Eliminate Cancer Cells Research Articles

Natural compounds targeting miRNAs: a novel approach in oral cancer therapy.

Oral cancer (OC) is a significant global health issue, with high rates of both mortality and morbidity. Conventional treatments, including surgery, radiation, and chemotherapy, are commonly used, but they often come with serious side effects and may not fully eliminate cancer cells, resulting in recurrence and resistance to treatment. In recent years, natural products derived from plants and other biological sources have gained attention for their potential anticancer properties. These compounds offer advantages such as lower toxicity compared to traditional chemotherapy. Notable natural compounds like quercetin, berberine, curcumin, andrographolide, nimbolide, ovatodiolide, and cucurbitacin B have demonstrated effectiveness in inhibiting OC cell growth by targeting various signaling pathways involved in cancer progression. Recent breakthroughs in molecular biology have highlighted the crucial role of microRNAs (miRNAs) in the development of OC. Targeting dysregulated miRNAs with natural products offers a promising strategy for treating the disease. Natural compounds exert anticancer effects by influencing both altered cellular signaling pathways and miRNA expression profiles. This study aims to explore the role of miRNAs as potential molecular targets in OC and to investigate how natural products may regulate these miRNAs. Additionally, this review will shed light on the therapeutic potential of phytochemicals in modulating miRNA expression and their significance in OC treatment.

Near‐Infrared Nanoparticle‐Mediated Photothermal Cancer Therapy: A Comprehensive Review of Advances in Monitoring and Controlling Thermal Effects for Effective Cancer Treatment

ABSTRACTPhotothermal therapy (PTT) has emerged as a promising alternative to conventional cancer treatments such as radiation therapy, chemotherapy, and surgery. PTT uses light‐absorbing nanomaterials to induce localized hyperthermia and selectively eliminate cancer cells, thus offering advantages over traditional interventions. This literature review focuses on nanoparticles for PTT, their heating properties, and their functions in theragnostic applications for photothermal cancer treatment. It highlights the fundamental principles, recent spectroscopic developments for diagnosis and treatment monitoring, clinical advancements in near‐infrared (NIR) nanoparticle‐mediated PTT, and emerging numerical methods for preclinical planning of PTT.

Immune Checkpoint Inhibitors in the Emergency Department

Immune-checkpoint inhibitors (ICIs) have transformed the landscape for cancer treatment by enhancing the endogenous immune system’s ability to eliminate cancer cells. Tumor cells evade the body’s immune response by blocking T cell activation; ICIs function by blocking this inhibition, thereby boosting the immune system’s ability to kill tumor cells. Despite producing astonishing improvements in prognosis and remission-free time frames for cancer patients, ICIs carry risks for well documented treatment-related complications and immune-related adverse events (irAEs) that can be life-threatening. IrAEs can occur in almost any organ system, and they usually occur early in treatment, typically within the first three months. Some common complications involve the cutaneous, gastrointestinal tract, pulmonary, and endocrine organ systems. Guidelines outlining the general treatment algorithms for irAEs have been published by the Society for Immunotherapy of Cancer (SITC) and the National Comprehensive Cancer Network (NCCN). When patients present to the Emergency Department with symptoms consistent with irAEs, a rigorous and thorough infectious work-up is required, and treatment usually begins. This includes immunosuppression with corticosteroids, symptomatic treatment, and/or discontinuation of the ICI depending on the grade and severity of presentation. Early recognition and management of irAEs among ED providers, in conjunction with treating oncologists, are imperative to improve patient outcomes in the Emergency Department.

