Fusobacterium nucleatum promotes tumor progression in KRAS p.G12D-mutant colorectal cancer by binding to DHX15.

Fusobacterium nucleatum (F. nucleatum) promotes intestinal tumor growth and its relative abundance varies greatly among patients with CRC, suggesting the presence of unknown, individual-specific effectors in F. nucleatum-dependent carcinogenesis. Here, we identify that F. nucleatum is enriched preferentially in KRAS p.G12D mutant CRC tumor tissues and contributes to colorectal tumorigenesis in Villin-Cre/KrasG12D+/- mice. Additionally, Parabacteroides distasonis (P. distasonis) competes with F. nucleatum in the G12D mouse model and human CRC tissues with the KRAS mutation. Orally gavaged P. distasonis in mice alleviates the F. nucleatum-dependent CRC progression. F. nucleatum invades intestinal epithelial cells and binds to DHX15, a protein of RNA helicase family expressed on CRC tumor cells, mechanistically involving ERK/STAT3 signaling. Knock out of Dhx15 in Villin-Cre/KrasG12D+/- mice attenuates the CRC phenotype. These findings reveal that the oncogenic effect of F. nucleatum depends on somatic genetics and gut microbial ecology and indicate that personalized modulation of the gut microbiota may provide a more targeted strategy for CRC treatment.

NIR-II imaging-guided precise photodynamic therapy for augmenting tumor-starvation therapy by glucose metabolism reprogramming interference.

Metabolic reprogramming is a mechanism by which cancer cells alter their metabolic patterns to promote cell proliferation and growth, thereby enabling their resistance to external stress. 2-Deoxy-D-glucose (2DG) can eliminate their energy source by inhibiting glucose glycolysis, leading to cancer cell death through starvation. However, a compensatory increase in mitochondrial metabolism inhibits its efficacy. Herein, we propose a synergistic approach that combines photodynamic therapy (PDT) with starvation therapy to address this challenge. To monitor the nanodrugs and determine the optimal triggering time for precise tumor therapy, a multifunctional nano-platform comprising lanthanide-doped nanoparticle (LnNP) cores was constructed and combined with mesoporous silicon shells loaded with 2DG and photosensitizer chlorin e6 (Ce6) in the mesopore channels. Under 980 nm near-infrared light excitation, the downshifted 1550 nm fluorescence signal in the second near-infrared (NIR-II, 1000-1700 nm) window from the LnNPs was used to monitor the accumulation of nanomaterials in tumors. Furthermore, upconverted 650 nm light excited the Ce6 to generate singlet oxygen for PDT, which damaged mitochondrial function and enhanced the efficacy of 2DG by inhibiting hexokinase 2 and lactate dehydrogenase A expressions. As a result, glucose metabolism reprogramming was inhibited and the efficiency of starvation therapy was significantly enhanced. Overall, the proposed NIR-II bioimaging-guided PDT-augmented starvation therapy, which simultaneously inhibited glycolysis and mitochondria, facilitated the effects of a cancer theranostic system.

Early enteral nutrition versus early supplemental parenteral nutrition in patients undergoing major abdominal surgery: a secondary analysis of 2 randomized clinical trials.

BACKGROUND: The effect of early isoenergetic feeding routes [early enteral nutrition (E-EN) or early supplemental parenteral nutrition (E-SPN)] on the outcome of patients undergoing major abdominal surgery is controversial. OBJECTIVES: The aim of this study was to investigate the impact of early isoenergetic EN compared with early isoenergetic SPN on nosocomial infections in patients undergoing major abdominal surgery. METHODS: This study is a secondary, post hoc analysis of data from 2 open-label randomized clinical trials. Participants were recruited from the general surgery department of 11 academic hospitals in China undergoing major abdominal surgery and with Nutritional Risk Screening 2002 score ≥3. All eligible patients were categorized into 2 groups based on their achievement of the 100% energy target on postoperative day (POD) 3: the E-EN group (n = 199) and the E-SPN group (n = 115). The primary outcome was the incidence of nosocomial infections between POD 3 and hospital discharge. RESULTS: In total, 314 patients [mean (SD) age, 59.2 (11.4) y; 113 (36.0%) females] were included. Patients in the E-EN group showed no significant difference in nosocomial infections compared with those in the E-SPN group {17/199 [8.5%] compared with 10/115 [8.7%], risk difference, 0.2% [95% confidence interval (CI): -6.3, 6.6]}. The hematological nutritional status of the E-EN group showed a significant improvement at discharge compared with the E-SPN group (albumin: 38.0 ± 6.0 g/L compared with 35.5 ± 7.6 g/L; mean difference, -2.5 g/L; 95% CI: -4.0, -1.0 g/L; prealbumin: 200.0 ± 8.0 mg/L compared with 158.4 ± 38.1 mg/L; mean difference, -41.6 mg/L; 95% CI: -41.7, -36.1 mg/L). Other indicators were comparable between groups. CONCLUSION: E-EN compared with isoenergetic SPN may not be associated with a reduced rate of nosocomial infection in patients undergoing major abdominal surgery, but may be associated with improved hematological nutritional status. TRIAL REGISTRATION NUMBER: This trial was registered at clinicaltrials.gov as NCT03115957 (https://clinicaltrials.gov/ct2/show/NCT03115957) and NCT03117348 (https://clinicaltrials.gov/ct2/show/NCT03117348).

