Tumor Killing Research Articles

CD73/adenosine dynamics in treatment-induced pneumonitis: balancing efficacy with risks of adverse events in combined radio-immunotherapies

Consolidation with PD-1/PD-L1-based immune checkpoint blockade after concurrent platinum-based chemo-radiotherapy has become the new standard of care for advanced stage III unresectable non-small cell lung cancer (NSCLC) patients. In order to further improve therapy outcomes, innovative combinatorial treatment strategies aim to target additional immunosuppressive barriers in the tumor microenvironment such as the CD73/adenosine pathway. CD73 and adenosine are known as crucial endogenous regulators of lung homeostasis and inflammation, but also contribute to an immunosuppressive tumor microenvironment. Furthermore, the CD73/adenosine pathway can also limit the immune-activating effects of cytotoxic therapies by degrading the pro-inflammatory danger molecule ATP, which is released into the tumor microenvironment and normal lung tissue upon therapy-induced cell damage. Thus, while targeting CD73 may enhance the efficacy of radio-immunotherapies in cancer treatment by mitigating tumor immune escape and improving immune-mediated tumor killing, it also raises concerns about increased immune-related adverse events (irAEs) in the normal tissue. In fact, combined radio-immunotherapies bear an increased risk of irAEs in the lungs, and additional pharmacologic inhibition of CD73 may further enhance the risk of overwhelming or overlapping pulmonary toxicity and thereby limit therapy outcome. This review explores how therapeutic interventions targeting CD73/adenosine dynamics could enhance radiation-induced immune activation in combined radio-immunotherapies, whilst potentially driving irAEs in the lung. We specifically investigate the interactions between radiotherapy and the CD73/adenosine pathway in radiation pneumonitis. Additionally, we compare the incidence of (radiation) pneumonitis reported in relevant trials to determine if there is an increased risk of irAEs in the clinical setting. By understanding these dynamics, we aim to inform future strategies for optimizing radio-immunotherapy regimens, ensuring effective cancer control while preserving pulmonary integrity and patient quality of life.

Platinum(IV)-Backboned Polymer Prodrug-Functionalized Manganese Oxide Nanoparticles for Enhanced Lung Cancer Chemoimmunotherapy via Amplifying Stimulator of Interferon Genes Activation.

The stimulator of interferon genes (STING) pathway exhibits great potential in remodeling the immunosuppressive tumor microenvironment and initiating antitumor immunity. However, how to effectively activate STING and avoid undesired toxicity after systemic administration remains challenging. Herein, platinum(IV)-backboned polymer prodrug-coated manganese oxide nanoparticles (DHP/MnO2NP) with pH/redox dual responsive properties are developed to precisely release cisplatin and Mn2+ in the tumor microenvironment and synergistically amplify STING activation. In vitro, we demonstrate that DHP/MnO2NP can effectively induce tumor cell DNA damage and leak into the cytoplasm, cooperating with Mn2+ to promote STING activation and significantly upregulate the expression of proinflammatory cytokines. Additionally, DHP/MnO2NP can selectively release cisplatin and Mn2+ to mediate tumor killing while reducing toxicity to normal cells. In vivo, DHP/MnO2NP exerted increased therapeutic efficacy by inducing STING activation and initiating robust antitumor immunity. Specifically, DHP/MnO2NP effectively skewed tumor-associated macrophages toward a proinflammatory phenotype and upregulated the expression of proinflammatory cytokines in tumors by up to 99-fold relative to the control. And the infiltration of CD8+ T cells was also significantly increased. When STING signaling was blocked, the antitumor effects and immunostimulatory efficacy of DHP/MnO2NP were significantly inhibited. Moreover, DHP/MnO2NP possess the advantage of enhanced tumor homing and retention, resulting in stronger and longer-lasting anticancer effects. Overall, DHP/MnO2NP provide a potential platform for potentiating cancer chemoimmunotherapy and hold promise for precision treatment.