Evaluation of Annona muricata Linn Leaves Extracts from Maceration and Ultrasonic-Assisted Methods for Anticancer Activity on HLFa Cells

Non-small cell lung cancer (NSCLC) is a deadly kind of cancer that contributes significantly to the global cancer mortality rate. It is distinguished by a significant level of malignancy and unfavourable prognosis. The molecular pathways responsible for tumour invasion and migration in NSCLC are not fully understood, despite their widespread occurrence and significant consequences. Moreover, the ability of cancer cells to withstand the effects of chemical treatments presents a substantial obstacle in the creation of successful treatment approaches for NSCLC. Annona muricata Linn (A. muricata) is known to possess powerful anticancer bioactive components. A. muricata extracts have demonstrated significant therapeutic potential among a wide range of botanical compounds. However, the specific molecular interactions of the plant have not yet been revealed. This study aims to evaluate the anticancer potential of A. muricata leaves extracts on the NSCLC cell line and compare the efficacy of two different extraction methods, namely maceration extraction (ME) and ultrasonic-assisted extraction (UAE). Results showed that ME demonstrated significantly higher antioxidant activity compared to UAE, with respective percentages of 81.4% and 29.4%. However, the UAE extract demonstrated more pronounced cytotoxic effects on the NSCLC cell line (HLFa) with an IC50 value of 139.6 µg/ml, indicating a stronger antiproliferative effect on cancer cell. Both ME and UAE extracts reduced nitrite release in HLFa cell supernatants, with the ME extract showing superior activity. Treatment with ME and UAE also resulted in the activation of Caspase3/7, indicating the induction of apoptosis in HLFa cells compared to the untreated control. The extracts and Cisplatin differ approximately 0.3-fold in caspase 3/7 activation though it was not statistically significant. This activation suggests that both extraction methods effectively initiate the apoptotic cascade which is crucial for the elimination of cancer cells. Furthermore, the UAE extract significantly reduced BCL-2 mRNA levels (p<0.05). The significant reduction in BCL-2, a protein that prevents apoptosis reflect the extract’ ability to modulate key apoptotic regulators with the most significant activity when UAE extracts were used. In summary, A.muricata leaves extracts obtained through both ME and UAE methods exhibited promising anticancer effects against NSCLC, with UAE extracts exhibiting superior activity. These findings pave the way for further investigations into the use of A.muricata in cancer treatment and the development of new therapeutic agents based on its properties.

The outcome of advanced and recurrent cervical cancer patients treated with first-line platinum and paclitaxel with or without indication for immune checkpoint inhibitors: the comparative study

ObjectiveImmune checkpoint inhibitor (ICI) therapy activates the immune system to recognize and eliminate cancer cells that have escaped surveillance. This study aimed to compare the treatment outcome of advanced and recurrent cervical cancer patients treated with first-line platinum and paclitaxel with or without ICI.MethodsData from 69 advanced and recurrent cervical cancer patients treated with first-line ICI plus platinum and paclitaxel (N = 33) or first-line platinum and paclitaxel (N = 36) were reviewed between March 2020 and January 2023 in this retrospective study. Patients chose treatment based on the actual disease condition, patient willingness, and medical advice. Additionally, objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were calculated, and adverse events were gained.ResultsThere was no difference in baseline data between patients receiving the two different treatments (all P > 0.05). Complete response rate (18.2% vs. 8.3%; P = 0.294), ORR (48.5% vs. 30.6%; P = 0.127), and DCR (81.8% vs. 72.2%; P = 0.345) tended to ascend in patients treated with ICI plus platinum and paclitaxel compared to those treated with platinum and paclitaxel, although there was no statistical significance. In patients treated with ICI plus platinum and paclitaxel, the median PFS was 10.3 months and the median OS was not reached. Meanwhile, the median PFS and OS were 7.7 and 16.9 months in patients treated with platinum and paclitaxel. PFS (P = 0.036) and OS (P = 0.033) were increased in patients treated with ICI plus platinum and paclitaxel versus those treated with platinum and paclitaxel, which was verified by multivariate Cox regression analyses (both P < 0.05). No difference was observed in the occurrence of adverse events between patients receiving the two different treatments (all P > 0.05).ConclusionFirst-line ICI plus platinum and paclitaxel yields better treatment responses, longer survival, and non-differential adverse events versus first-line platinum and paclitaxel in advanced and recurrent cervical cancer patients.

