Hepatocyte estrogen sulfotransferase inhibition protects female mice from concanavalin A-induced T cell-mediated hepatitis independent of estrogens.

Autoimmune hepatitis (AIH) is a typical T cell-mediated chronic liver disease with a higher incidence in females. However, the molecular mechanism for the female predisposition is poorly understood. Estrogen sulfotransferase (Est) is a conjugating enzyme best known for its function in sulfonating and deactivating estrogens. The goal of this study is to investigate whether and how Est plays a role in the higher incidence of AIH in females. Concanavalin A (ConA) was used to induce T cell-mediated hepatitis in female mice. We first showed that Est was highly induced in the liver of ConA-treated mice. Systemic or hepatocyte-specific ablation of Est, or pharmacological inhibition of Est, protected female mice from ConA-induced hepatitis regardless of ovariectomy, suggesting the effect of Est inhibition was estrogen independent. In contrast, we found that hepatocyte-specific transgenic reconstitution of Est in the whole-body Est knockout (EstKO) mice abolished the protective phenotype. Upon the ConA challenge, EstKO mice exhibited a more robust inflammatory response with elevated production of proinflammatory cytokines and changed liver infiltration of immune cells. Mechanistically, we determined that ablation of Est led to the hepatic induction of lipocalin 2 (Lcn2), whereas ablation of Lcn2 abolished the protective phenotype of EstKO females. Our findings demonstrate that hepatocyte Est is required for the sensitivity of female mice to ConA-induced and T cell-mediated hepatitis in an estrogen-independent manner. Est ablation may have protected female mice from ConA-induced hepatitis by upregulating Lcn2. Pharmacological inhibition of Est might be a potential strategy for the treatment of AIH.

Physiological Investigation and Transcriptome Analysis Reveals the Mechanisms of Setaria italica's Yield Formation under Heat Stress.

Setaria italica is an important crop in China that plays a vital role in the Chinese dietary structure. In the last several decades, high temperature has become the most severe climate issue in the world, which causes great harm to the yield and quality formation of millet. In this study, two main cultivated varieties (ZG2 and AI88) were used to explore the photosynthesis and yield index of the whole plant under heat stress. Results implied that photosynthesis was not inhibited during the heat stress, and that the imbalance in sugar transport between different tissues may be the main factor that affects yield formation. In addition, the expression levels of seven SiSUT and twenty-four SiSWEET members were explored. Sugar transporters were heavily affected during the heat stress. The expression of SiSWEET13a was inhibited by heat stress in the stems, which may play a vital role in sugar transport between different tissues. These results provide new insights into the yield formation of crops under heat stress, which will provide guidance to crop breeding and cultivation.

Overcoming pancreatic cancer immune resistance by codelivery of CCR2 antagonist using a STING-activating gemcitabine-based nanocarrier.

STING agonist has recently gained much attention for cancer treatment, but the therapeutic potential of STING agonist is hampered by STING-associated tumor immune resistance. In this work, guided by both bioinformatics and computer modeling, we rationally designed a "one stone hits two birds" nanoparticle-based strategy to simultaneously activate STING innate immune response while eliminating STING-associated immune resistance for the treatment of pancreatic ductal adenocarcinoma (PDAC). We discovered that the ultra-small sized micellar system based on gemcitabine-conjugated polymer (PGEM), which showed superior capacity of penetration in pancreatic tumor spheroid model and orthotopic tumor model, could serve as a novel "STING agonist". The activation of STING signaling in dendritic cells (DCs) by PGEM increased both innate nature killer (NK) and adaptive anti-tumor T cell response. However, activation of STING signaling by PGEM in tumor cells also drove the induction of chemokines CCL2 and CCL7, resulting in immune resistance by recruiting tumor associated macrophage (TAM) and myeloid-derived suppressor cells (MDSCs). Through the combination of computer modeling and experimental screening, we developed a dual delivery modality by incorporating a CCR2 (the receptor shared by both CCL2 and CCL7) antagonist PF-6309 (PF) into PGEM micellar system. Our studies demonstrated that PGEM/PF formulation significantly reduced pancreatic tumor burden and induced potent anti-tumor immunity through reversing the CCL2/CCL7-mediated immunosuppression. Moreover, PGEM/PF sensitized PDAC tumors to anti-PD-1 therapy, leading to complete suppression/eradication of the tumors. Our work has shed light to the multi-faceted role of STING activation and provided a novel immunotherapy regimen to maximize the benefit of STING activation for PDAC treatment. In addition, this work paved a new way for bioinformatics and computer modeling-guided rational design of nanomedicine.