Doxorubicin prodrug for γ-glutamyl transpeptidase imaging and on-demand cancer therapy.

The γ-glutamyl transpeptidase (γ-GGT) is an important tumor marker, which has been reported to be firmly associated with the developmental stage of liver cancer. Therefore, it makes sense to image and monitor γ-GGT level and design γ-GGT-responsive prodrug for integrated diagnosis and treatment of liver cancer. Herein, we prepare a doxorubicin (Dox) prodrug for imaging γ-GGT and on-demand treating liver cancer. When γ-GGT exists, the γ-glutamyl group will be cut off to liberate free Dox for monitoring cancer progression and killing tumor cells. Fortunately, little Dox is released due to the low level of γ-GGT in normal cells, which improves the safety and efficiency of chemotherapy. To further improve the tumor targeted ability, Dox prodrug is loaded in hyaluronic acid modified liposome nanoparticles to form the nano-prodrug. Then nano-prodrug is enriched in the tumor by binding to the high expressed CD44 on cancer cells. With the assistance of anti-PD-L1, nano-prodrug effectively inhibits the growth of proximal and distal tumors.

Glycyrrhizic acid reduces neutrophil extracellular trap formation to ameliorate colitis-associated colorectal cancer by inhibiting peptidylarginine deiminase 4.

In traditional Chinese medicine, the radices of Glycyrrhiza uralensis Fisch., known as liquorice, have been used for relieving cough, alleviating pain and harmonizing the actions of all medicinals in a formula. Glycyrrhizic acid (GA), a natural compound derived from licorice, exhibits notable anti-inflammatory properties. Neutrophil extracellular trap (NET) generated by peptidylarginine deiminase 4 (PAD4) has been implicated in the progression of colitis to colitis-associated colorectal cancer (CAC). This study aims to investigate whether GA can ameliorate CAC through the inhibition of PAD4 activity and reduction of NET formation. We investigated the correlation between PAD4 expression levels and immune cell infiltration in colorectal cancer utilizing the TIMER database, while also assessing PAD4 levels and activity in human CAC biopsy samples. To evaluate the therapeutic potential of licorice acid on CAC in vivo, we employed the AOM/DSS model and confirmed its inhibitory effects on NET formation in vitro. Furthermore, we explored whether licorice acid can restore immune cell cytotoxicity by diminishing NET formation through fluorescence transfection of CT26cell lines and subsequent sorting of CD8+ T cells. Additionally, we elucidated the detrimental role of PAD4 in CAC progression using PAD4-/- mice. We observed that GA ameliorated colonic inflammation, reduced tumorigenicity, and decreased NET formation, as evidenced by decreased levels of PAD4, citH3, MPO and MMP-9. In vitro experiments demonstrated that GA effectively bound to PAD4 and inhibited its enzyme activity. Furthermore, GA prevented epithelial cell destruction while enhancing CD8+ T-cell-mediated tumor killing through the suppression of NET formation in a coculture system. We demonstrate that GA inhibits CAC occurrence by suppressing PAD4 activity and reducing NET formation.

Novel Modifications and Delivery Modes of Cyclic Dinucleotides for STING Activation in Cancer Treatment.

The microenvironment tends to be immunosuppressive during tumor growth and proliferation. Immunotherapy has attracted much attention because of its ability to activate tumor-specific immune responses for tumor killing. The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is an innate immune pathway that activates antitumor immunity by producing type I interferons. Cyclic dinucleotides (CDNs), produced by cGAS sensing cytoplasmic abnormal DNA, are major intermediate activating molecules in the STING pathway. Nowadays, CDNs and their derivatives have widely worked as powerful STING agonists in tumor immunotherapy. However, their clinical translation is hindered by the negative electrical properties, sensitivity to hydrolytic enzymes, and systemic toxicity. Recently, various CDN delivery systems have made significant progress in addressing these issues, either through monotherapy or in combination with other treatment modalities. This review details recent advances in CDNs-based pharmaceutical development or delivery strategies for enriching CDNs at tumor sites and activating the STING pathway.

