FLI1 promotes IFN-γ-induced kynurenine production to impair anti-tumor immunity.

Nasopharyngeal carcinoma (NPC)-mediated immunosuppression within the tumor microenvironment (TME) frequently culminates in the failure of otherwise promising immunotherapies. In this study, we identify tumor-intrinsic FLI1 as a critical mediator in impairing T cell anti-tumor immunity. A mechanistic inquiry reveals that FLI1 orchestrates the expression of CBP and STAT1, facilitating chromatin accessibility and transcriptional activation of IDO1 in response to T cell-released IFN-γ. This regulatory cascade ultimately leads to augmented IDO1 expression, resulting in heightened synthesis of kynurenine (Kyn) in tumor cells. This, in turn, fosters CD8+ T cell exhaustion and regulatory T cell (Treg) differentiation. Intriguingly, we find that pharmacological inhibition of FLI1 effectively obstructs the CBP/STAT1-IDO1-Kyn axis, thereby invigorating both spontaneous and checkpoint therapy-induced immune responses, culminating in enhanced tumor eradication. In conclusion, our findings delineate FLI1-mediated Kyn metabolism as an immune evasion mechanism in NPC, furnishing valuable insights into potential therapeutic interventions.

Deciphering the causal association and co-disease mechanisms between psoriasis and breast cancer.

Background: Prior research has indicated a link between psoriasis and the susceptibility to breast cancer (BC); however, a definitive causal relationship remains elusive. This study sought to elucidate the causal connection and shared underlying mechanisms between psoriasis and BC through bidirectional Mendelian randomization (MR) and bioinformatic approaches. Methods: We employed a bidirectional MR approach to examine the potential causal connection between psoriasis and BC. Genetic data pertaining to psoriasis and BC were sourced from extensive published genome-wide association studies. The inverse -variance weighted or wald ratio served as the primary method for estimating causal effects. Sensitivity analysis of the MR results was applied with multiple methods. Leveraged datasets from the Gene Expression Omnibus and the Cancer Genome Atlas repositories to identify common differentially expressed genes, shedding light on the shared mechanisms underlying these two conditions. Results: The MR analysis revealed that when considering psoriasis as an exposure factor, the incidences of BC (OR=1.027) and estrogen receptor negative (ER-) BC (OR=1.054) were higher than in the general population. When using Her2+ BC as an exposure factor, the risk of psoriasis was 0.822 times higher (OR=0.822) than in the general population. Sensitivity analysis indicated that the results were robust. Transcriptome analysis showed that CXCL13 and CCL20 were activated in both BC and psoriasis. Both diseases were also linked to neutrophil chemotaxis, the IL-17 pathway, and the chemokine pathway. Conclusion: The results suggest that psoriasis may increase the risk of BC, especially ER- BC, while reverse MR suggests a decreased risk of psoriasis in Her2+ BC. Transcriptome analysis revealed a shared mechanism between psoriasis and BC.

Unveiling the Mechanism of the ChaiShao Shugan Formula Against Triple-Negative Breast Cancer.

Background: The ChaiShao Shugan Formula (CSSGF) is a traditional Chinese medicine formula with recently identified therapeutic value in triple-negative breast cancer (TNBC). This study aimed to elucidate the underlying mechanism of CSSGF in TNBC treatment. Methods: TNBC targets were analyzed using R and data were from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The major ingredients and related protein targets of CSSGF were explored via the Traditional Chinese Medicine Systems Pharmacology database, and an ingredient-target network was constructed via Cytoscape to identify hub genes. The STRING database was used to construct the PPI network. GO and KEGG enrichment analyses were performed via R to obtain the main targets. The online tool Kaplan‒Meier plotter was used to identify the prognostic genes. Molecular docking was applied to the core target genes and active ingredients. MDA-MB-231 and MCF-7 cell lines were used to verify the efficacy of the various drugs. Results: A total of 4562 genes were screened as TNBC target genes. The PPI network consisted of 89 nodes and 845 edges. Our study indicated that quercetin, beta-sitosterol, luteolin and catechin might be the core ingredients of CSSGF, and EGFR and c-Myc might be the latent therapeutic targets of CSSGF in the treatment of TNBC. GO and KEGG analyses indicated that the anticancer effect of CSSGF on TNBC was mainly associated with DNA binding, transcription factor binding, and other biological processes. The related signaling pathways mainly involved the TNF-a, IL-17, and apoptosis pathways. The molecular docking data indicated that quercetin, beta-sitosterol, luteolin, and catechin had high affinity for EGFR, JUN, Caspase-3 and ESR1, respectively. In vitro, we found that CSSGF could suppress the expression of c-Myc or promote the expression of EGFR. In addition, we found that quercetin downregulates c-Myc expression in two BC cell lines. Conclusion: This study revealed the effective ingredients and latent molecular mechanism of action of CSSGF against TNBC and confirmed that quercetin could target c-Myc to induce anti-BC effects.