Reciprocal regulation of TWIST1 and OGT determines the decitabine efficacy in MDS/AML.

Chemoresistance poses a significant impediment to effective treatment strategies for myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Our previous study unveiled that oncogene TWIST1 interacted with DNA methyltransferase 3a (DNMT3a) to regulate the decitabine (DAC) resistance in MDS/AML. However, the underlying mechanism of TWIST1 dysregulation in DAC resistance remained enigmatic. Here, we found that O-GlcNAc modification was upregulated in CD34+ cells from MDS/AML patients who do not respond to DAC treatment. Functional study revealed that O-GlcNAcylation could stabilize TWIST1 by impeding its interaction with ubiquitin E3 ligase CBLC. In addition, as one typical transcription factor, TWIST1 could bind to the promoter of O-GlcNAc transferase (OGT) gene and activate its transcription. Collectively, we highlighted the crucial role of the O-GlcNAcylated TWIST1 in the chemoresistance capacity of MDS/AML clonal cells, which may pave the way for the development of a new therapeutic strategy targeting O-GlcNAcylated proteins and reducing the ratio of MDS/AML relapse. Video Abstract.

Separate effect of turbulent pulsation on internal mass transfer in porous biofilms.

Turbulence is considered to be the result of coupled time-averaged and pulsating velocities, making it difficult to distinguish the respective effects, and the quantitative effect of turbulent pulsation alone on mass transfer within biofilms has not been discussed in the literature. In this study, we constructed a special oscillating grid biofilm reactor combining Particle Image Velocimetry (PIV) measurements and Computational Fluid Dynamics (CFD) simulations to achieve nearly isotropic turbulence in a designed ambient without time-averaged velocity and shear stress. Subsequently, velocity and contaminant concentration distributions were obtained by solving a mass transfer model with a k-ε turbulence model, combined with measurements of biofilm structure parameters. The results showed that the increase in turbulent pulsation intensity led to a significant stratification of the percolation velocity gradient in biofilms, which enhanced convective mass transfer. The changes of biofilm density and porosity under turbulent pulsation were more strongly correlated with convective mass transfer. When the turbulent intensity (q) increased to 2.50 cm s-1, the removal rate reached the highest value of 96.93%, accelerating the migration of contaminant concentration and the diffusive mass transfer effect was obvious. In addition, the trend of biofilm thickness under turbulent pulsation was consistent with the change of contaminant concentration distribution, and the correlation between them was greater. In summary, at q of 2.50 cm s-1, there was a positive effect on both convection and diffusion mechanisms in biofilms, and the contaminant removal rate and biofilm thickness reached the maximum, which was the recommended turbulent pulsation conditions.

The Invasiveness Classification of Ground-Glass Nodules Using 3D Attention Network and HRCT.

The early stage lung cancer often appears as ground-glass nodules (GGNs). The diagnosis of GGN as preinvasive lesion (PIL) or invasive adenocarcinoma (IA) is very important for further treatment planning. This paper proposes an automatic GGNs' invasiveness classification algorithm for the adenocarcinoma. 1431 clinical cases and a total of 1624 GGNs (3-30 mm) were collected from Shanghai Cancer Center for the study. The data is in high-resolution computed tomography (HRCT) format. Firstly, the automatic GGN detector which is composed by a 3D U-Net and a 3D multi-receptive field (multi-RF) network detects the location of GGNs. Then, a deep 3D convolutional neural network (3D-CNN) called Attention-v1 is used to identify the GGNs' invasiveness. The attention mechanism was introduced to the 3D-CNN. This paper conducted a contract experiment to compare the performance of Attention-v1, ResNet, and random forest algorithm. ResNet is one of the most advanced convolutional neural network structures. The competition performance metrics (CPM) of automatic GGN detector reached 0.896. The accuracy, sensitivity, specificity, and area under curve (AUC) value of Attention-v1 structure are 85.2%, 83.7%, 86.3%, and 92.6%. The algorithm proposed in this paper outperforms ResNet and random forest in sensitivity, accuracy, and AUC value. The deep 3D-CNN's classification result is better than traditional machine learning method. Attention mechanism improves 3D-CNN's performance compared with the residual block. The automatic GGN detector with the addition of Attention-v1 can be used to construct the GGN invasiveness classification algorithm to help the patients and doctors in treatment.