Immune Checkpoint Inhibitors: Challenges and Potential Strategies

With the rapid development of science and technology, the treatment of cancer is also constantly being upgraded, but the number of cancer patients continues to grow, this has led to an increasing emphasis on such diseases. Therefore, immune checkpoint inhibitors have become the focus of our research today. In tumor cell proliferation, immune checkpoints develop as one of the ways to assist tumor cells in immune escape, so the use of immune checkpoint inhibitors can activate T cells, reduce T cell function exhaustion and inability, and achieve the purpose of killing tumor cells. In recent years, the results of PD-1, PD-L1 and CTLA-4 inhibitors have also been widely used in the treatment of patients, new treatments based on these inhibitors are also emerging. Despite the success of the ICIs in some ways, however, the researchers still found a number of factors that hindered its continued development, for example, research gaps with overall low response efficiency, therefore, new treatments need to be better improved and designed. Consequently, the research topic of this paper is the problems encountered by immune checkpoint inhibitors in this field and their solutions.

Combination of Bremachlorin PDT and immune checkpoint inhibitor anti-PD-1 shows response in murine immunological T-cell high and T-cell low PDAC models.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most challenging types of cancer with little or no response to immune checkpoint inhibitors (ICIs). Photodynamic therapy (PDT) has been shown to ablate tumors and induce an immune response. In our study, we investigated the effect of photodynamic therapy (PDT), using the photosensitizer Bremachlorin, in its ability to reduce tumor burden and to sensitize immunologically T-cell high and T-cell low murine PDAC tumors to the ICI that blocks programmed cell death-1 (PD-1) immune checkpoint. In addition, we monitored the effect on survival and investigated if there was a response in PDT-treated and non PDT-treated distant tumors. Our results showed that Bremachlorin PDT induces direct tumor killing which increased survival in both 'hot' T-cell high and 'cold' T-cell low PDAC tumors and that it can make the T-cell high tumors more sensitive to ICI blocking PD-1. We found that T-cell high tumor bearing mice had an overall greater response to therapy than T-cell low tumor bearing mice. One mouse with T-cell high tumors exhibited complete tumor regression in both the treated and non-treated distant tumor 90 days after treatment. These results indicate that combining immune checkpoint inhibitors (ICIs) with Bremachlorin PDT could be a promising therapeutic intervention for enhancing PDAC's response to therapy.

Machine Learning-Engineered Nanozyme System for Synergistic Anti-Tumor Ferroptosis/Apoptosis Therapy.

Nanozymes with multienzyme-like activity have sparked significant interest in anti-tumor therapy via responding to the tumor microenvironment (TME). However, the consequent induction of protective autophagy substantially compromises the therapeutic efficacy. Here, a targeted nanozyme system (Fe-Arg-CDs@ZIF-8/HAD, FZH) is shown, which enhances synergistic anti-tumor ferroptosis/apoptosis therapy by leveraging machine learning (ML). A novel ML model, termed the sequential backward Tree-Classifier for Gaussian Process Regression (TCGPR), is proposed to improve data pattern recognition following the divide-and-conquer principle. Based on this, a Bayesian optimization algorithm is employed to select candidates from the extensive search space. Leveraging this fresh material discovery framework, a novel strategy for enhancing nanozyme-based tumor therapy, has been developed. The results reveal that FZH effectively exerts anti-tumor effects by sequentially responding to the TME, having a cascade reaction to induce ferroptosis. Moreover, the endogenous elevation of high concentration nitric oxide (NO) serves as a direct mechanism for killing tumor cells while concurrently suppressing the protective autophagy induced by oxidative stress (OS), enhancing synergistic ferroptosis/apoptosis therapy. Overall, a novel strategy for improving nanozyme-based tumor therapy has been proposed, underlying the integration of ML, experiments, and biological applications.

