Multi-stage mechanisms of tumor metastasis and therapeutic strategies.

The cascade of metastasis in tumor cells, exhibiting organ-specific tendencies, may occur at numerous phases of the disease and progress under intense evolutionary pressures. Organ-specific metastasis relies on the formation of pre-metastatic niche (PMN), with diverse cell types and complex cell interactions contributing to this concept, adding a new dimension to the traditional metastasis cascade. Prior to metastatic dissemination, as orchestrators of PMN formation, primary tumor-derived extracellular vesicles prepare a fertile microenvironment for the settlement and colonization of circulating tumor cells at distant secondary sites, significantly impacting cancer progression and outcomes. Obviously, solely intervening in cancer metastatic sites passively after macrometastasis is often insufficient. Early prediction of metastasis and holistic, macro-level control represent the future directions in cancer therapy. This review emphasizes the dynamic and intricate systematic alterations that occur as cancer progresses, illustrates the immunological landscape of organ-specific PMN creation, and deepens understanding of treatment modalities pertinent to metastasis, thereby identifying some prognostic and predictive biomarkers favorable to early predict the occurrence of metastasis and design appropriate treatment combinations.

Clinical evaluation of oxaliplatin-loaded drug-eluting callispheres beads transarterial chemoembolization for unresectable or recurrent esophageal carcinoma.

BACKGROUND: A majority of esophageal carcinoma patients are diagnosed at an advanced stage and are no longer suitable for surgical resection. Drug-eluting beads transarterial chemoembolization (DEB-TACE) with oxaliplatin-loaded CalliSpheres beads (CB) have been used for advanced hepatocellular carcinoma and lung cancer, but they have not been reported for the treatment of unresectable or recurrent esophageal carcinoma. METHODS: DEB-TACE was performed on 22 patients with unresectable or recurrent esophageal carcinoma between March 2019 and May 2022. The clinical outcomes, complications, and efficacy were retrospectively recorded and analyzed. RESULTS: A total of 39 sessions of DEB-TACE were performed in 22 patients, with a technical success rate of 92.3% and clinical success rate of 65.0%. No severe complications such as procedure-related death, esophageal rupture or paraplegia were observed. Complete response, partial response, and stable disease were observed in 14.3% (2/14), 42.9% (6/14), and 21.4% (3/14) of patients 6 months after DEB-TACE, respectively. The objective response rates were 62.5%, 42.9% and 57.1% respectively at 1-, 3-, and 6-month after DEB-TACE. Subsequent interventional treatments were administered to 12 patients, including DEB-TACE for hepatic metastasis in 3 (13.6%), esophageal stenting in 5 (22.7%), and airway stent placement in 5 (22.7%). Two patients were lost to follow up. A total of 9 patients died due to tumor progression (n = 5), pneumatic infection (n = 1), and tumor-related massive esophageal hemorrhage (n = 3). The median overall survivals were 13.9 months and 26.5 months from the first session of DEB-TACE and the diagnosis of esophageal carcinoma, respectively. CONCLUSIONS: DEB-TACE with oxaliplatin-loaded CB is suggested as a safe and effective treatment of unresectable or recurrent esophageal carcinoma, and more studies are required to confirm its efficacy and safety.

Clinical outcomes of drug-coated balloons dilatation for benign esophageal stricture.

BACKGROUND: Drug-coated balloons (DCBs) angioplasty is safe and effective for coronary artery disease. However, DCBs dilatation for the treatment of benign esophageal strictures is rarely reported. PURPOSE: We aimed to report the clinical outcomes of DCBs dilatation for patients with benign esophageal strictures. METHODS: From May 2020 to August 2023, 18 patients underwent DCBs dilatation for benign esophageal strictures. Baseline demographics were recorded and evaluated, including gender, age, comorbidities, stricture diameter and length, dilatation session, complications. RESULTS: A total of 24 dilatation sessions of DCBs were performed, with a mean of 1.3 ± 0.6 sessions per patients (range 1.0-5.0). Dysphagia score decreased significantly after DCBs dilatation (2.6 ± 1.1 vs. 0.9 ± 1.3, p = 0.0002). Both stricture diameter and stricture index decreased significantly after DCBs dilatation (p < 0.0001). No procedure-related death, massive bleeding or esophageal perforation was observed during or after DCBs dilatation. Minor complications were found in only 3 patients (16.7%). All 18 patients were successfully followed up for a median period of 12.0 months. By the end of follow up, 10 patients showed no dysphagia, 6 patients showed mild dysphagia and 2 patients showed no improvement in dysphagia. The clinical success rate of DCBs dilatation is 88.9%. CONCLUSION: DCBs dilatation may be a safe, effective and feasible treatment for benign esophageal strictures, and can be utilized as an alternative option after standard dilatation has failed. Prospective studies with large samples are needed to further validate its clinical efficacy.