Elucidating the power of arginine restriction: taming type I interferon response in breast cancer via selective autophagy

BackgroundType I interferons (IFN-I) are potent alarm factors that initiate cancer cell elimination within tumors by the immune system. This critical immune response is often suppressed in aggressive tumors, thereby facilitating cancer immune escape and unfavorable patient outcome. The mechanisms underpinning IFN-I suppression in tumors are incompletely understood. Arginase-1 (ARG1)-expressing immune cells that infiltrate tumors can restrict arginine availability by ARG1-mediated arginine degradation. We hypothesized that arginine restriction suppresses the IFN-I response in tumors.MethodsComprehensive, unbiased open approach omics analyses, various in vitro techniques, including microscopy, qPCR, immunoblotting, knock-down experiments, and flow cytometry were employed, as well as ex vivo analysis of tumor tissue from mice. Several functional bioassays were utilized to assess metabolic functions and autophagy activity in cancer cells.ResultsArginine restriction potently induced expression of selective autophagy receptors, enhanced bulk and selective autophagy and strongly suppressed the IFN-I response in cancer cells in an autophagy-dependent manner.ConclusionOur study proposes a mechanism for how tumor-infiltrating immune cells can promote cancer immune escape by dampening the IFN-I response. We suggest ARG1 and autophagy as putative therapeutic targets to activate the IFN-I response in tumors.

Two-photon photodynamic therapy with curcumin nanocomposite

Two-photon photodynamic therapy (TP-PDT) offers an innovative approach to cancer treatment that utilizes near-infrared light to activate photosensitizers and generate reactive oxygen species (ROS) for targeted cancer cell elimination. TiO2-CUR-Sofast (TCS), which uses TiO2 nanoparticles and Sofast cationic polymer to modify curcumin (CUR), has demonstrated potential as a photosensitizer under visible light irradiation, addressing the limitations of CUR's narrow spectral range and low bioavailability. This study explores the utility of the two-photon technique to activate TCS within the infrared spectrum, aiming to enhance ROS production and penetration depth compared to traditional CUR. TCS exhibits a significantly higher ROS production at 900 nm excitation wavelength, approximately 6–7 times that of CUR, signifying a substantial increase in efficiency. In TP-PDT, TCS showed significant phototoxicity against HeLa and T24 cell lines compared to CUR. Furthermore, TCS's photodynamic efficacy is further confirmed by cell apoptosis and necrosis studies, where approximately 89 % of cells treated with TCS under 900 nm light irradiation were observed in an apoptosis/necrosis state. And the TP-PDT effect in deep tissue was simulated using pig skin. It shows that the two-photon excitation has a significant penetration depth advantage over the single-photon excitation. These results indicate that the two-photon PDT scheme of TCS has greater potential than the single-photon PDT scheme in the treatment of cancer, and provides an experimental foundation for the effective treatment of deep lesions.

Modulating dual carrier-transfer channels and band structure in carbon nitride to amplify ROS storm for enhanced cancer photodynamic therapy

Graphite carbon nitride (CN) eliminates cancer cells by converting H2O2 to highly toxic •OH under visible light. However, its in vivo applications are constrained by insufficient endogenous H2O2, accumulation of OH− and finite photocarriers. We designed Fe/NV-CN, co-modified CN with nitrogen vacancies (NV) and ferric ions (Fe3+). NV and Fe3+, not only adjust the band structure of CN through quantum confinement effect and the altered coupled oscillations of atomic orbitals to facilitates •OH production by oxidizing OH−, but also construct dual carrier-transfer channels for electrons and holes to respective active sites by introducing stepped electrostatic potential and shortening three-electron bonds, thereby involving more carriers in •OH production. Fe/NV-CN, the novel reactor, effectually produces vast •OH under illumination by expanding OH− as the raw material of •OH and augmenting carriers at active sites, which induces cancer cell apoptosis by disrupting mitochondrial function for significant shrinkage of Cal27 cell-induced tumor under illumination. This work provides not only an effective photosensitizer avoiding the accumulation of OH− for cancer therapy but also a novel strategy by constructing dual carrier-transfer channels on semiconductor photosensitizers for improving the therapeutic effect of photodynamic therapy.

Clinical applications of STING agonists in cancer immunotherapy: current progress and future prospects.