The T cell-mediated tumor killing patterns revealed tumor heterogeneous and proposed treatment recommendation in ovary cancer

BackgroundImmune checkpoint inhibitors (ICIs) have greatly improved cancer treatment, but the role of genes related to T cell-mediated tumor killing (TTK) sensitivity in ovarian cancer (OV) is unclear.MethodsThis study analyzed 1367 OV patients and 11 independent cohorts. The unsupervised clustering was conducted to identify three tumor subtypes based on genes that regulate tumor cell sensitivity to TTK (GSTTKs). The biological characteristics, genetic variations, immunological landscape, and therapeutic evaluation for each subtype were further explored.ResultsPatients were divided into three reproducible subtypes based on 61 GSTKKs associated with prognosis. C1 was likely to be an invasive subtype with the worst prognosis and highly unstable genome. C2 might be an immune-active subtype with the best prognosis, high immune infiltration and preferable response to immunotherapy. C3 might be a metabolic subtype, resistant to immunotherapy, but sensitive to drug therapy. Following an extensive exploration into a variety of distinct molecular features between the three subtypes, the results suggested that C2 patients were considered to derive significant efficacy from immunotherapy. For C1 and C3 patients, chemotherapy might be an ideal treatment strategy.ConclusionsIn this study, three GSTKKs-based subtypes were identified by assessing TTK patterns in OV. These new insights further improved our understanding of GSTTKs and might refine clinical treatment strategies for OV patients.

An Activatable Heavy-Atom-Free Upconversion Photosensitizer for Targeted Imaging and Treatment of Tumors.

Photodynamic therapy (PDT) is an innovative and promising method for treating tumors that has attracted significant interest but still faces several challenges, such as a lack of selectivity, deep penetration of light, and efficient ROS generation. To address these challenges, we optimized and synthesized a series of photosensitizers and successfully developed a heavy-atom-free near-infrared FUCL photosensitizer NFh-NMe-2. This photosensitizer can generate singlet oxygen (1O2) and induce cellular apoptosis under 808 nm light. For the safe ablation of microtumors in vivo, an activatable FUCL photosensitizer NFh-NTR was developed based on the overexpression of nitroreductase (NTR). NFh-NTR could be activated by NTR, leading to the release of the photosensitizer NFh-NMe-2, restoring the fluorescence signal, and effectively killing tumor cells under 808 nm light irradiation. This work opens new possibilities in the chemical design of an FUCL photosensitizer for cancer treatment.

NIR Diradical-Featured Croconaine Nanoagent for Cancer Photoacoustic Imaging and Photothermal Therapy.

Radical-featured organic materials usually demonstrate significantly narrower bandgap than that of regular organic materials, which is beneficial for near-infrared (NIR) absorption and non-radiative decay process, making them good candidates for photothermal agents (PTAs) of photothermal therapy (PTT). However, most organic radicals are too short-lived to be separated and stable. Herein, a stable pyrylium-croconaine (CR) dye CR845 with high diradical character was synthesized and assembled into CR845 nanoparticles (NPs) to explore the photoacoustic imaging (PAI) and photothermal therapeutic performance under NIR irradiation in vitroand in vivo. CR845 exhibited a stable NIR absorption at 845 nm (ε= 3.37 × 105L mol-1cm-1) and a relatively high photothermal conversion efficiency (PCE) of 58.8%. When assembled into nanoparticles, CR845 NPs showed good photostability, good biocompatibility, favorable NIR photoacoustic potential, effective cancer cell killing and complete tumor elimination upon 850 nm laser irradiation. The work demonstrates a diradical-featured CR PTA with favorable PAI/PTT effects, which can help to provide new ideas for the development of NIR PTAs, and further promote the application of organic radical materials in the field of biomedicine.