Dual-Responsive Nanomedicine Activates Programmed Antitumor Immunity through Targeting Lymphatic System.

Effective antitumor immunotherapy depends on evoking a cascade of cancer-immune cycles with lymph nodes (LNs) as the initial sites for activating antitumor immunity, making drug administration through the lymphatic system highly attractive. Here, we describe a nanomedicine with dual responsiveness to pH and enzyme for a programmed activation of antitumor immune through the lymphatic system. The proposed nanomedicine can release the STING agonist diABZI-C2-NH2 in the LNs' acidic environment to activate dendritic cells (DCs) and T cells. Then, the remaining nanomedicine hitchhikes on the activated T cells (PD-1+ T cells) through binding to PD-1, resulting in an effective delivery into tumor tissues owing to the tumor-homing capacity of PD-1+ T cells. The enzyme matrix metalloproteinase-2 (MMP-2) being enriched in tumor tissue triggers the release of PD-1 antibody (aPD-1) which exerts immune checkpoint blockade (ICB) therapy. Eventually, the nanomedicine delivers a DNA methylation inhibitor GSK-3484862 (GSK) into tumor cells, and then the latter combines with granzyme B (GZMB) to trigger tumor cell pyroptosis. Consequently, the pyroptotic tumor cells induce robust immunogenic cell death (ICD) enhancing the DCs maturation and initiating the cascading antitumor immune response. Study on a 4T1 breast tumor mouse model demonstrates the prominent antitumor therapeutic outcome of this nanomedicine through creating a positive feedback loop of cancer-immunity cycles including immune activation in LNs, T cell-mediated drug delivery, ICB therapy, and tumor cell pyroptosis-featured ICD.

Ferroptosis and ferroptosis-inducing nanomedicine as a promising weapon in combination therapy of prostate cancer.

Incidence and mortality of prostate cancer (PCa) rank in the top five among male tumors. However, single treatment modalities are often restricted due to biochemical recurrence and drug resistance, necessitating the development of new approaches for the combination treatment of castration-resistant and neuroendocrine PCa. Ferroptosis is characterized by the accumulation of iron-overload-mediated lipid peroxidation and has shown promising outcomes in anticancer treatment, prompting us to present a review reporting the application of ferroptosis in the treatment of PCa. First, the process and mechanism of ferroptosis are briefly reviewed. Second, research advances combining ferroptosis-inducing agents and clinical treatment regimens, which exhibit a "two-pronged approach" effect, are further summarized. Finally, the recent progress on ferroptosis-inducing nanomaterials for combination anticancer therapy is presented. This review is expected to provide novel insights into ferroptosis-based combination treatment in drug-resistant PCa.

A novel TOX3-WDR5-ABCG2 signaling axis regulates the progression of colorectal cancer by accelerating stem-like traits and chemoresistance.