TRAF4-Mediated LAMTOR1 Ubiquitination Promotes mTORC1 Activation and Inhibits the Inflammation-Induced Colorectal Cancer Progression.

Mechanistic target of rapamycin complex 1 (mTORC1) is a conserved serine/threonine kinase that integrates various environmental signals to regulate cell growth and metabolism. mTORC1 activation requires tethering to lysosomes by the Ragulator-Rag complex. However, the dynamic regulation of the interaction between Ragulator and Rag guanosine triphosphatase (GTPase) remains unclear. In this study, that LAMTOR1, an essential component of Ragulator, is dynamically ubiquitinated depending on amino acid abundance is reported. It is found that the E3 ligase TRAF4 directly interacts with LAMTOR1 and catalyzes the K63-linked polyubiquitination of LAMTOR1 at K151. Ubiquitination of LAMTOR1 by TRAF4 promoted its binding to Rag GTPases and enhanced mTORC1 activation, K151R knock-in or TRAF4 knock-out blocks amino acid-induced mTORC1 activation and accelerates the development of inflammation-induced colon cancer. This study revealed that TRAF4-mediated LAMTOR1 ubiquitination is a regulatory mechanism for mTORC1 activation and provides a therapeutic target for diseases involving mTORC1 dysregulation.

7-Dehydrocholesterol dictates ferroptosis sensitivity.

Ferroptosis, a form of regulated cell death that is driven by iron-dependent phospholipid peroxidation, has been implicated in multiple diseases, including cancer1-3, degenerative disorders4 and organ ischaemia-reperfusion injury (IRI)5,6. Here, using genome-wide CRISPR-Cas9 screening, we identified that the enzymes involved in distal cholesterol biosynthesis have pivotal yet opposing roles in regulating ferroptosis through dictating the level of 7-dehydrocholesterol (7-DHC)-an intermediate metabolite of distal cholesterol biosynthesis that is synthesized by sterol C5-desaturase (SC5D) and metabolized by 7-DHC reductase (DHCR7) for cholesterol synthesis. We found that the pathway components, including MSMO1, CYP51A1, EBP and SC5D, function as potential suppressors of ferroptosis, whereas DHCR7 functions as a pro-ferroptotic gene. Mechanistically, 7-DHC dictates ferroptosis surveillance by using the conjugated diene to exert its anti-phospholipid autoxidation function and shields plasma and mitochondria membranes from phospholipid autoxidation. Importantly, blocking the biosynthesis of endogenous 7-DHC by pharmacological targeting of EBP induces ferroptosis and inhibits tumour growth, whereas increasing the 7-DHC level by inhibiting DHCR7 effectively promotes cancer metastasis and attenuates the progression of kidney IRI, supporting a critical function of this axis in vivo. In conclusion, our data reveal a role of 7-DHC as a natural anti-ferroptotic metabolite and suggest that pharmacological manipulation of 7-DHC levels is a promising therapeutic strategy for cancer and IRI.

Targeting integrin α5 in fibroblasts potentiates colorectal cancer response to PD-L1 blockade by affecting extracellular-matrix deposition.