Modified Oxygen Metabolism Toward “Sunlight‐Friendly” Photodynamic Therapy

AbstractPhototoxicity poses a substantial challenge in photodynamic therapy, resulting in intolerable skin damage, visual impairment, and reduced quality of life. Current coping strategies, primarily focus on avoiding inappropriate photoactivation and developing targeted photosensitizers, have not effectively addressed this problem. Hence, this study aims to develop a “sunlight‐friendly” photodynamic therapy strategy. Here, 1‐methoxyphenazine methosulfate (MPMS) is innovatively identified as a key substance in achieving modified oxygen metabolism. MPMS demonstrates efficient catalytic shuttling under abnormal intracellular H2O2 levels, introducing a novel protective approach for oxygen metabolism and numerous life processes. By controlling MPMS administration, the switch of the photosensitizer states between “ON” (killing tumor cells) and “OFF” (safeguarding normal cells) can be achieved. This approach effectively mitigated phototoxicity and holds the potential for widespread clinical application.

Immune Checkpoint Inhibitor-Associated Celiac Disease: A Retrospective Analysis and Literature Review.

Immune checkpoint inhibitors (ICI) are used to treat various malignancies. They block the inhibitory signals of tumor cells and enhance the inflammatory cascade, which results in tumor killing. However, this can lead to unchecked inflammation throughout the body, leading to various adverse effects. A rare gastrointestinal adverse effect of ICI therapy is the development of immune-mediated celiac disease. This entity has a similar clinical presentation to the more common ICI-induced enterocolitis. Our study aims to determine the clinical characteristics and optimal treatment strategies for this rare ICI toxicity and differentiate it from ICI-induced enterocolitis. We conducted a retrospective analysis of eight cases of ICI-induced celiac disease and 24 cases of ICI-induced enterocolitis from the literature. Data on patient demographics, clinical history, therapeutic interventions and outcomes were collected. A comparative analysis was performed to identify the key differences between the two groups. Patients with ICI-induced celiac disease were more likely to have a pre-existing autoimmune condition and HLA-DQ2 positivity. Significant differences in clinical manifestations, histological findings, and treatment outcomes were observed. Notably, weight loss, nutritional deficiencies and electrolyte abnormalities were more commonly associated with ICI-induced celiac disease. Regarding pathology, duodenal villous blunting was noted more commonly with ICI-induced celiac disease. Initiating a gluten-free diet led to a rapid improvement in patients with ICI-induced celiac disease, while immunosuppressive therapy did not have an impact. ICI-induced celiac disease is a rare and underrecognized gastrointestinal adverse effect of ICI therapy, often misdiagnosed as ICI-induced enterocolitis. Early recognition and treatment with a gluten-free diet can lead to rapid symptom resolution, sparing patients from unnecessary systemic immunosuppression and the discontinuation of antineoplastic immunotherapy.

Exploring and Anticipating the Applications of Organic Room-Temperature Phosphorescent Materials in Biomedicine and Dentistry.

As popular materials, organic room-temperature phosphorescent (RTP) materials have been studied and developed in many fields. RTP materials have the characteristics of a high signal-to-noise ratio (SNR) and high reactive oxygen species (ROS) quantum yield, which can achieve clear bioimaging and efficient ability of anti-tumor and antibacterial, and have received extensive attention from researchers for imaging, tumor therapy, and antibacterial treatment. Moreover, owing to their flexible molecular structures and various synthesis systems and methods, it may be possible to design and synthesize materials according to individual physiologic environments of patients in medical applications, making bioimaging more accurate and greatly improving tumor and bacterial killing rates. So they have great development potential in the medical field. On the basis of introducing the mechanism of RTP materials that emit phosphorescence and generate ROS, this review summarizes the medical applications of RTP materials from three aspects-bioimaging, tumor treatment and antibacterial treatment-to provide a basis for their application in the field of stomatology.