The eradication of cancer stem cells (CSCs) with drug resistance confers the probability of local tumor control after chemotherapy or targeted therapy. As the main drug resistance marker, ABCG2 is also critical for colorectal cancer (CRC) evolution, in particular cancer stem-like traits expansion. Hitherto, the knowledge about the expression regulation of ABCG2, in particular its upstream transcriptional regulatory mechanisms, remains limited in cancer, including CRC. Here, ABCG2 was found to be markedly up-regulated in CRC CSCs (cCSCs) expansion and chemo-resistant CRC tissues and closely associated with CRC recurrence. Mechanistically, TOX3 was identified as a specific transcriptional factor to drive ABCG2 expression and subsequent cCSCs expansion and chemoresistance by binding to -261 to -141 segments of the ABCG2 promoter region. Moreover, we found that TOX3 recruited WDR5 to promote tri-methylation of H3K4 at the ABCG2 promoter in cCSCs, which further confers stem-like traits and chemoresistance to CRC by co-regulating the transcription of ABCG2. In line with this observation, TOX3, WDR5, and ABCG2 showed abnormal activation in chemo-resistant tumor tissues of in situ CRC mouse model and clinical investigation further demonstrated the comprehensive assessment of TOX3, WDR5, and ABCG2 could be a more efficient strategy for survival prediction of CRC patients with recurrence or metastasis. Thus, our study found that TOX3-WDR5/ABCG2 signaling axis plays a critical role in regulating CRC stem-like traits and chemoresistance, and a combination of chemotherapy with WDR5 inhibitors may induce synthetic lethality in ABCG2-deregulated tumors.

Tumor acidity-activatable macromolecule autophagy inhibitor and immune checkpoint blockade for robust treatment of prostate cancer.

Immune checkpoint blockade (ICB) antibody such as anti-PD-L1 (aPD-L1) activates cytotoxic T cells (CTLs) to combat cancer, but they showed poor efficacy in prostate cancer (PCa). Lysosome-dependent autophagy is utilized by cancer cells to degrade their MHC-I and to lower their vulnerability to TNF-α and CTLs. Lysosomal pH-sensitive polymeric nanoparticle as a drug delivery carrier may also be a novel autophagy inhibitor to boost immunotherapy, but such an important effect has not been investigated. Herein, we developed a unique tumor acidity-activatable macromolecular nanodrug (called P-PDL1-CP) with the poly(2-diisopropylaminoethyl methacrylate) (PDPA) core and the conjugations of both aPD-L1 and long-chain polyethylene glycol (PEG) coating. The PDPA core was demonstrated to disturb lysosome to block the autophagic flux, thus elevating the cancer cell's MHC-I expression and vulnerability to the TNF-α and CTLs. Long-chain PEG facilitated a good tumor accumulation of P-PDL1-CP nanodrug. Furthermore, P-PDL1-CP nanodrug inhibited tumor autophagy, which synergized with aPD-L1 to promote the tumor-infiltrating CTLs and DCs maturation, to elevate intratumoral TNF-α and IFN-γ levels, and to elicit an anti-tumor immune memory effect in mice for PCa growth inhibition with low side effects. This study verified the synergistic anti-PCa treatment between autophagy inhibition and PD-L1 blockade and meantime broadened the application of pH-sensitive macromolecular nanodrug. STATEMENT OF SIGNIFICANCE: A macromolecular nanodrug, comprising the PDPA core and the surface conjugation of both aPD-L1 antibodies and long-chain PEG coating via a tumor acidity-labile α-carboxy-dimethylmaleic anhydride amine bond, was developed. Tumoral acidity triggered the release of aPD-L1 for immunotherapy. Meantime, the charge switch of the remanent nanodrug enhanced the cancer cell uptake of PDPA, which disturbed the lysosomes to inhibit autophagy. This advanced nanodrug promoted the tumor-infiltrating CTLs and DCs maturation, elevated the intratumoral TNF-α and IFN-γ levels, and elicited the robust anti-tumor immune memory effect. This study demonstrated that the pH-sensitive PDPA macromolecule could serve as a carrier for the aPD-L1 delivery and as an efficient autophagy inhibitor to boost the immunotherapy of prostate cancer.

Efficacy and safety of SOXIRI versus mFOLFIRINOX in advanced pancreatic cancer.