BACKGROUND: One reason patients with cancer cannot benefit from immunotherapy is the lack of immune cell infiltration in tumor tissues. Cancer-associated fibroblasts (CAFs) are emerging as central players in immune regulation that shapes tumor microenvironment (TME). Earlier we reported that integrin α5 was enriched in CAFs in colorectal cancer (CRC), however, its role in TME and cancer immunotherapy remains unclear. Here, we aimed to investigate the role for integrin α5 in fibroblasts in modulating antitumor immunity and therapeutic efficacy combined with checkpoint blockade in CRC. METHODS: We analyzed the CRC single-cell RNA sequencing (scRNA-seq) database to define the expression of ITGA5 in CRC tumor stroma. Experimentally, we carried out in vivo mouse tumor xenograft models to confirm the targeting efficacy of combined α5ß1 inhibition and anti-Programmed death ligand 1 (PD-L1) blockade and in vitro cell-co-culture assay to investigate the role of α5 in fibroblasts in affecting T-cell activity. Clinically, we analyzed the association between α5 expression and infiltrating T cells and evaluated their correlation with patient survival and immunotherapy prognosis in CRC. RESULTS: We revealed that ITGA5 was enriched in FAP-CAFs. Both ITGA5 knockout fibroblasts and therapeutic targeting of α5 improved response to anti-PD-L1 treatment in mouse subcutaneous tumor models. Mechanistically, these treatments led to increased tumor-infiltrating CD8+ T cells. Furthermore, we found that α5 in fibroblasts correlated with extracellular matrix (ECM)-related genes and affected ECM deposition in CRC tumor stroma. Both in vivo analysis and in vitro culture and cell killing experiment showed that ECM proteins and α5 expression in fibroblasts influence T-cell infiltration and activity. Clinically, we confirmed that high α5 expression was associated with fewer CD3+ T and CD8+ T cells, and tissues with low α5 and high CD3+ T levels correlated with better patient survival and immunotherapy response in a CRC cohort with 29 patients. CONCLUSIONS: Our study identified a role for integrin α5 in fibroblasts in modulating antitumor immunity by affecting ECM deposition and showed therapeutic efficacy for combined α5ß1 inhibition and PD-L1 blockade in CRC.

Colorectal cancer-associated T cell receptor repertoire abnormalities are linked to gut microbiome shifts and somatic cell mutations.

As with many diseases, tumor formation in colorectal cancer (CRC) is multifactorial and involves immune, environmental factors and various genetics that contribute to disease development. Accumulating evidence suggests that the gut microbiome is linked to the occurrence and development of CRC, and these microorganisms are important for immune maturation. However, a systematic perspective integrating microbial profiling, T cell receptor (TCR) and somatic mutations in humans with CRC is lacking. Here, we report distinct features of the expressed TCRß repertoires in the peripheral blood of and CRC patients (n = 107) and healthy donors (n = 30). CRC patients have elevated numbers of large TCRß clones and they have very low TCR diversity. The metagenomic sequencing data showed that the relative abundance of Fusobacterium nucleatum (F. nucleatum), Escherichia coli and Dasheen mosaic virus were elevated consistently in CRC patients (n = 97) compared to HC individuals (n = 30). The abundance of Faecalibacterium prausnitzii and Roseburia intestinalis was reduced in CRC (n = 97) compared to HC (n = 30). The correlation between somatic mutations of target genes (16 genes, n = 79) and TCR clonality and microbial biomarkers in CRC had been investigated. Importantly, we constructed a random forest classifier (contains 15 features) based on microbiome and TCR repertoires, which can be used as a clinical detection method to screen patients for CRC. We also analysis of F. nucleatum-specific TCR repertoire characteristics. Collectively, our large-cohort multi-omics data aimed to identify novel biomarkers to inform clinical decision-making in the detection and diagnosis of CRC, which is of possible etiological and diagnostic significance.

Construction of a novel cancer-associated fibroblast-related signature to predict clinical outcome and immune response in colon adenocarcinoma.