The STING (Stimulator of Interferon Genes) pathway is pivotal in activating innate immunity, making it a promising target for cancer immunotherapy. STING agonists have shown potential in enhancing immune responses, particularly in tumors resistant to traditional therapies. This scholarly review examines the diverse categories of STING agonists, encompassing CDN analogues, non-CDN chemotypes, CDN-infused exosomes, engineered bacterial vectors, and hybrid structures of small molecules-nucleic acids. We highlight their mechanisms, clinical trial progress, and therapeutic outcomes. While these agents offer significant promise, challenges such as toxicity, tumor heterogeneity, and delivery methods remain obstacles to their broader clinical use. Ongoing research and innovation are essential to overcoming these hurdles. STING agonists could play a transformative role in cancer treatment, particularly for patients with hard-to-treat malignancies, by harnessing the body's immune system to target and eliminate cancer cells.

Revisiting T-cell adhesion molecules as potential targets for cancer immunotherapy: CD226 and CD2.

Cancer immunotherapy aims to initiate or amplify immune responses that eliminate cancer cells and create immune memory to prevent relapse. Immune checkpoint inhibitors (ICIs), which target coinhibitory receptors on immune effector cells, such as CTLA-4 and PD-(L)1, have made significant strides in cancer treatment. However, they still face challenges in achieving widespread and durable responses. The effectiveness of anticancer immunity, which is determined by the interplay of coinhibitory and costimulatory signals in tumor-infiltrating immune cells, highlights the potential of costimulatory receptors as key targets for immunotherapy. This review explores our current understanding of the functions of CD2 and CD226, placing a special emphasis on their potential as novel agonist targets for cancer immunotherapy. CD2 and CD226, which are present mainly on T and NK cells, serve important functions in cell adhesion and recognition. These molecules are now recognized for their costimulatory benefits, particularly in the context of overcoming T-cell exhaustion and boosting antitumor responses. The importance of CD226, especially in anti-TIGIT therapy, along with the CD2‒CD58 axis in overcoming resistance to ICI or chimeric antigen receptor (CAR) T-cell therapies provides valuable insights into advancing beyond the current barriers of cancer immunotherapy, underscoring their promise as targets for novel agonist therapy.

Metallic-based phthalocyanine nanoemulsions for photodynamic purging of ovarian tissue in leukemia patients

For cancer patients with a high risk of ovarian tissue metastasis, ovarian autotransplantation is not advised due to the potential spread of malignant cells. Ex vivo purging of ovarian fragments may offer a more suitable alternative for fertility restoration. Eradicating malignant cells should be done selectively without affecting follicles or ovarian stromal cells (SCs). As a clinically licensed method, photodynamic therapy (PDT) is a minimally invasive treatment to destroy cancer cells. This study evaluates the effectiveness of nanoemulsions (NE) containing two phthalocyanine photosensitizers; aluminum (III) phthalocyanine (AlPc) and zinc (II) phthalocyanine (ZnPc) in eliminating cancer cells. Human leukemic malignant (HL-60) and ovarian stromal cells (SCs) were treated with AlPc/ZnPc loaded NEs with or without diode laser irradiation. HL-60 leukemia cells in 2D culture were eliminated by treatment with 10nM AlPc-NE or 0.1µM ZnPc-NE, while no toxicity was observed in SCs. In 3D culture models, although the cells showed more resistance to the NEs as a result of limited oxygen and photosensitizer penetration, the treatment remained selective for cancer cells. These approaches have the potential to eliminate malignant cells from ovarian tissue fragments.

Phytochemical Profiling and Bioactive Properties of Essential Oils from Endemic Palestinian Satureja thymbrifolia.