Hypoxia-induced HMGB1 expression of HCC promotes tumor invasiveness and metastasis via regulating macrophage-derived IL-6.

Hypoxia is associated with the progression of hepatocellular carcinoma through promotion of spontaneous metastasis but the mechanism remains unclear. Here, we hypothesis that tumor cell-derived HMGB1 orchestrates macrophages infiltration and promotes metastasis of HCC via enhancing macrophage-secreted IL-6 under hypoxia. HMGB1 expression was robustly exacerbated in tumors of HCC patients with PVTT. Meanwhile, hypoxia exposure gave rise to HMGB1 expression in hepatoma cells of human and mouse in a HIF-1α-dependent manner and subsequently induced the infiltration and reprogramming of macrophages to augment the expression of Il-6. Further study demonstrated macrophage-derived IL-6 enhanced the invasiveness and metastasis of murine HCC cells. Therefore, our study provides a novel understanding of the relationship between tumor cells and tumor associated macrophages (TAMs) in the context of hypoxia.

The biological function of Serpinb9 and Serpinb9-based therapy.

Recent breakthroughs in discovering novel immune signaling pathways have revolutionized different disease treatments. SERPINB9 (Sb9), also known as Proteinase Inhibitor 9 (PI-9), is a well-known endogenous inhibitor of Granzyme B (GzmB). GzmB is a potent cytotoxic molecule secreted by cytotoxic T lymphocytes and natural killer cells, which plays a crucial role in inducing apoptosis in target cells during immune responses. Sb9 acts as a protective mechanism against the potentially harmful effects of GzmB within the cells of the immune system itself. On the other hand, overexpression of Sb9 is an important mechanism of immune evasion in diseases like cancers and viral infections. The intricate functions of Sb9 in different cell types represent a fine-tuned regulatory mechanism for preventing immunopathology, protection against autoimmune diseases, and the regulation of cell death, all of which are essential for maintaining health and responding effectively to disease challenges. Dysregulation of the Sb9 will disrupt human normal physiological condition, potentially leading to a range of diseases, including cancers, inflammatory conditions, viral infections or other pathological disorders. Deepening our understanding of the role of Sb9 will aid in the discovery of innovative and effective treatments for various medical conditions. Therefore, the objective of this review is to consolidate current knowledge regarding the biological role of Sb9. It aims to offer insights into its discovery, structure, functions, distribution, its association with various diseases, and the potential of nanoparticle-based therapies targeting Sb9.

Knocking down of Xkr8 enhances chemotherapy efficacy through modulating tumor immune microenvironment.

Scramblase Xkr8 regulates the externalization of phosphatidylserine (PS) during apoptosis and holds a pivotal role in fostering tumor immunosuppression. Targeting Xkr8 in conjunction with chemotherapy demonstrated a novel avenue for amplifying antitumor immune response and overcoming chemo-immune resistance. Here we further evaluated this strategy by using a clinically relevant orthotopic model and elucidated the mechanism through in-depth single-cell RNA sequencing (scRNA-seq). We found that Xkr8 knockdown exhibited the potential to lead to immunogenic cell death (ICD) by impeding the normal clearance of apoptotic cells. Co-delivery of Xkr8 small interference RNA (siRNA) and chemo prodrug FuOXP showed remarkable therapeutic efficacy in an orthotopic pancreatic tumor model with an increase of proliferative NK cells and activated macrophages infiltration in the tumor microenvironment (TME). Single-cell trajectory analysis further unveiled that tumor infiltrating CD8+ T cells are differentiated favorably to cytotoxic over exhausted phenotype after combination treatment. Our study sheds new light on the impact of Xkr8 knockdown on TME and solidifies the rationale of combining Xkr8 knockdown with chemotherapy to treat various types of cancers.