The interaction between the tumour and the surrounding microenvironment determines the malignant biological behaviour of the tumour. Cancer-associated fibroblasts (CAFs) coordinate crosstalk between cancer cells in the tumour immune microenvironment (TIME) and are extensively involved in tumour malignant behaviours, such as immune evasion, invasion and drug resistance. Here, we performed differential and prognostic analyses of genes associated with CAFs and constructed CAF-related signatures (CAFRs) to predict clinical outcomes in individuals with colon adenocarcinoma (COAD) based on machine learning algorithms. The CAFRs were further validated in an external independent cohort, GSE17538. Additionally, Cox regression, receiver operating characteristic (ROC) and clinical correlation analysis were utilised to systematically assess the CAFRs. Moreover, CIBERSORT, single sample Gene Set Enrichment Analysis (ssGSEA) and Estimation of Stromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE) analysis were utilised to characterise the TIME in patients with COAD. Microsatellite instability (MSI) and tumour mutation burden were also analysed. Furthermore, Gene Set Variation Analysis (GSVA), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) elucidated the biological functions and signalling pathways involved in the CAFRs. Consensus clustering analysis was used for the immunological analysis of patients with COAD. Finally, the pRRophic algorithm was used for sensitivity analysis of common drugs. The CAFRs constructed herein can better predict the prognosis in COAD. The cluster analysis based on the CAFRs can effectively differentiate between immune 'hot' and 'cold' tumours, determine the beneficiaries of immune checkpoint inhibitors (ICIs) and provide insight into individualised treatment for COAD.

The relationship between cadmium exposure and hepatitis B susceptibility and the establishment of its prediction model.

Cadmium, a common metal, is an environmental contaminant that is hepatotoxic and immunotoxic. Cadmium exposure may affect hepatitis B immunity. The purpose of this study was to assess the association between cadmium exposure and hepatitis B serology in the US population and to develop a model to predict susceptibility of hepatitis B. The study included 50,588 individuals in the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2016. Univariate and multivariate logistic regression and dose-response curves were used to evaluate the relationship between cadmium exposure and hepatitis B serology. Through multivariate logistic regression results, a predictive model was established, and relevant indicators were used to verify the clinical value of the model and evaluate prognostic value of serum cadmium concentration in patients with hepatitis B. We selected 5989 (≥ 6 years old) participants. Univariate logistic regression analysis showed that gender (aOR = 0.7192, 95% CI = 0.6492-0.7968), age (aOR = 1.030, 95% CI = 1.026-1.033), race (aOR = 0.8974, 95% CI = 0.8591-0.9374), poverty ratio (aOR = 1.042, 95% CI = 0.9872-1.101), body mass index (BMI) (aOR = 1.052, 95% CI = 1.044-1.061), hypertension (aOR = 2.017, 95% CI = 1.763-2.306), diabetes (aOR = 2.673, 95% CI = 2.119-3.370), vigorous recreational activities (aOR = 0.6369, 95% CI = 0.5725-0.7085), moderate recreational activity (aOR = 0.7681, 95% CI = 0.6935-0.8574) and cadmium (aOR = 1.295, 95% CI = 1.168-1.436) were closely related to hepatitis B virus (HBV) susceptibility. After adjusting for these confounding factors, multivariate logistic regression analysis showed that the odds ratio of HBV susceptibility was positively correlated with the level of cadmium in serum. The effectiveness of the model was then evaluated by establishing a nomogram, and by calibration curves, ROC curves, and clinical decision curves. Our study shows that cadmium exposure is positively associated with HBV susceptibility risk in the US population, and the constructed model has clinical significance.

Activation of autophagy by in situ Zn2+ chelation reaction for enhanced tumor chemoimmunotherapy.

Chemotherapy can induce a robust T cell antitumor immune response by triggering immunogenic cell death (ICD), a process in which tumor cells convert from nonimmunogenic to immunogenic forms. However, the antitumor immune response of ICD remains limited due to the low immunogenicity of tumor cells and the immunosuppressive tumor microenvironment. Although autophagy is involved in activating tumor immunity, the synergistic role of autophagy in ICD remains elusive and challenging. Herein, we report an autophagy amplification strategy using an ion-chelation reaction to augment chemoimmunotherapy in cancer treatments based on zinc ion (Zn2+)-doped, disulfiram (DSF)-loaded mesoporous silica nanoparticles (DSF@Zn-DMSNs). Upon pH-sensitive biodegradation of DSF@Zn-DMSNs, Zn2+ and DSF are coreleased in the mildly acidic tumor microenvironment, leading to the formation of toxic Zn2+ chelate through an in situ chelation reaction. Consequently, this chelate not only significantly stimulates cellular apoptosis and generates damage-associated molecular patterns (DAMPs) but also activates autophagy, which mediates the amplified release of DAMPs to enhance ICD. In vivo results demonstrated that DSF@Zn-DMSNs exhibit strong therapeutic efficacy via in situ ion chelation and possess the ability to activate autophagy, thus enhancing immunotherapy by promoting the infiltration of T cells. This study provides a smart in situ chelation strategy with tumor microenvironment-responsive autophagy amplification to achieve high tumor chemoimmunotherapy efficacy and biosafety.