Despite several studies on the Satureja L. genus, the chemical composition and biological activities of the traditional medicinal plant Satureja thymbrifolia (White Thyme), a Palestinian endemic species, are still unknown. It grows in arid regions and is used by Bedouins as a traditional medicinal herb. This study aimed to investigate S. thymbrifolia essential oils (EOs), mainly from its phytochemical pattern and biological properties. The GC-MS study identified p-cymene (48.53%) and thymol (23.27%) as the leading EOs components. Compared to Trolox, the EOs showed potential anti-DPPH free radical activity and had broad-spectrum antimicrobial potentials, with MIC values ranging from 0.13 ± 0.05 to 25 ± 0.00 µL/mL. They were most effective against Candida albicans species. The S. thymbrifolia EOs most effectively eliminated cancer cells when tested against CaCo-2 and HeLa cell lines (IC50 values of 192.15 ± 2.47 and 194.80 ± 1.87 µg/mL, respectively). The present investigation is the first documented study of S. thymbrifolia EOs' phytochemical composition and bioactivities. The results revealed that S. thymbrifolia EOs have potential antioxidant, antimicrobial, and cytotoxic effects. These outcomes emphasized S. thymbrifolia EO's potential dietary, pharmacological, and cosmetic applications.

Impact of Proton Irradiation Depending on Breast Cancer Subtype in Patient-Derived Cell Lines

Research on different types of ionizing radiation’s effects has been ongoing for years, revealing its efficacy in damaging cancer cells. Solid tumors comprise diverse cell types, each being able to respond differently to radiation. This study evaluated the radiobiological response of established (MDA-MB-231 (Triple negative breast cancer, TNBC), MCF-7 (Luminal A)) and patient-derived malignant cell lines, cancer-associated fibroblasts, and skin fibroblasts following proton IRR. All cell line types were irradiated with the proton dose of 2, 4, and 6 Gy. The radiobiological response was assessed using clonogenic assay, γH2AX, and p53 staining. It was noticeable that breast cancer lines of different molecular subtypes displayed no significant variations in their response to proton IRR. In terms of cancer-associated fibroblasts extracted from the tumor tissue, the line derived from a TNBC subtype tumor demonstrated higher resistance to ionizing radiation compared to lines isolated from luminal A tumors. Fibroblasts extracted from patients’ skin responded identically to all doses of proton radiation. This study emphasizes that tumor response is not exclusively determined by the elimination of breast cancer cells, but also takes into account tumor microenvironmental variables and skin reactions.

Blockade of Crk eliminates Yki/YAP-activated tumors via JNK-mediated apoptosis in Drosophila

Selective elimination of cancer cells without causing deleterious effects on normal cells is an ideal anti-cancer strategy. Here, using Drosophila cancer model, we performed an in vivo RNAi screen for anti-cancer targets that selectively eliminate tumors without affecting normal tissue growth. In Drosophila imaginal epithelium, clones of cells expressing oncogenic Ras with simultaneous mutations in the cell polarity gene scribble (RasV12/scrib−/−) develop into malignant tumors. We found that knockdown of Crk, the Drosophila ortholog of human CRK (CT10 regulatory kinase) and CRKL (Crk-like) adapter proteins, significantly suppresses growth of RasV12/scrib−/− tumors by inducing c-Jun N-terminal kinase (JNK)-mediated apoptosis, while it does not affect growth of normal epithelium. Mechanistically, Crk inhibition blocks Yorkie (Yki)/YAP activity by impairing F-actin accumulation, an upstream event of Yki/YAP activation in tumors. Inhibition of Yki/YAP in tumors causes intracellular JNK signaling to be used for apoptosis induction. Given that molecules and signaling pathways identified in Drosophila are highly conserved and activated in human cancers, our findings would provide a novel, to the best of our knowledge, anti-cancer strategy against YAP-activated cancers.

Novel protein-based prognostic signature linked to immunotherapeutic efficiency in ovarian cancer