B7H6 is the predominant activating ligand driving natural killer cell-mediated killing in patients with liquid tumours: evidence from clinical, in silico, in vitro, and in vivo studies

Natural killer (NK) cells are a subset of innate lymphoid cells that are inherently capable of recognizing and killing infected or tumour cells. This has positioned NK cells as a promising live drug for tumour immunotherapy, but limited success suggests incomplete knowledge of their killing mechanism. NK cell-mediated killing involves a complex decision-making process based on integrating activating and inhibitory signals from various ligand-receptor repertoires. However, the relative importance of the different activating ligand-receptor interactions in triggering NK killing remains unclear. We employed a systematic approach combining clinical, in silico, invitro, and invivo data analysis to quantify the impact of various activating ligands. Clinical data analysis was conducted using massive pan-cancer data (n=10,595), where patients with high NK cell levels were stratified using CIBERSORT. Subsequently, multivariate Cox regression and Kaplan-Meier (KM) survival analysis were performed based on activating ligand expression. To examine the impact of ligand expression on NK killing at the cellular level, we assessed surface expression of five major activating ligands (B7H6, MICA/B, ULBP1, ULBP2/5/6, and ULBP3) of human tumour cell lines of diverse origins (n=33) via flow cytometry (FACs) and their NK cell-mediated cytotoxicity on by calcein-AM assay using human primary NK cells and NK-92cell lines. Based on this data, we quantified the contribution of each activating ligand to the NK killing activity using mathematical models and Bayesian statistics. To further validate the results, we performed calcein-AM assays upon ligand knockdown and overexpression, conjugation assays, and co-culture assays in activating ligand-downregulated/overexpressed in liquid tumour (LT) cell lines. Moreover, we established LT-xenograft mouse models to assess the efficacy of NK cell targeting toward tumours with dominant ligands. Through the clinical analysis, we discovered that among nearly all 18 activating ligands, only patients with LT who were NK cell-rich and specifically had higher B7H6 level exhibited a favorable survival outcome (p=0.0069). This unexpected dominant role of B7H6 was further confirmed by the analysis of datasets encompassing multiple ligands and a variety of tumours, which showed that B7H6 exhibited the highest contribution to NK killing among five representative ligands. Furthermore, LT cell lines (acute myeloid leukemia (AML), B cell lymphoma, and T-acute lymphocytic leukemia (ALL)) with lowered B7H6 demonstrated decreased susceptibility to NK cell-mediated cytotoxicity compared to those with higher levels. Even within the same cell line, NK cells selectively targeted cells with higher B7H6 levels. Finally, LT-xenograft mouse models (n=24) confirmed that higher B7H6 results in less tumour burden and longer survival in NK cell-treated LT mice (p=0.0022). While NK cells have gained attention for their potent anti-tumour effects without causing graft-versus-host disease (GvHD), thus making them a promising off-the-shelf therapy, our limited understanding of NK killing mechanisms has hindered their clinical application. This study illuminates the crucial role of the activating ligand B7H6 in driving NK cell killing, particularly in the context of LT. Therefore, the expression level of B7H6 could serve as a prognostic marker for patients with LT. Moreover, for the development of NK cell-based immunotherapy, focusing on increasing the level of B7H6 on its cognate receptor, NKp30, could be the most effective strategy. This work was supported by the National Research Council of Science & Technology (NST) grant (CAP-18-02-KRIBB, GTL24021-000), a National Research Foundation grant (2710012258, 2710004815), and an Institute for Basic Science grant (IBS-R029-C3).

Cooperative tumor inhibition by CpG-oligodeoxynucleotide and cyclic dinucleotide in head and neck cancer involves T helper cytokine and macrophage phenotype reprogramming