Background: Modified fluorouracil/leucovorin/irinotecan/oxaliplatin (FOLFIRINOX) regimen (mFOLFIRINOX), comprised of fluorouracil, leucovorin, irinotecan and oxaliplatin, is the first-line standard chemotherapy in patients with advanced pancreatic cancer. The S-1/oxaliplatin/irinotecan (SOXIRI) regimen has also been studied recently under similar conditions. This study compared its efficacy and safety. Methods: All cases of locally advanced or metastatic pancreatic cancer treated with the SOXIRI or mFOLFIRINOX regimen in Sun Yat-sen University Cancer Centre from July 2012 to June 2021 were reviewed retrospectively. The data of patients who satisfied the inclusion criteria were compared between two cohorts, including overall survival (OS), progression-free survival (PFS), objective response rate, disease control rate and safety. Results: A total of 198 patients were enrolled in the study, including 102 patients treated with SOXIRI and 96 patients treated with mFOLFIRINOX. There was no significant difference in OS [12.1 months versus 11.2 months, hazard ratio (HR) = 1.04, p = 0.81] or PFS (6.5 months versus 6.8 months, HR = 0.99, p = 0.96) between patients treated with SOXIRI and mFOLFIRINOX. In the subgroup analysis, patients with slightly elevated baseline total bilirubin (TBIL) or underweight patients before chemotherapy were more likely to have a longer OS or PFS from SOXIRI than from mFOLFIRINOX. In addition, the carbohydrate antigen (CA)19-9 decline was a good predictor for the efficacy and prognosis of both chemotherapy regimens. All grade adverse events were parallel in all kinds of toxicities except that anaemia was more common in the SOXIRI group than in the mFOLFIRINOX group (41.4% versus 24%, p = 0.03). The occurrence of any grade 3 to 4 toxicity was similar in the two groups. Conclusions: For locally advanced or metastatic pancreatic cancer patients, the SOXIRI regimen had similar efficacy and controllable safety compared with the mFOLFIRINOX regimen.

Nanodrug Augmenting Antitumor Immunity for Enhanced TNBC Therapy via Pyroptosis and cGAS-STING Activation.

Pyroptosis is a proinflammatory form of programmed cell death that results in the release of cellular contents and activation of immune responses. However, GSDME (a pyroptosis-executed protein) is suppressed in many cancers. Herein, we constructed a nanoliposome (GM@LR) for codelivering the GSDME-expressing plasmid and manganese carbonyl (MnCO) into TNBC cells. MnCO generated Mn2+ and carbon monoxide (CO) in the presence of H2O2. The CO-activated caspase-3, which cleaved the expressed GSDME, converting apoptosis to pyroptosis in 4T1 cells. In addition, Mn2+ promoted maturation of dendritic cells (DCs) by the activation of STING signaling pathway. The increased proportion of intratumoral mature DCs brought about massive infiltration of cytotoxic lymphocytes, leading to a robust immune response. Besides, Mn2+ could be applied for magnetic resonance imaging (MRI)-guided metastasis detection. Taken together, our study showed that GM@LR nanodrug could effectively inhibit tumor growth via pyroptosis and STING activation combined immunotherapy.

A novel scoring model based on RNA modification "writers" can predict the prognosis and guide immunotherapy in gastric cancer.

Although extensive research has been carried out on the epigenetic regulation of single RNA modifications in gastric cancer, little is known regarding the crosstalk of four major RNA adenosine modifications, namely, m6A, m1A, alternative polyadenylation and adenosine-to-inosine RNA editing. By analyzing 26 RNA modification "writers" in 1750 gastric cancer samples, we creatively constructed a scoring model called the "Writers" of the RNA Modification Score (WRM_Score), which was able to quantify the RNA modification subtypes of individual patients. In addition, we explored the relationship between WRM_Score and transcriptional and posttranscriptional regulation, tumor microenvironment, clinical features and molecular subtypes. We constructed an RNA modification scoring model including two different subgroups: WRM_Score_low and WRM_Score_high. The former was associated with survival benefit and good efficacy of immune checkpoint inhibitors (ICIs) due to gene repair and immune activation, while the latter was related to poor prognosis and bad efficacy of ICIs because of stromal activation and immunosuppression. The WRM score based on immune and molecular characteristics of the RNA modification pattern is a reliable predictor of the prognosis of gastric cancer and the therapeutic efficacy of immune checkpoint inhibitors in gastric cancer.

Inflammatory bowel disease increases the risk of hepatobiliary pancreatic cancer: A two-sample Mendelian randomization analysis of European and East Asian populations.