Knocking down of Xkr8 enhances chemotherapy efficacy through modulating tumor immune microenvironment.

Scramblase Xk-related protein 8 (Xkr8) regulates the externalization of phosphatidylserine (PS) during apoptosis and holds a pivotal role in fostering tumor immunosuppression. Targeting Xkr8 in conjunction with chemotherapy demonstrated a novel avenue for amplifying antitumor immune response and overcoming chemo-immune resistance. Here we further evaluated this strategy by using a clinically relevant orthotopic model and elucidated the mechanism through in-depth single-cell RNA sequencing (scRNA-seq). We found that Xkr8 knockdown exhibited the potential to lead to immunogenic cell death (ICD) by impeding the normal clearance of apoptotic cells. Co-delivery of Xkr8 small interference RNA (siRNA) and a prodrug conjugate of 5-fluorouracil (5-Fu) and oxoplatin (FuOXP) showed remarkable therapeutic efficacy in an orthotopic pancreatic tumor model with increased infiltration of proliferative NK cells and activated macrophages in the tumor microenvironment (TME). Single-cell trajectory analysis further unveiled that tumor infiltrating CD8+ T cells are differentiated favorably to cytotoxic over exhausted phenotype after combination treatment. Our study sheds new light on the impact of Xkr8 knockdown on TME and solidifies the rationale of combining Xkr8 knockdown with chemotherapy to treat various types of cancers.

Habitat-based radiomics analysis for evaluating immediate response in colorectal cancer lung metastases treated by radiofrequency ablation.

PURPOSE: To create radiomics signatures based on habitat to assess the instant response in lung metastases of colorectal cancer (CRC) after radiofrequency ablation (RFA). METHODS: Between August 2016 and June 2019, we retrospectively included 515 lung metastases in 233 CRC patients who received RFA (412 in the training group and 103 in the test group). Multivariable analysis was performed to identify independent risk factors for developing the clinical model. Tumor and ablation regions of interest (ROI) were split into three spatial habitats through K-means clustering and dilated with 5 mm and 10 mm thicknesses. Radiomics signatures of intratumor, peritumor, and habitat were developed using the features extracted from intraoperative CT data. The performance of these signatures was primarily evaluated using the area under the receiver operating characteristics curve (AUC) via the DeLong test, calibration curves through the Hosmer-Lemeshow test, and decision curve analysis. RESULTS: A total of 412 out of 515 metastases (80%) achieved complete response. Four clinical variables (cancer antigen 19-9, simultaneous systemic treatment, site of lung metastases, and electrode type) were utilized to construct the clinical model. The Habitat signature was combined with the Peri-5 signature, which achieved a higher AUC than the Peri-10 signature in the test set (0.825 vs. 0.816). The Habitat+Peri-5 signature notably surpassed the clinical and intratumor radiomics signatures (AUC: 0.870 in the test set; both, p < 0.05), displaying improved calibration and clinical practicality. CONCLUSIONS: The habitat-based radiomics signature can offer precise predictions and valuable assistance to physicians in developing personalized treatment strategies.

Systematic investigation of chemo-immunotherapy synergism to shift anti-PD-1 resistance in cancer.

Chemo-immunotherapy combinations have been regarded as one of the most practical ways to improve immunotherapy response in cancer patients. In this study, we integrate the transcriptomics data from anti-PD-1-treated tumors and compound-treated cancer cell lines to systematically screen for chemo-immunotherapy synergisms in silico. Through analyzing anti-PD-1 induced expression changes in patient tumors, we develop a shift ability score to measure if a chemotherapy or a small molecule inhibitor treatment can shift anti-PD-1 resistance in tumor cells. By applying shift ability analysis to 41,321 compounds and 16,853 shRNA treated cancer cell lines transcriptomic data, we characterize the landscape of chemo-immunotherapy synergism and experimentally validated a mitochondrial RNA-dependent mechanism for drug-induced immune activation in tumor. Our study represents an effort to mechanistically characterize chemo-immunotherapy synergism and will facilitate future pre-clinical and clinical studies.

