage and PD‐L1 Blockade for Orthotopic Pancreatic Cancer Therapy

AbstractPancreatic cancer is a malignancy tumor with luxuriant extracellular matrix (ECM) and highly immunosuppressive microenvironment and its therapy remains an enormous challenge. A two‐step targeting‐tunable strategy is proposed for orthotopic pancreatic cancer therapy via designing semiconducting nanoswitches (C/SPNT/αP) to amplify the mitochondrion damage and programmed death ligand 1 (PD‐L1) blockade. A mitochondrion‐targeting small nanoparticle (SPNT) consisting of mitochondrial targeting moiety triphenylphosphine (TPP) and semiconducting polymer is embedded with PD‐L1 antibody (αPD‐L1) into sono‐responsive collagen binding peptide (CBP)‐conjugated nanoliposomes to form C/SPNT/αP. In the first targeting step, C/SPNT/αP achieve ECM targeting to observably increase their enrichment into orthotopic pancreatic tumor sites because CBP can effectively bind to collagen in ECM. Upon ultrasound (US) irradiation, C/SPNT/αP mediate a sono‐responsive structural failure via sonodynamic effect for on‐demand releases of SPNT and αPD‐L1. In the second targeting step, SPNT target to mitochondria to induce mitochondrial damage under US irradiation for triggering amplified cell apoptosis and immunogenic cell death (ICD). Moreover, the released αPD‐L1 blocks the immunosuppressive pathway to further boost immunological effect. Such a novel therapeutic regimen can almost completely eradicate orthotopic pancreatic Panc02 and KPC tumors in mouse models. This study presents the first two‐step targeting‐tunable nanomedicine for treatments of deep‐seated orthotopic tumors.

Generating Immunological Memory Against Cancer by Camouflaging Gold-Based Photothermal Nanoparticles in NIR-II Biowindow for Mimicking T-Cells.

Photothermal therapy (PTT) against cancer not only directly ablates tumors but also induces tumor immunogenic cell death (ICD). However, the antitumor immune response elicited by ICD is insufficient to prevent relapse and metastasis because of the immunosuppressive tumor microenvironment (TME). A biomimetic nanoplatform (bmNP) mimicking cytotoxic lymphocytes (CTLs) for combinational photothermal-immunotherapy to effectively regulate the immunosuppressive TME is reported here. The bmNP is constructed by wrapping the T-cell membrane onto a new type of photothermal agents, spherical Au-based PNCs (sAuPNCs). Similar to T-cells, the bmNP enhanced accumulation at the tumor site by targeting the tumor via adhesion proteins on T-cell membrane. The obtained sAuPNCs have a wide absorption band in the second near-infrared (NIR-II) region with a high photothermal conversion efficiency (PCE) up to about 75% and excellent photostability. The bmNP with a smaller size is more superior compete with T-cells to bond with tumor cells via PD-1/PD-L1 interaction to effectively block the PD-1 checkpoint of T-cells for preventing T-cell exhaustion. Furthermore, in vivo studies reveal the immunological memory effect is significantly elicited in mice received bmNPs therapy. Collectively, bmNPs show great potential in photothermal-enhanced immunotherapy.

CCL21 Induces Plasmacytoid Dendritic Cell Migration and Activation in a Mouse Model of Glioblastoma

Dendritic cells (DCs) are professional antigen-presenting cells that are traditionally divided into two distinct subsets: myeloid DCs (mDCs) and plasmacytoid DCs (pDCs). pDCs are known for their ability to secrete large amounts of cytokine type I interferons (IFN- α). In our previous work, we have demonstrated that pDC infiltration promotes glioblastoma (GBM) tumor immunosuppression through decreased IFN-α secretion via TLR-9 signaling and increased suppressive function of regulatory T cells (Tregs) via increased IL-10 secretion, resulting in poor overall outcomes in mouse models of GBM. Further dissecting the overall mechanism of pDC-mediated GBM immunosuppression, in this study, we identified CCL21 as highly upregulated by multiple GBM cell lines, which recruit pDCs to tumor sites via CCL21-CCR7 signaling. Furthermore, pDCs are activated by CCL21 in the GBM microenvironment through intracellular signaling of β-arrestin and CIITA. Finally, we found that CCL21-treated pDCs directly suppress CD8+ T cell proliferation without affecting regulatory T cells (Tregs) differentiation, which is considered the canonical pathway of immunotolerant regulation. Taken together, our results show that pDCs play a multifaced role in GBM immunosuppression, and CCL21 could be a novel therapeutic target in GBM to overcome pDC-mediated immunosuppression.