BACKGROUND: Both inflammatory bowel disease (IBD) and hepato-pancreato-biliary cancers (HPBC) have been established to cause a huge socioeconomic burden. Epidemiological studies have revealed a close association between IBD and HPBC. METHODS: Herein, we utilized inverse-variance weighting to conduct a two-sample Mendelian randomization analysis. We sought to investigate the link between various subtypes of IBD and HPBC. To ensure the accuracy and consistency of our findings, we conducted heterogeneity tests, gene pleiotropy tests, and sensitivity analyses. RESULTS: Compared to the general population, IBD patients in Europe exhibited a 1.22-fold increased incidence of pancreatic cancer (PC) with a 95% confidence interval (CI) of 1.0022-1.4888 (p = 0.0475). We also found a 1.14-fold increased incidence of PC in Crohn's disease (CD) patients with (95% CI: 1.0017-1.3073, p = 0.0472). In the East Asian population, the incidence of hepatocellular carcinoma (HCC) was 1.28-fold higher (95% CI = 1.0709-1.5244, p = 0.0065) in IBD patients than in the general population. Additionally, ulcerative colitis (UC) patients displayed 1.12-fold (95% CI: 1.1466-1.3334, p < 0.0001) and 1.31-fold (95% CI: 1.0983-1.5641, p = 0.0027) increased incidences of HCC and cholangiocarcinoma (CCA), respectively. Finally, the incidence of PC was 1.19-fold higher in CD patients than in the general population (95% CI = 1.0741-1.3132, p = 0.0008). CONCLUSION: Our study validated that IBD is a risk factor for HPBC. This causal relationship exhibited significant heterogeneity in different European and East Asian populations.

Efficacy of Aidi injection combined with chemotherapy, radiotherapy or chemoradiotherapy for unresectable esophageal cancer treatment: A meta-analysis and systematic review of 29 randomized controlled trials based on Asian populations (China).

OBJECTIVES: This study aimed to assess the efficacy of Aidi combined with standard treatment, including radiotherapy (R), chemotherapy (C), or chemoradiotherapy (CR), for unresectable esophageal cancer (EC). METHODS: Eight online databases were queried to collect randomized controlled trials (RCTs) published from database construction to August 2022. Patients in the control group underwent standard treatment with R, C, or CR, whereas those in the experimental group underwent Aidi combined with standard treatment. RESULTS: In this meta-analysis, 29 reports with 2079 patients were included. The results showed that the Aidi-based combination therapy groups had higher objective response rates (ORRs), disease control rates (DCRs), one-year overall survival (OS) and improvement and stability of Karnofsky performance status (KPS) than the control group (risk ratio (RR) = 1.24 (95% CI = 1.17-1.33), 1.09 (95% CI = 1.05-1.14), 1.50 (95% CI = 1.31-1.72), and 1.28 (95% CI = 1.16-1.41)). The Aidi-based combination therapy groups also had lower total incidence rates of bone marrow suppression (BMS), chemotherapy-induced nausea and vomiting (CINV) and radiation esophagitis (RE) than the control group (RR = 0.48 (95% CI = 0.41-0.56), 0.46 (95% CI = 0.36-0.58), and 0.49 (95% CI = 0.38-0.62)). In addition, subgroup analysis suggested that the optimal dose and cycle of Aidi injection combined therapy was 80-100 ml/time and 30 days/2 cycles. The efficacy of Aidi combined with DP (docetaxel + cisplatin) was better than the Aidi combined with PF (cisplatin plus fluorouracil). CONCLUSION: Aidi-based combination therapy showed high efficacy for unresectable EC treatment and reduced the incidence rates of adverse events. However, further studies including higher-quality RCTs are needed to validate these findings. TRIAL REGISTRATION NUMBER: INPLASY 202290020.

Analysis of Risk Factors for Distant Metastasis of Pancreatic Ductal Adenocarcinoma without Regional Lymph Node Metastasis and a Nomogram Prediction Model for Survival.