Head and neck cancer ranks as the sixth most common cancer worldwide, highlighting the critical need for the development of new therapies to enhance treatment efficacy. The activation of innate immune receptors given their potent immune stimulatory properties aid in the eradication of cancer cells. In this study, we investigated the immune mechanism and anti-tumor function of a Toll-like receptor 9 (TLR9) agonist, CpG-oligodeoxynucleotide-2722 (CpG-2722), in combination with cyclic dinucleotides, which are agonists of stimulator of interferon genes (STING). Our results revealed that CpG-2722 stimulation increased the expression of Th1 pro-inflammatory cytokines. Stimulation by STING agonists exhibited lower expression of Th1 cytokines but higher expression of Th2 cytokines compared to CpG-2722. However, the combination of these two agonists significantly enhanced Th1 cytokines while reducing Th2 cytokines. Moreover, in vivo experiment showed that both CpG-2722 and 2'3'-c-di-AMP suppressed head and neck tumor growth, with their combination proving more effective than the use of these agonists alone. The combined treatment cooperatively promoted the production of Th1 cytokines and type I interferons, while suppressing Th2 cytokines in the tumors as observed in vitro. Additionally, it led to the accumulation of M1 macrophages, dendritic cells, and T cells, shaping a favorable tumor microenvironment for T cell-mediated tumor killing. The anti-tumor activity of the CpG-2722 and 2'3'-c-di-AMP combination depends on the macrophage presence but does not directly activate M1 macrophage polarization, instead working through a reprogrammed cytokine profile. Furthermore, this combination shows a cooperative anti-tumor activity with anti-PD-1 in treating head and neck tumors. Overall, these findings highlight a Th response and macrophage phenotype reprograming involved functional mechanism underlying the cooperative activity of the combination of TLR9 and STING agonists in the immunotherapy of head and neck cancer.

The PROTAC selectively degrading BCL-XL inhibits the growth of tumors and significantly synergizes with Paclitaxel.

B-cell lymphoma extra large (BCL-XL) is an important anti-apoptotic protein of BCL-2 family. It is frequently overexpressed in various hematologic and solid tumors, often positively correlated with chemotherapy resistance in tumors. However, the clinical development of the small molecule BCL-XL inhibitor ABT-263 has been challenged on account of its on-target and dose-limiting toxicity. We have previously reported that SIAIS361034, a Proteolysis Targeting Chimera (PROTAC) specifically targeting BCL-XL to cereblon (CRBN) E3 ligase for degradation, represents a novel Hedgehog (Hh) inhibitor and inhibits tumors addiction to the Hh pathway activity with little influence on platelets. However, the inhibitory effect of SIAIS361034 on tumors independent on Hh pathway remains to be fully elucidated. In the present study, we explored its inhibitory effect on the growth of hematologic malignancies and small cell lung cancer (SCLC). Our results showed that SIAIS361034 selectively and efficiently degraded BCL-XL in tumor cells via a CRBN- and proteasome-dependent manner, with the half-maximal degradation concentration (DC50) of below 10 nM. Moreover, SIAIS361034 effectively killed BCL-XL-dependent MOLT-4 acute lymphoblastic leukemia (ALL) cells in vitro, with the half-maximal effective concentration (EC50) of 16.09 nM, and triggered apoptosis of MOLT-4 cells. SIAIS361034 obviously inhibited the growth of MOLT-4 xenografts with tumor growth inhibition rate (TGI) of 96.1 %, and did not induce acute and severe thrombocytopenia at therapeutic dosages. Furthermore, SIAIS361034 potently boosted the response of SCLC cells to Paclitaxel (PTX) and yielded more apoptosis in vitro by concurrently reduced the expression of BCL-XL and myeloid cell leukemia 1 (MCL-1), respectively. Meanwhile, we observed that SIAIS361034 significantly synergized with PTX to inhibit the growth of SCLC xenografts in vivo, without causing exacerbating PTX-induced neutropenia. Taken together, SIAIS361034, shows great potentiality in killing tumors cells, both as a monotherapy and in combination with PTX.