In Situ Formation of Fibronectin-Enriched Protein Corona on Epigenetic Nanocarrier for Enhanced Synthetic Lethal Therapy.

PARP inhibitors (PARPi)-based synthetic lethal therapy demonstrates limited efficacy for most cancer types that are homologous recombination (HR) proficient. To potentiate the PARPi application, a nanocarrier based on 5-azacytidine (AZA)-conjugated polymer (PAZA) for the codelivery of AZA and a PARP inhibitor, BMN673 (BMN) is developed. AZA conjugation significantly decreased the nanoparticle (NP) size and increased BMN loading. Molecular dynamics simulation and experimental validations shed mechanistic insights into the self-assembly of effective NPs. The small PAZA NPs demonstrated higher efficiency of tumor targeting and penetration than larger NPs, which is mediated by a new mechanism of active targeting that involves the recruitment of fibronectin from serum proteins following systemic administration of PAZA NPs. Furthermore, it is found that PAZA carrier sensitize the HR-proficient nonsmall cell lung cancer (NSCLC) to BMN, a combination therapy that is more effective at a lower AZA/BMN dosage. To investigate the underlying mechanism, the tumor immune microenvironment and various gene expressions by RNAseq are explored. Moreover, the BMN/PAZA combination increased the immunogenicity and synergized with PD-1 antibody in improving the overall therapeutic effect in an orthotopic model of lung cancer (LLC).

Inhibition of iRhom1 by CD44-targeting nanocarrier for improved cancer immunochemotherapy.

The multifaceted chemo-immune resistance is the principal barrier to achieving cure in cancer patients. Identifying a target that is critically involved in chemo-immune-resistance represents an attractive strategy to improve cancer treatment. iRhom1 plays a role in cancer cell proliferation and its expression is negatively correlated with immune cell infiltration. Here we show that iRhom1 decreases chemotherapy sensitivity by regulating the MAPK14-HSP27 axis. In addition, iRhom1 inhibits the cytotoxic T-cell response by reducing the stability of ERAP1 protein and the ERAP1-mediated antigen processing and presentation. To facilitate the therapeutic translation of these findings, we develop a biodegradable nanocarrier that is effective in codelivery of iRhom pre-siRNA (pre-siiRhom) and chemotherapeutic drugs. This nanocarrier is effective in tumor targeting and penetration through both enhanced permeability and retention effect and CD44-mediated transcytosis in tumor endothelial cells as well as tumor cells. Inhibition of iRhom1 further facilitates tumor targeting and uptake through inhibition of CD44 cleavage. Co-delivery of pre-siiRhom and a chemotherapy agent leads to enhanced antitumor efficacy and activated tumor immune microenvironment in multiple cancer models in female mice. Targeting iRhom1 together with chemotherapy could represent a strategy to overcome chemo-immune resistance in cancer treatment.

Percutaneous computed tomography-guided core needle biopsy can be used to histologically confirm the clinical features and long-term prognosis of pulmonary neuroendocrine neoplasms.