Destroying pathogen-tumor symbionts synergizing with catalytic therapy of colorectal cancer by biomimetic protein-supported single-atom nanozyme.

The crucial role of intratumoral bacteria in the progression of cancer has been gradually recognized with the development of sequencing technology. Several intratumoral bacteria which have been identified as pathogens of cancer that induce progression, metastasis, and poor outcome of cancer, while tumor vascular networks and immunosuppressive microenvironment provide shelters for pathogens localization. Thus, the mutually-beneficial interplay between pathogens and tumors, named "pathogen-tumor symbionts", is probably a potential therapeutic site for tumor treatment. Herein, we proposed a destroying pathogen-tumor symbionts strategy that kills intratumoral pathogens, F. nucleatum, to break the symbiont and synergize to kill colorectal cancer (CRC) cells. This strategy was achieved by a groundbreaking protein-supported copper single-atom nanozyme (BSA-Cu SAN) which was inspired by the structures of native enzymes that are based on protein, with metal elements as the active center. BSA-Cu SAN can exert catalytic therapy by generating reactive oxygen species (ROS) and depleting GSH. The in vitro and in vivo experiments demonstrate that BSA-Cu SAN passively targets tumor sites and efficiently scavenges F. nucleatum in situ to destroy pathogen-tumor symbionts. As a result, ROS resistance of CRC through elevated autophagy mediated by F. nucleatum was relieved, contributing to apoptosis of cancer cells induced by intracellular redox imbalance generated by BSA-Cu SAN. Particularly, BSA-Cu SAN experiences renal clearance, avoiding long-term systemic toxicity. This work provides a feasible paradigm for destroying pathogen-tumor symbionts to block intratumoral pathogens interplay with CRC for antitumor therapy and an optimized trail for the SAN catalytic therapy by the clearable protein-supported SAN.

Methionine restriction promotes cGAS activation and chromatin untethering through demethylation to enhance antitumor immunity.

Cyclic GMP-AMP synthase (cGAS) is the major sensor for cytosolic DNA and activates type I interferon signaling and plays an essential role in antitumor immunity. However, it remains unclear whether the cGAS-mediated antitumor activity is affected by nutrient status. Here, our study reports that methionine deprivation enhances cGAS activity by blocking its methylation, which is catalyzed by methyltransferase SUV39H1. We further show that methylation enhances the chromatin sequestration of cGAS in a UHRF1-dependent manner. Blocking cGAS methylation enhances cGAS-mediated antitumor immunity and suppresses colorectal tumorigenesis. Clinically, cGAS methylation in human cancers correlates with poor prognosis. Thus, our results indicate that nutrient stress promotes cGAS activation via reversible methylation, and suggest a potential therapeutic strategy for targeting cGAS methylation in cancer treatment.

Effect of early achievement of energy target by different nutritional support strategies on nosocomial infections in patients undergoing major abdominal surgery: a secondary analysis of two randomized clinical trials.

BACKGROUND: The effect of early achievement of energy targets (EAETs) using different nutritional support strategies in patients undergoing major abdominal surgery is unclear. This study determined the impact of EAETs on the incidence of nosocomial infections in patients undergoing major abdominal surgery. METHODS: This was a secondary analysis of two open-label randomized clinical trials. Patients from the general surgery department of 11 academic hospitals in China undergoing major abdominal surgery and at nutritional risk (Nutritional risk screening 2002≥3) were divided into two groups based on whether they met the 70% energy targets, the EAET (521 EAET and non-achievement of energy target (114 NAET) groups. The primary outcome was the incidence of nosocomial infections between postoperative day 3 and discharge, and the secondary outcomes were actual energy and protein intake, postoperative noninfectious complications, intensive care unit admission, mechanical ventilation, and hospital stay. RESULTS: Overall, 635 patients [mean (SD) age, 59.5 (11.3) years] were included. The EAET group received more mean energy between days 3 and 7 than the NAET group (22.7±5.0 vs. 15.1±4.8 kcal/kg/d; P <0.001). The EAET group had significantly fewer nosocomial infections than the NAET group [46/521(8.8%) vs. 21/114(18.4%); risk difference, 9.6%; 95% CI, 2.1-17.1%; P =0.004]. A significant difference was found in the mean (SD) number of noninfectious complications between the EAET and NAET groups [121/521(23.2%) vs. 38/114(33.3%); risk difference, 10.1%; 95% CI, 0.7-19.5%; P =0.024]. The nutritional status of the EAET group was significantly improved at discharge compared with the NAET group ( P <0.001), and other indicators were comparable between groups. CONCLUSION: EAETs was associated with fewer nosocomial infections and improved clinical outcomes, regardless of the nutritional support strategy (early enteral nutrition alone or combined with early supplemental parenteral nutrition).