Background: Negative regional lymph nodes do not indicate a lack of distant metastasis. A considerable number of patients with negative regional lymph node pancreatic cancer will skip the step of regional lymph node metastasis and directly develop distant metastasis. Methods: We retrospectively analyzed the clinicopathological characteristics of patients with negative regional lymph node pancreatic cancer and distant metastasis in the Surveillance, Epidemiology, and End Results database from 2010 to 2015. Multivariate logistic analysis and Cox analysis were used to determine the independent risk factors that promoted distant metastasis and the 1-, 2-, and 3-year cancer-specific survival in this subgroup. Results: Sex, age, pathological grade, surgery, radiotherapy, race, tumor location, and tumor size were significantly correlated with distant metastasis (P < 0.05). Among these factors, pathological grade II and above, tumor site other than the pancreatic head, and tumor size >40 mm were independent risk factors for distant metastasis; age ≥60 years, tumor size ≤21 mm, surgery, and radiation were protective factors against distant metastasis. Age, pathological grade, surgery, chemotherapy, and metastasis site were identified as predictors of survival. Among them, age ≥40 years, pathological grade II and above, and multiple distant metastasis were considered independent risk factors for cancer-specific survival. Surgery and chemotherapy were considered protective factors for cancer-specific survival. The prediction performance of the nomogram was significantly better than that of the traditional American Joint Committee on Cancer tumor, node, metastasis staging system. We also established an online dynamic nomogram calculator, which can predict the survival rate of patients at different follow-up time points. Conclusion: Pathological grade, tumor location, and tumor size were independent risk factors for distant metastasis in pancreatic ductal adenocarcinoma with negative regional lymph nodes. Older age, smaller tumor size, surgery, and radiotherapy were protective factors against distant metastasis. A new nomogram that was constructed could effectively predict cancer-specific survival in pancreatic ductal adenocarcinoma with negative regional lymph nodes and distant metastasis. Furthermore, an online dynamic nomogram calculator was established.

Nanodrug removes physical barrier to promote T-cell infiltration for enhanced cancer immunotherapy.

The dense extracellular matrix (ECM) is a key barrier to tumor infiltration of cytotoxic T lymphocytes (CTLs), which greatly compromises T cell-dependent immunotherapy of hepatocellular carcinoma (HCC). Herein, hyaluronidase (HAase), IL-12, and anti-PD-L1 antibody (αPD-L1) were co-delivered using a pH and MMP-2 dual-sensitive polymer/calcium phosphate (CaP) hybrid nanocarrier. The dissolution of CaP triggered by tumor acidity facilitated the release of IL-12 and HAase responsible for ECM digestion, enhancing the tumor infiltration and proliferation of CTLs. Furthermore, the in situ-released αPD-L1 inside tumor, as triggered by an overexpressed MMP-2, prevented the tumor cell from escaping the killing effects of CTLs. Such combination strategy induced a robust antitumor immunity for efficiently suppressing HCC growth in mice. Additionally, tumor acidity-sheddable polyethylene glycol (PEG) coating enhanced the tumor accumulation of nanocarrier and reduced the immune-related adverse events (irAEs) induced by on-target off-tumor αPD-L1. This dual-sensitive nanodrug demonstrates an effective immunotherapy paradigm for other dense ECM-characterized solid tumors.

Cation-free siRNA-cored nanocapsules for tumor-targeted RNAi therapy.