PURPOSE: We investigated the clinical features and prognosis outcomes of pulmonary neuroendocrine neoplasms (PNENs) which were histologically confirmed after percutaneous computed tomography-guided core needle biopsy (PCT-CNB). MATERIALS AND METHODS: We retrospectively investigated 173 patients who had PNENs which were histologically confirmed after PCT-CNB; patients were split into low and intermediate-grade neuroendocrine tumor (LIGNET) (typical carcinoid (TC) and atypical carcinoid (AC)) and high-grade neuroendocrine carcinoma-tumor (HGNEC) groups. In this latter group, patients were further subdivided into large-cell neuroendocrine carcinoma (LCNEC), small-cell lung cancer (SCLC), and high-grade neuroendocrine carcinoma-not otherwise specified (HGNEC-NOS) groups. Complications after biopsy were recorded. We also assessed overall survival (OS) rates using Kaplan-Meier curves, with prognostic factors determined using univariate and multivariate analyses. RESULTS: Complications were mainly pneumothorax (22.5; 39/173 patients), chest tube placement (4.0; 7/173 patients), and pulmonary bleeding (33.5%; 58/173 procedures)-no patient mortality was recorded. Definitive diagnoses were ascribed to 102 SCLC, 10 LCNEC, 43 HGNEC-NOS, 7 TC, and 11 AC patients. The 1- and 3-year OS rates in the LIGNET group were 87.5% and 68.1%, respectively, and 59.2 and 20.9% in the HGNEC group, respectively these data were statistically significant (P = 0.010). For SCLC, 1- and 3-year OS rates were 63.3 and 22.3%, 30.0 and 10.0% for LCNEC, and 53.3% and 20.1% for HGNEC-NOS, respectively (P = 0.031). Independent prognostic factors for OS included disease type and distant metastasis. CONCLUSION: PNENs may be pathologically diagnosed using PCT-CNB. While differential diagnoses between LCNEC and SCLC are problematic in some patients, a HGNEC-NOS diagnosis was ascribed and PCT-CNB samples were shown to predict NEN OS rates.

A CT-based radiomics approach to predict immediate response of radiofrequency ablation in colorectal cancer lung metastases.

Objectives: To objectively and accurately assess the immediate efficacy of radiofrequency ablation (RFA) on colorectal cancer (CRC) lung metastases, the novel multimodal data fusion model based on radiomics features and clinical variables was developed. Methods: This case-control single-center retrospective study included 479 lung metastases treated with RFA in 198 CRC patients. Clinical and radiological data before and intraoperative computed tomography (CT) scans were retrieved. The relative radiomics features were extracted from pre- and immediate post-RFA CT scans by maximum relevance and minimum redundancy algorithm (MRMRA). The Gaussian mixture model (GMM) was used to divide the data of the training dataset and testing dataset. In the process of modeling in the training set, radiomics model, clinical model and fusion model were built based on a random forest classifier. Finally, verification was carried out on an independent test dataset. The receiver operating characteristic curves (ROC) were drawn based on the obtained predicted scores, and the corresponding area under ROC curve (AUC), accuracy, sensitivity, and specificity were calculated and compared. Results: Among the 479 pulmonary metastases, 379 had complete response (CR) ablation and 100 had incomplete response ablation. Three hundred eighty-six lesions were selected to construct a training dataset and 93 lesions to construct a testing dataset. The multivariate logistic regression analysis revealed cancer antigen 19-9 (CA19-9, p<0.001) and the location of the metastases (p< 0.05) as independent risk factors. Significant correlations were observed between complete ablation and 9 radiomics features. The best prediction performance was achieved with the proposed multimodal data fusion model integrating radiomic features and clinical variables with the highest accuracy (82.6%), AUC value (0.921), sensitivity (80.3%), and specificity (81.4%). Conclusion: This novel multimodal data fusion model was demonstrated efficient for immediate efficacy evaluation after RFA for CRC lung metastases, which could benefit necessary complementary treatment.

Improved antitumor activity against prostate cancer via synergistic targeting of Myc and GFAT-1.

Inhibition of Myc promotes the regression of many types of tumors, including prostate cancer. However, the success of anti-Myc therapy is hampered by the lack of a strategy to effectively deliver the inhibitors to the tumor site and by the feedback mechanisms that cancer cells use to adapt to metabolic reprogramming. Methods: The effects of Myc inhibitors (10074-G5 or 10058-F4), alone or in combination with 6-diazo-5-oxo-L-norleucine (DON), were evaluated in cultured human or murine prostate cancer cells by cell viability assay, qRT-PCR and Western blot. To facilitate the in vivo therapeutic evaluation, a prodrug conjugate of 10074-G4 and DON (10074-DON) was developed, which could be effectively loaded into a polysaccharide-based nanocarrier (PS). Results: The treatment with Myc inhibitors led to significant induction of glutamine: fructose-6-phosphate amidotransferase-1 (GFAT1) and enhanced protein glycosylation. Mechanistically, Myc inhibition triggered GFAT1 induction through the IREα-Xbp1s pathway. The combination use of Myc inhibitors and GFAT1 inhibitor DON led to a synergistic effect in inhibiting the proliferation and migration of prostate cancer cells. Enhanced in vivo delivery of 10074-DON via the PS nanocarrier led to a significant inhibition of tumor growth along with an improvement in tumor immune microenvironment in several PCa animal models. Conclusion: Simultaneous targeting of Myc and GFAT-1 may represent a novel strategy for the treatment of prostate cancer.