Modulation of Intratumoral Fusobacterium nucleatum to Enhance Sonodynamic Therapy for Colorectal Cancer with Reduced Phototoxic Skin Injury.

Intratumoral pathogens can contribute to cancer progression and affect therapeutic response. Fusobacterium nucleatum, a core pathogen of colorectal cancer (CRC), is an important cause of low therapeutic efficacy and metastasis. Thus, the modulation of intratumoral pathogens may provide a target for cancer therapy and metastasis inhibition. Herein, we propose an intratumoral F. nucleatum-modulating strategy for enhancing the therapeutic efficacy of CRC and inhibiting lung metastasis by designing an antibacterial nanoplatform (Au@BSA-CuPpIX), which produced reactive oxygen species (ROS) under ultrasound and exhibited strong antibacterial activity. Importantly, Au@BSA-CuPpIX reduced the levels of apoptosis-inhibiting proteins by inhibiting intratumoral F. nucleatum, thereby enhancing ROS-induced apoptosis. In vivo results demonstrated that Au@BSA-CuPpIX effectively eliminated F. nucleatum to enhance the therapeutic efficacy of sonodynamic therapy (SDT) for orthotopic CRC and inhibit lung metastasis. Notably, entrapped gold nanoparticles reduced the phototoxicity of metalloporphyrin accumulated in the skin during tumor treatment, preventing severe inflammation and damage to the skin. Therefore, this study proposes a strategy for the elimination of F. nucleatum in CRC to enhance the therapeutic effect of SDT, thus providing a promising paradigm for improving cancer treatment with fewer toxic side effects and promoting the clinical translational potential of SDT.

Pathogenesis and therapy of radiation enteritis with gut microbiota.

Radiotherapy is widely used in clinic due to its good effect for cancer treatment. But radiotherapy of malignant tumors in the abdomen and pelvis is easy to cause radiation enteritis complications. Gastrointestinal tract contains numerous microbes, most of which are mutualistic relationship with the host. Abdominal radiation results in gut microbiota dysbiosis. Microbial therapy can directly target gut microbiota to reverse microbiota dysbiosis, hence relieving intestinal inflammation. In this review, we mainly summarized pathogenesis and novel therapy of the radiation-induced intestinal injury with gut microbiota dysbiosis and envision the opportunities and challenges of radiation enteritis therapy.

Enzyme-catalyzed synthesis of selenium-doped manganese phosphate for synergistic therapy of drug-resistant colorectal cancer.

BACKGROUND: The development of multidrug resistance (MDR) during postoperative chemotherapy for colorectal cancer substantially reduces therapeutic efficacy. Nanostructured drug delivery systems (NDDSs) with modifiable chemical properties are considered promising candidates as therapies for reversing MDR in colorectal cancer cells. Selenium-doped manganese phosphate (Se-MnP) nanoparticles (NPs) that can reverse drug resistance through sustained release of selenium have the potential to improve the chemotherapy effect of colorectal cancer. RESULTS: Se-MnP NPs had an organic-inorganic hybrid composition and were assembled from smaller-scale nanoclusters. Se-MnP NPs induced excessive ROS production via Se-mediated activation of the STAT3/JNK pathway and a Fenton-like reaction due to the presence of manganese ions (Mn2+). Moreover, in vitro and in vivo studies demonstrated Se-MnP NPs were effective drug carriers of oxaliplatin (OX) and reversed multidrug resistance and induced caspase-mediated apoptosis in colorectal cancer cells. OX@Se-MnP NPs reversed MDR in colorectal cancer by down-regulating the expression of MDR-related ABC (ATP binding cassette) transporters proteins (e.g., ABCB1, ABCC1 and ABCG2). Finally, in vivo studies demonstrated that OX-loaded Se-MnP NPs significantly inhibited proliferation of OX-resistant HCT116 (HCT116/DR) tumor cells in nude mice. CONCLUSIONS: OX@Se-MnP NPs with simple preparation and biomimetic chemical properties represent promising candidates for the treatment of colorectal cancer with MDR.