Targeting immunosenescence for improved tumor immunotherapy.

Tumor immunotherapy has significantly transformed the field of oncology over the past decade. An optimal tumor immunotherapy would ideally elicit robust innate and adaptive immune responses within tumor immune microenvironment (TIME). Unfortunately, immune system experiences functional decline with chronological age, a process termed "immunosenescence," which contributes to impaired immune responses against pathogens, suboptimal vaccination outcomes, and heightened vulnerability to various diseases, including cancer. In this context, we will elucidate hallmarks and molecular mechanisms underlying immunosenescence, detailing alterations in immunosenescence at molecular, cellular, organ, and disease levels. The role of immunosenescence in tumorigenesis and senescence-related extracellular matrix (ECM) has also been addressed. Recognizing that immunosenescence is a dynamic process influenced by various factors, we will evaluate treatment strategies targeting hallmarks and molecular mechanisms, as well as methods for immune cell, organ restoration, and present emerging approaches in immunosenescence for tumor immunotherapy. The overarching goal of immunosenescence research is to prevent tumor development, recurrence, and metastasis, ultimately improving patient prognosis. Our review aims to reveal latest advancements and prospective directions in the field of immunosenescence research, offering a theoretical basis for development of practical anti-immunosenescence and anti-tumor strategies.

Circadian disruption in cancer hallmarks: Novel insight into the molecular mechanisms of tumorigenesis and cancer treatment.

Circadian rhythms are 24-h rhythms governing temporal organization of behavior and physiology generated by molecular clocks composed of autoregulatory transcription-translation feedback loops (TTFLs). Disruption of circadian rhythms leads to a spectrum of pathologies, including cancer by triggering or being involved in different hallmarks. Clock control of phenotypic plasticity involved in tumorigenesis operates in aberrant dedifferentiating to progenitor-like cell states, generation of cancer stem cells (CSCs) and epithelial-to-mesenchymal transition (EMT) events. Circadian rhythms might act as candidates for regulatory mechanisms of cellular senescent and functional determinants of senescence-associated secretory phenotype (SASP). Reciprocal control between clock and epigenetics sheds light on post-transcriptional regulation of circadian rhythms and opens avenues for novel anti-cancer strategies. Additionally, disrupting circadian rhythms influences microbiota communities that could be associated with altered homeostasis contributing to cancer development. Herein, we summarize recent advances in support of the nexus between disruptions of circadian rhythms and cancer hallmarks of new dimensions, thus providing novel perspectives on potentially effective treatment approaches for cancer management.

Proteogenomics offers a novel avenue in neoantigen identification for cancer immunotherapy.

Cancer neoantigens are tumor-specific non-synonymous mutant peptides that activate the immune system to produce an anti-tumor response. Personalized cancer vaccines based on neoantigens are currently one of the most promising therapeutic approaches for cancer treatment. By utilizing the unique mutations within each patient's tumor, these vaccines aim to elicit a strong and specific immune response against cancer cells. However, the identification of neoantigens remains challenging due to the low accuracy of current prediction tools and the high false-positive rate of candidate neoantigens. Since the concept of "proteogenomics" emerged in 2004, it has evolved rapidly with the increased sequencing depth of next-generation sequencing technologies and the maturation of mass spectrometry-based proteomics technologies to become a more comprehensive approach to neoantigen identification, allowing the discovery of high-confidence candidate neoantigens. In this review, we summarize the reason why cancer neoantigens have become attractive targets for immunotherapy, the mechanism of cancer vaccines and the advances in cancer immunotherapy. Considerations relevant to the application emerging of proteogenomics technologies for neoantigen identification and challenges in this field are described.