C/EBPβ-dependent autophagy inhibition hinders NK cell function in cancer

NK cells are endowed with tumor killing ability, nevertheless most cancers impair NK cell functionality, and cell-based therapies have limited efficacy in solid tumors. How cancers render NK cell dysfunctional is unclear, and overcoming resistance is an important immune-therapeutic aim. Here, we identify autophagy as a central regulator of NK cell anti-tumor function. Analysis of differentially expressed genes in tumor-infiltrating versus non-tumor NK cells from our previously published scRNA-seq data of advanced human prostate cancer shows deregulation of the autophagic pathway in tumor-infiltrating NK cells. We confirm this by flow cytometry in patients and in diverse cancer models in mice. We further demonstrate that exposure of NK cells to cancer deregulates the autophagic process, decreases mitochondrial polarization and impairs effector functions. Mechanistically, CCAAT enhancer binding protein beta (C/EBPβ), downstream of CXCL12-CXCR4 interaction, acts as regulator of NK cell metabolism. Accordingly, inhibition of CXCR4 and C/EBPβ restores NK cell fitness. Finally, genetic and pharmacological activation of autophagy improves NK cell effector and cytotoxic functions, which enables tumour control by NK and CAR-NK cells. In conclusion, our study identifies autophagy as an intracellular checkpoint in NK cells and introduces autophagy regulation as an approach to strengthen NK-cell-based immunotherapies.

Sequentially Activated Smart DNA Nanospheres for Photoimmunotherapy and Immune Checkpoint Blockade.

Due to the inherent immunosuppression and immune evasion of cancer cells, combining photoimmunotherapy with immune checkpoint blockade leverages phototherapy and immune enhancement, overcoming mutual limitations and demonstrating significant anticancer potential. The main challenges include nonspecific accumulation of agents, uncontrolled activation, and drug carrier safety. Smart DNA nanospheres (NS) is developed with targeted delivery and controllable release of photosensitizers and immune agents to achieve effective synergistic therapy and minimize side effects. The multifunctional NS incorporate a targeting module for programming aptamers, a response module for programming i-motif and DNA/RNA hybrid sequences, and a therapeutic module for packaging photosensitizers and PD-L1 siRNA. NS navigate to the tumor site and are sequentially activated by intracellular acid and enzymes to release photosensitizers and programmed death ligand 1 (PD-L1) small interfering RNA (siRNA) programmed death protein 1 (PD-1) and programmed cell death ligands. Besides tumor killing and immune promotion, activated NS downregulate PD-L1 expression, alleviating immune tolerance and evasion, thus enhancing the immune response. These results indicate that NS significantly enhance antitumor immune responses, synergistically improve antitumor efficacy, and reduce systemic toxicity. This study broadens the application of DNA nanomaterials in precision drug delivery and tumor therapy.

A four in one nanoplatform: Theranostic bismuth-containing nanoMOFs for chemo-photodynamic- radiation therapy and CT scan imaging

Integration of different therapeutic performances into one platform is an innovative development for using multiple applications in real-time. In this paper, for the first time we exploited the concurrent capacity of radio and photosensitizing in a theranostic nanoMOFs based on bismuth, zirconium, and porphyrin. The porosity of nanoMOFs provided the capability of doxorubicin loading and chemotherapy besides enhanced photodynamic and radiation therapy (PDT & RT). Its PEGylation and aptamer (MUC1) immobilization endowed the platform with high biocompatibility and targeted tumor killing, respectively. In vitro assay exhibited that this aptamer immobilized DOX-loaded PEGylated MOF (Apt@DOX) produced more toxicity against 4 T1 cells compared to non-targeted nanoparticles (NP@DOX), especially when the treatment combined with PDT or/and RT. In vivo experiment also provided great results for tumor growth, survival rate, and body weight for 4 T1 bearing mice injected by Apt@DOX in combination with irradiation by 660 nm laser and/or exposure to 3 Gy dosage of X-ray radiation. The CT imaging of injected mice with targeted and non-targeted bismuth-based MOF introduced this nanoplatform as a promising CT contrast agent. Resultantly, we can present our as-synthesized nanoplatform as an efficient multifunctional theranostics with the ability of multimodal therapy and diagnostic performance.