BackgroundPersonalized medicine remains an unmet need in ovarian cancer due to its heterogeneous nature and complex immune microenvironments, which has gained increasing attention in the era of immunotherapy. A key obstacle is the lack of reliable biomarkers to identify patients who would benefit significantly from the therapy. While conventional clinicopathological factors have exhibited limited efficacy as prognostic indicators in ovarian cancer, multi-omics profiling presents a promising avenue for comprehending the interplay between the tumor and immune components. Here we aimed to leverage the individual proteomic and transcriptomic profiles of ovarian cancer patients to develop an effective protein-based signature capable of prognostication and distinguishing responses to immunotherapy.MethodsThe workflow was demonstrated based on the Reverse Phase Protein Array (RPPA) and RNA-sequencing profiles of ovarian cancer patients from The Cancer Genome Atlas (TCGA). The algorithm began by clustering patients using immune-related gene sets, which allowed us to identify immune-related proteins of interest. Next, a multi-stage process involving LASSO and Cox regression was employed to distill a prognostic signature encompassing five immune-related proteins. Based on the signature, we subsequently calculated the risk score for each patient and evaluated its prognostic performance by comparing this model with conventional clinicopathological characteristics.ResultsWe developed and validated a protein-based prognostic signature in a cohort of 377 ovarian cancer patients. The risk signature outperformed conventional clinicopathological factors, such as age, grade, stage, microsatellite instability (MSI), and homologous recombination deficiency (HRD) status, in terms of prognoses. Patients in the high-risk group had significantly unfavorable overall survival (p < 0.001). Moreover, our signature effectively stratified patients into subgroups with distinct immune landscapes. The high-risk group exhibited higher levels of CD8 T-cell infiltration and a potentially greater proportion of immunotherapy responders. The co-activation of the TGF-β pathway and cancer-associated fibroblasts could impair the ability of cytotoxic T cells to eliminate cancer cells, leading to poor outcomes in the high-risk group.ConclusionsThe protein-based signature not only aids in evaluating the prognosis but also provides valuable insights into the tumor immune microenvironments in ovarian cancer. Together our findings highlight the importance of a thorough understanding of the immunosuppressive tumor microenvironment in ovarian cancer to guide the development of more effective immunotherapies.

Sandwich Layer-Modified Ω-Shaped Fiber-Optic LSPR Enables the Development of an Aptasensor for a Cytosensing-Photothermal Therapy Circuit.

The metastasis of cancer cells is a principal cause of morbidity and mortality in cancer. The combination of a cytosensor and photothermal therapy (PTT) cannot completely eliminate cancer cells at one time. Hence, this study aimed to design a localized surface plasmonic resonance (LSPR)-based aptasensor for a circuit of cytosensing-PTT (COCP). This was achieved by coating a novel sandwich layer of polydopamine/gold nanoparticles/polydopamine (PDA/AuNPs/PDA) around the Ω-shaped fiber-optic (Ω-FO). The short-wavelength peak of the sandwich layer with strong resonance exhibited a high refractive index sensitivity (RIS). The modification with the T-shaped aptamer endowed FO-LSPR with unique characteristics of time-dependent sensitivity enhancement behavior for a sensitive cytosensor with the lowest limit of detection (LOD) of 13 cells/mL. The long-wavelength resonance peak in the sandwich layer appears in the near-infrared region. Hence, the rate of increased localized temperature of FO-LSPR was 160 and 30-fold higher than that of the bare and PDA-coated FO, indicating strong photothermal conversion efficiency. After considering the localized temperature distribution around the FO under the flow environment, the FO-LSPR-enabled aptasensor killed 77.6% of cancer cells in simulated blood circulation after five cycles of COCP. The FO-LSPR-enabled aptasensor improved the efficiency of the cytosensor and PTT to effectively kill cancer cells, showing significant potential for application in inhibiting cancer metastasis.

Photoacoustic thermal-strain measurement towards noninvasive and accurate temperature mapping in photothermal therapy

Photothermal therapy is a promising tumor treatment approach that selectively eliminates cancer cells while assuring the survival of normal cells. It transforms light energy into thermal energy, making it gentle, targeted, and devoid of radiation. However, the efficacy of treatment is hampered by the absence of accurate and noninvasive temperature measurement method in the therapy. Therefore, there is a pressing demand for a noninvasive temperature measurement method that is real-time and accurate. This article presents one such attempt based on thermal strain photoacoustic (PA) temperature measurement. The method was first modelled, and a circular array-based photoacoustic photothermal system was developed. Experiments with Indian ink as tumor simulants suggest that the temperature monitoring in this work achieves a precision of down to 0.3 °C. Furthermore, it is possible to accomplish real-time temperature imaging, providing accurate two-dimensional temperature mapping for photothermal therapy. Experiments were also conducted on human fingers and nude mice, validating promising potentials of the proposed method for practical implementations.