Immune surveillance of brain metastatic cancer cells is mediated by IFITM1.

Brain metastasis, most commonly originating from lung cancer, increases cancer morbidity and mortality. Although metastatic colonization is the rate-limiting and most complex step of the metastatic cascade, the underlying mechanisms are poorly understood. Here, in vivo genome-wide CRISPR-Cas9 screening revealed that loss of interferon-induced transmembrane protein 1 (IFITM1) promotes brain colonization of human lung cancer cells. Incipient brain metastatic cancer cells with high expression of IFITM1 secrete microglia-activating complement component 3 and enhance the cytolytic activity of CD8+ T cells by increasing the expression and membrane localization of major histocompatibility complex class I. After activation, microglia (of the innate immune system) and cytotoxic CD8+ T lymphocytes (of the adaptive immune system) were found to jointly eliminate cancer cells by releasing interferon-gamma and inducing phagocytosis and T-cell-mediated killing. In human cancer clinical trials, immune checkpoint blockade therapy response was significantly correlated with IFITM1 expression, and IFITM1 enhanced the brain metastasis suppression efficacy of PD-1 blockade in mice. Our results exemplify a novel mechanism through which metastatic cancer cells overcome the innate and adaptive immune responses to colonize the brain, and suggest that a combination therapy increasing IFITM1 expression in metastatic cells with PD-1 blockade may be a promising strategy to reduce metastasis.

MnOOH-Catalyzed Autoxidation of Glutathione for Reactive Oxygen Species Production and Nanocatalytic Tumor Innate Immunotherapy.

The antioxidant system, signed with reduced glutathione (GSH) overexpression, is the key weapon for tumor to resist the attack by reactive oxygen species (ROS). Counteracting the ROS depletion by GSH is an effective strategy to guarantee the antitumor efficacy of nanocatalytic therapy. However, simply reducing the concentration of GSH does not sufficiently improve tumor response to nanocatalytic therapy intervention. Herein, a well-dispersed MnOOH nanocatalyst is developed to catalyze GSH autoxidation and peroxidase-like reaction concurrently and respectively to promote GSH depletion and H2O2 decomposition to produce abundant ROS such as hydroxyl radical (·OH), thereby generating a highly effective superadditive catalytic therapeutic efficacy. Such a therapeutic strategy that transforms endogenous "antioxidant" into "oxidant" may open a new avenue for the development of antitumor nanocatalytic medicine. Moreover, the released Mn2+ can activate and sensitize the cGAS-STING pathway to the damaged intratumoral DNA double-strands induced by the produced ROS to further promote macrophage maturation and M1-polarization, which will boost the innate immunotherapeutic efficacy. Resultantly, the developed simple MnOOH nanocatalytic medicine capable of simultaneously catalyzing GSH depletion and ROS generation, and mediating innate immune activation, holds great potential in the treatment of malignant tumors.

Effective personalized neoantigen vaccine plus anti-PD-1 in a PD-1 blockade-resistant lung cancer patient.

Background: Although significant progress has been made in immune checkpoint inhibitor (ICI) treatment of advanced squamous cell carcinoma (SqCC), most patients still experience acquired drug resistance. Methods: We used a dendritic cell-based neoantigen vaccine combined with ICIs to treat advanced SqCC in a PD-1 blockade-resistant patient. Results: The follow-up of this patient after 12 months revealed significant tumor regression. We also identified a new JAK1 ICI-resistant mutation that could become a potential universal neoantigen target for tumor vaccines. Conclusion: Individualized management of advanced SqCC through a combined neoantigen vaccine and ICI administration could yield beneficial clinical outcomes. Vaccines targeting anti-PD-1-resistant JAK1 mutations might be of particular benefit to a specific group of solid tumor patients.

Immunotherapy based on immune checkpoint inhibitors (ICIs) is very effective in lung cancer treatment. However, many patients with initial response will later develop resistance. There are not many treatment options for patients with drug resistance. Herein, we report a patient with lung cancer who became resistant to ICI, treated with personalized vaccine plus ICI. Based on the patient's own somatic mutational profile, personalized neoantigen vaccines were designed and manufactured unique to the patient. Our report indicated that personalized vaccine plus ICI was safe and might overcome ICI resistance. A new ICI resistance mutation on JAK1 as a potential universal neoantigen target for off-the-shelf vaccine was found, which is promising for the effective treatment of a specific group of patients with JAK1 mutations.