Systematic investigation of chemo-immunotherapy synergism to shift anti-PD-1 resistance in cancer.

Chemo-immunotherapy combinations have been regarded as one of the most practical ways to improve immunotherapy response in cancer patients. In this study, we integrated the transcriptomics data from immunotherapy-treated tumors and compound-treated cell lines to systematically identify chemo-immunotherapy synergisms and their underlying mechanisms. Through analyzing anti-PD-1 treatment induced expression changes in patient tumors, we developed a shift ability score that can measure whether a chemotherapy treatment shifts anti-PD-1 response. By applying the shift ability analysis on 41,321 compounds and 16,853 shRNA treated cancer cell line expression profiles, we characterized a systematic landscape of chemo-immunotherapy synergism and prioritized 17 potential synergy targets. Further investigation of the treatment induced transcriptomic data revealed that a mitophagy-dsRNA-MAVS-dependent activation of type I IFN signaling may be a novel mechanism for chemo-immunotherapy synergism. Our study represents the first comprehensive effort to mechanistically characterize chemo-immunotherapy synergism and will facilitate future pre-clinical and clinical studies.

Targeting Xkr8 via nanoparticle-mediated in situ co-delivery of siRNA and chemotherapy drugs for cancer immunochemotherapy.

Activation of scramblases is one of the mechanisms that regulates the exposure of phosphatidylserine to the cell surface, a process that plays an important role in tumour immunosuppression. Here we show that chemotherapeutic agents induce overexpression of Xkr8, a scramblase activated during apoptosis, at the transcriptional level in cancer cells, both in vitro and in vivo. Based on this finding, we developed a nanocarrier for co-delivery of Xkr8 short interfering RNA and the FuOXP prodrug to tumours. Intravenous injection of our nanocarrier led to significant inhibition of tumour growth in colon and pancreatic cancer models along with increased antitumour immune response. Targeting Xkr8 in combination with chemotherapy may represent a novel strategy for the treatment of various types of cancers.

Exploration of the impact of multimode thermal therapy versus radiofrequency ablation on CD8+ T effector cells of liver malignancies based on single cell transcriptomics.

Introduction: Multimode thermal therapy (MTT) is an innovative interventional therapy developed for the treatment of liver malignancies. When compared to the conventional radiofrequency ablation (RFA), MTT typically offers improved prognosis for patients. However, the effect of MTT on the peripheral immune environment and the mechanisms underlying the enhanced prognosis have yet to be explored. The aim of this study was to further investigate the mechanisms responsible for the difference in prognosis between the two therapies. Methods: In this study, peripheral blood samples were collected from four patients treated with MTT and two patients treated with RFA for liver malignancies at different time points before and after the treatment. Single cell sequencing was performed on the blood samples to compare and analyze the activation pathways of peripheral immune cells following the MTT and RFA treatment. Results: There was no significant effect of either therapy on the composition of immune cells in peripheral blood. However, the differential gene expression and pathway enrichment analysis demonstrated enhanced activation of T cells in the MTT group compared to the RFA group. In particular, there was a remarkable increase in TNF-α signaling via NF-κB, as well as the expression of IFN-α and IFN-γ in the CD8+ effector T (CD8+ Teff) cells subpopulation, when compared to the RFA group. This may be related to the upregulation of PI3KR1 expression after MTT, which promotes the activation of PI3K-AKT-mTOR pathway. Conclusion: This study confirmed that MTT could more effectively activate peripheral CD8+ Teff cells in patients compared with RFA and promote the effector function, thus resulting in a better prognosis. These results provide a theoretical basis for the clinical application of MTT therapy.