Enhancing cancer immunotherapy using cordycepin and Cordyceps militaris extract to sensitize cancer cells and modulate immune responses

Integrating immunotherapy with natural compounds holds promise in enhancing the immune system’s ability to eliminate cancer cells. Cordyceps militaris, a traditional Chinese medicine, emerges as a promising candidate in this regard. This study investigates the effects of cordycepin and C. militaris ethanolic extract (Cm-EE) on sensitizing cancer cells and regulating immune responses against breast cancer (BC) and hepatocellular carcinoma (HCC) cells. Cordycepin, pentostatin and adenosine were identified in Cm-EE. Cordycepin treatment decreased HLA-ABC-positive cells in pre-treated cancer cells, while Cm-EE increased NKG2D ligand and death receptor expression. Additionally, cordycepin enhanced NKG2D receptor and death ligand expression on CD3-negative effector immune cells, particularly on natural killer (NK) cells, while Cm-EE pre-treatment stimulated IL-2, IL-6, and IL-10 production. Co-culturing cancer cells with effector immune cells during cordycepin or Cm-EE incubation resulted in elevated cancer cell death. These findings highlight the potential of cordycepin and Cm-EE in improving the efficacy of cancer immunotherapy for BC and HCC.

CD91 and its ligand gp96 confer cross-priming capabilities to multiple APCs during immune responses to nascent, emerging tumors.

During cancer immunosurveillance, dendritic cells (DCs) play a central role in orchestrating T-cell responses against emerging tumors. Capture of miniscule amounts of antigen along with tumor-initiated costimulatory signals can drive maturation of DCs. Expression of CD91 on DCs is essential in cross-priming of T-cell responses in the context of nascent tumors. Multiple DC and macrophage subsets express CD91 and engage tumor-derived gp96 to initiate antitumor immune responses, yet the specific CD91+ antigen-presenting cells (APCs) that are required for T-cell cross-priming during cancer immunosurveillance are unknown. In this study, we determined that CD91 expression on type 1 conventional DCs (cDC1) is necessary for cancer immunosurveillance. Specifically, CD91-expressing cDC1 were found to capture the CD91 ligand gp96 from tumors and, upon migration to the lymph nodes, distribute gp96 among lymph-node resident APCs. However, cDC1 that captured tumor-derived gp96 only provided early tumor control, while sustained and long-term tumor rejection was bestowed to the host by other gp96+ cross-priming DCs. We further found that the CD91-induced transcriptome in APCs promoted cross-priming of T-cell responses while downregulating immune regulatory pathways. Our results show an elaborate and synchronized division of labor of APCs in the successful elimination of cancer cells via CD91. We predict that the specialized functions of APC subsets can be harnessed for immunotherapy of disease.

Novel FRET-based Immunological Synapse Biosensor for the Prediction of Chimeric Antigen Receptor-T Cell Function.

Chimeric antigen receptor (CAR)-T cell therapy has revolutionized cancer treatment. CARs are activated at the immunological synapse (IS) when their single-chain variable fragment (scFv) domain engages with an antigen, allowing them to directly eliminate cancer cells. Here, an innovative IS biosensor based on fluorescence resonance energy transfer (FRET) for the real-time assessment of CAR-IS architecture and signaling competence is presented. Using this biosensor, scFv variants for mesothelin-targeting CARs and identified as a novel scFv with enhanced CAR-T cell functionality despite its lower affinity than the original screened. The original CAR promoted internalization and trogocytosis, disrupting stable IS formation and impairing functionality are further observed. These findings emphasize the importance of enhancing IS quality rather than maximizing scFv affinity for superior CAR-T cell responses. Therefore, the FRET-based IS biosensor is a powerful tool for predicting CAR-T cell function, enabling the efficient engineering of next-generation CARs with enhanced antitumor potency.