Infiltrating treg reprogramming in the tumor immune microenvironment and its optimization for immunotherapy.

Immunotherapy has shown promising anti-tumor effects across various tumors, yet it encounters challenges from the inhibitory tumor immune microenvironment (TIME). Infiltrating regulatory T cells (Tregs) are important contributors to immunosuppressive TIME, limiting tumor immunosurveillance and blocking effective anti-tumor immune responses. Although depletion or inhibition of systemic Tregs enhances the anti-tumor immunity, autoimmune sequelae have diminished expectations for the approach. Herein, we summarize emerging strategies, specifically targeting tumor-infiltrating (TI)-Tregs, that elevate the capacity of organisms to resist tumors by reprogramming their phenotype. The regulatory mechanisms of Treg reprogramming are also discussed as well as how this knowledge could be utilized to develop novel and effective cancer immunotherapies.

Percutaneous transhepatic papillary ballooning and extraction for common bile duct stones: a single-center experience.

Background: At present, some common bile duct stones (CBDSs) cannot be removed by conventional endoscopic treatment. Percutaneous transhepatic papillary ballooning and extraction (PTPBE) is a promising treatment for CBDSs. This study aimed to evaluate the feasibility and efficacy of PTPBE for removing CBDSs. Methods: From April 2013 to April 2021, 29 patients with CBDSs underwent PTPBE at The First Affiliated Hospital of Zhengzhou University; their clinical data were retrospectively analyzed. The technical success, clinical success, procedure time, radiation dose, 1-year CBDSs recurrence rate, and incidence of early/late complications were recorded, and white blood cell (WBC) counts and alanine aminotransferase (ALT), C-reactive protein (CRP), total bilirubin (TBIL), and carbohydrate antigen-199 (CA-199) levels were compared before the interventional procedure and 1 month later. Results: The CBDSs were successfully removed in 29 patients (the CBDSs in 20 patients were resolved once, and in 9 patients, they were resolved twice). The mean procedure time and radiation dose were 56.38±13.56 minutes and 732.07±262.23 miligray (mGy), respectively. The technical and clinical success rates were both 100%. The incidence of early complications (including pancreatitis and bile duct bleeding) and late complications (reflux cholangitis) was 10.34% and 3.45%, respectively. The WBC (both P<0.01), ALT (both P<0.01), CRP (both P<0.01), CA-199 (both P<0.01), and TBIL (both P<0.01) significantly decreased before PTPBE and 1 month later. Conclusions: PTPBE is a safe and effective alternative solution for elderly patients who cannot undergo or refuse traditional surgical and endoscopic treatments.

Combining transcatheter arterial embolization with endoscopic debulking for hypervascular airway tumor management: a retrospective single center study.

Background: Airway obstruction due to tumor invasion or concurrent respiratory distress and hemoptysis poses a significant challenge in clinical management, often requiring prompt and effective intervention to alleviate symptoms and improve patient outcomes. This study aimed to evaluate the efficacy and safety of selective transcatheter arterial embolization (TAE) as a preparatory measure to mitigate airway obstruction before bronchoscopic debulking as an approach to address this clinical challenge. Methods: The data of patients with airway obstruction due to tumor invasion or concurrent respiratory distress and hemoptysis treated at The First Affiliated Hospital of Zhengzhou University from January 2018 to August 2022 were analyzed. After computed tomography (CT) scans and bronchoscopic findings were assessed, selective TAE was performed as a preparatory measure to alleviate airway obstruction before bronchoscopic debulking, and the occurrence of hemorrhage-related complications, Karnofsky Performance Status (KPS) score, breathlessness index, and the extent of airway obstruction were evaluated. Results: All 22 patients underwent selective TAE before bronchoscopic tumor debulking. The overall efficacy rate was 100%, with a significant improvement in the KPS score from preoperative (60.45±14.63) to postoperative (74.55±9.63) levels (t=-6.891; P<0.001). Similarly, there was a considerable reduction in the shortness of breath score from preoperative (2.91±0.81) to postoperative (1.73±0.63) levels (t=6.973; P<0.001). Airway obstruction decreased substantially from preoperative (79.14%±14.56%) to postoperative (21.27%±7.19%) levels (t=26.857; P<0.001). Furthermore, the severity classification of airway obstruction decreased from preoperative (4±0.82) to postoperative (1.36±0.49) levels (t=18.794; P<0.001). Among the patients, only one experienced moderate bleeding necessitating prolonged mechanical balloon compression and intracavitary lesion removal, while the other patients had minor and negligible bleeding. Conclusions: TAE combined with endoscopic debulking can effectively control intraoperative bleeding and respiratory distress and achieve successful local resolution of endotracheal hypervascular tumors.