Cation-associated cytotoxicity limits the systemic administration of RNA delivery in vivo, demanding the development of non-cationic nanosystems. In this study, cation-free polymer-siRNA nanocapsules with disulfide-crosslinked interlayer, namely T-SS(-), were prepared via the following steps: 1) complexation of siRNA with a cationic block polymer cRGD-poly(ethylene glycol)-b-poly[(2-aminoethanethiol)aspartamide]-b-poly{N'-[N-(2-aminoethyl)-2-ethylimino-1-aminomethyl]aspartamide}, abbreviated as cRGD-PEG-PAsp(MEA)-PAsp(C=N-DETA), 2) interlayer crosslinking via disulfide bond in pH 7.4 solution, and 3) removal of cationic DETA pendant at pH 5.0 via breakage of imide bond. The cationic-free nanocapsules with siRNA cores not only showed great performance (such as efficient siRNA encapsulation, high stability in serum, cancer cell targeting via cRGD modification, and GSH-triggered siRNA release), but also achieved tumor-targeted gene silencing in vivo. Moreover, the nanocapsules loaded with siRNA against polo-like kinase 1 (siRNA-PLK1) significantly inhibited tumor growth without showing cation-associated toxicity side effects and remarkably improved the survival rate of PC-3 tumor-bearing mice. The cation-free nanocapsules could potentially serve as a safe and effective platform for siRNA delivery. STATEMENT OF SIGNIFICANCE: Cation-associated toxicity limits the clinical translation of cationic carriers for siRNA delivery. Recently, several non-cationic carriers, such as siRNA micelles, DNA-based nanogels, and bottlebrush-architectured poly(ethylene glycol), have been developed to deliver siRNA. However, in these designs, siRNA as a hydrophilic macromolecule was attached to the nanoparticle surface instead of being encapsulated. Thus, it was easily degraded by serum nuclease and often induced immunogenicity. Herein, we demonstrate a new type of cation-free siRNA-cored polymeric nanocapsules. The developed nanocapsules not only showed capacities including efficient siRNA encapsulation, high stability in serum, and cancer cell targeting via cRGD modification, but also achieved an efficient tumor-targeted gene silencing in vivo. Importantly, unlike cationic carriers, the nanocapsules exhibited no cation-associated side effects.

Fine-Tuned Polymer Nanoassembly for Codelivery of Chemotherapeutic Drug and siRNA.

Successful clinical application of siRNA to liver-associated diseases reinvigorates the RNAi therapeutics and delivery vectors, especially for anticancer combination therapy. Fine tuning of copolymer-based assembly configuration is highly important for a desirable synergistic cancer cell-killing effect via the codelivery of chemotherapeutic drug and siRNA. Herein, an amphiphilic triblock copolymer methoxyl poly(ethylene glycol)-block-poly(L-lysine)-block-poly(2-(diisopropyl amino)ethyl methacrylate) (abbreviated as mPEG-PLys-PDPA or PLD) consisting of a hydrophilic diblock mPEG-PLys and a hydrophobic block PDPA is synthesized. Three distinct assemblies (i.e., nanosized micelle, nanosized polymersome, and microparticle) are acquired, along with the increase in PDPA block length. Furthermore, the as-obtained polymersome can efficiently codeliver doxorubicin hydrochloride (DOX) as a hydrophilic chemotherapeutic model and siRNA against ADP-ribosylation factor 6 (siArf6) as an siRNA model into cancer cell via lysosomal pH-triggered payload release. PC-3 prostate cell is synergistically killed by the DOX- and siArf6-coloading polymersome (namely PLD@DOX/siArf6). PLD@DOX/siArf6 may serve as a robust nanomedicine for anticancer therapy.

Endothelial cell-derived exosomes boost and maintain repair-related phenotypes of Schwann cells via miR199-5p to promote nerve regeneration.

BACKGROUND: Schwann cells (SCs) respond to nerve injury by transforming into the repair-related cell phenotype, which can provide the essential signals and spatial cues to promote axonal regeneration and induce target reinnervation. Endothelial cells (ECs) contribute to intraneural angiogenesis contributing to creating a permissive microenvironment. The coordination between ECs and SCs within injury sites is crucial in the regeneration process, however, it still unclear. As the intercellular vital information mediators in the nervous system, exosomes have been proposed to take a significant role in regulating regeneration. Thus, the main purpose of this study is to determine the facilitative effect of ECs-derived exosomes on SCs and to seek the underlying mechanism. RESULTS: In the present study, we collected exosomes from media of ECs. We demonstrated that exosomes derived from ECs possessed the favorable neuronal affinity both in vitro and in vivo. Further research indicated that EC-exosomes (EC-EXO) could boost and maintain repair-related phenotypes of SCs, thereby enhancing axonal regeneration, myelination of regenerated axons and neurologically functional recovery of the injured nerve. MiRNA sequencing in EXO-treated SCs and control SCs indicated that EC-EXO significantly up-regulated expression of miR199-5p. Furthermore, this study demonstrated that EC-EXO drove the conversion of SC phenotypes in a PI3K/AKT/PTEN-dependent manner. CONCLUSION: In conclusion, our research indicates that the internalization of EC-EXO in SCs can promote nerve regeneration by boosting and maintaining the repair-related phenotypes of SCs. And the mechanism may be relevant to the up-regulated expression of miR199-5p and activation of PI3K/AKT/PTEN signaling pathway.

Comparison the efficacy and safety of different neoadjuvant regimens for resectable and borderline resectable pancreatic cancer: a systematic review and network meta-analysis.

BACKGROUND: To date, the optimal recommended specific neoadjuvant regimens for resectable or borderline resectable pancreatic cancer (RPC or BRPC) remain an unanswered issue. METHODS: We systematically searched the electronic databases to identify randomized controlled trials (RCTs) comparing different neoadjuvant therapy strategies for RPC or BRPC. The primary outcome was overall survival (OS). Comprehensive analyses and evaluations were performed using the single-arm, paired, and network meta-analyses. RESULTS: Twelve RCTs involving 1279 patients with RPC or BRPC were enrolled. The paired meta-analysis showed that neoadjuvant therapy improved OS for both RPC (hazard ratio (HR) 0.69, 95% c.i. 0.54 to 0.87) and BRPC (HR 0.60, 0.42 to 0.86) compared with upfront surgery (UP-S). Neoadjuvant chemotherapy (NAC) also improved OS for both RPC (HR 0.63, 0.47 to 0.85) and BRPC (HR 0.44, 0.27 to 0.71), while neoadjuvant chemoradiotherapy (NACR) improved OS only for BRPC (HR 0.68, 0.52 to 0.89) and not for RPC (HR 0.79, 0.54 to 1.16). Network meta-analysis found that NAC was superior to NACR in OS for RPC/BRPC (HR 0.58, 0.37 to 0.90). Neoadjuvant chemotherapy based on modified fluorouracil/folinic acid/irinotecan/oxaliplatin (NAC-mFFX) and neoadjuvant chemotherapy based on abraxane/gemcitabine (NAC-AG) ranked first and second in OS for RPC/BRPC. CONCLUSIONS: Both RPC and BRPC could obtain OS benefits from neoadjuvant therapy compared with UP-S, and NAC improved OS both in RPC and BRPC while NACR only improved OS in BRPC. Furthermore, NAC was superior to NACR, and NAC-mFFX and NAC-AG might be recommended sequentially as the best neoadjuvant therapy strategies.

Identification of efferocytosis-related subtypes in gliomas and elucidating their characteristics and clinical significance.

Introduction: Gliomas, the most prevalent tumors of the central nervous system, are known for their aggressive nature and poor prognosis. The heterogeneity among gliomas leads to varying responses to the same treatments, even among similar glioma types. In our study, we efferocytosis-related subtypes and explored their characteristics in terms of immune landscape, intercellular communication, and metabolic processes, ultimately elucidating their potential clinical implications. Methods and Results: We first identified efferocytosis-related subtypes in Bulk RNA-seq using the NMF algorithm. We then preliminarily demonstrated the correlation of these subtypes with efferocytosis by examining enrichment scores of cell death pathways, macrophage infiltration, and the expression of immune ligands. Our analysis of single-cell RNA-seq data further supported the association of these subtypes with efferocytosis. Through enrichment analysis, we found that efferocytosis-related subtypes differ from other types of gliomas in terms of immune landscape, intercellular communication, and substance metabolism. Moreover, we found that the efferocytosis-related classification is a prognostic factor with robust predictive performance by calculating the AUC values. We also found that efferocytosis-related subtypes, when compared with other gliomas in drug sensitivity, survival, and TIDE scores, show a clear link to the effectiveness of chemotherapy, radiotherapy, and immunotherapy in glioma patients. Discussion: We identified efferocytosis-related subtypes in gliomas by analyzing the expression of 137 efferocytosis-associated genes, exploring their characteristics in immune landscape, intercellular communication, metabolic processes, and genomic variations. Moreover, we discovered that the classification of efferocytosis-related subtypes has a strong prognostic predictive power and holds potential significance in guiding clinical treatment.