Risk factors for acute pancreatitis post percutaneous transhepatic biliary stenting in patients with distal malignant obstruction.

Background: Percutaneous transhepatic biliary stenting (PTBS) is an effective treatment for distal malignant biliary obstruction (MBO). Postoperative acute pancreatitis (AP) is a dangerous complication of this procedure. This study sought to investigate the risk factors for AP after PTBS. Methods: A total of 463 patients who underwent PTBS to treat suspected MBO from October 2012 to October 2021 were enrolled in this retrospective study. Among them, 26 individuals met the diagnostic criteria for postoperative pancreatitis following PTBS. The incidence of AP at 1 month postoperatively was recorded and analyzed. Several risk factors for AP were analyzed, and the odds ratios (ORs) were calculated by univariate and multivariate logistic analyses. Results: The incidence of AP after PTBS was 10.88% (26/239). The results of the multivariate analyses showed that repeated bile duct hemorrhage (OR =14.370, P=0.0001), intraoperative dilation (OR =7.848, P=0.0003), an operation time >50 min (OR =5.783, P=0.0009), and previous endoscopic intervention (OR =5.468, P=0.0021) were correlated with a high incidence of AP, while sex, age, time to biliary obstruction, body mass index, Eastern Cooperative Oncology Group score, previous anticancer treatments, forceps biopsy, obstruction length, stent size, contrast volume, operators, 125I strand placement, and blood parameters were not significantly correlated with AP (all P>0.05). Conclusions: A long operation time, intraoperative dilation, repeated bile duct hemorrhage, and previous endoscopic intervention were independent risk factors for AP. These factors should be considered by clinicians in future practice.

High ratio of resident to exhausted CD4 + T cells predicts favorable prognosis and potentially better immunotherapeutic efficacy in hepatocellular carcinoma.

BACKGROUND: Tumor-infiltrating lymphocytes (TILs) are significantly implicated in regulating the tumor immune microenvironment (TIME) and immunotherapeutic response. However, little is known about the impact of the resident and exhausted status of TILs in hepatocellular carcinoma (HCC). METHODS: Single-cell RNA sequencing data was applied to discover resident and exhausted signatures of TILs. Survival outcomes, biological function, immune infiltration, genomic variation, immunotherapeutic efficacy, and sorafenib response were further explored the clinical significance and molecular association of TILs in HCC. Moreover, a candidate gene with predictive capability for the dismal subtype was identified through univariate Cox regression analysis, survival analysis, and the BEST website. RESULTS: Single-cell analysis revealed that CD8 + T, CD4 + T, and NK cells were strongly associated with resident and exhausted patterns. Specific resident and exhausted signatures for each subpopulation were extracted in HCC. Further multivariate Cox analysis revealed that the ratio of resident to exhausted CD4 + T cells in TIME was an independent prognostic factor. After incorporating tumor purity with the ratio of resident to exhausted CD4 + T cells, we stratified HCC patients into three subtypes and found that (i) CD4 residencyhighexhaustionlow subtype was endowed with favorable prognosis, immune activation, and sensitivity to immunotherapy; (ii) CD4 exhaustionhighresidencylow subtype was characterized by genome instability and sensitivity to sorafenib; (iii) Immune-desert subtype was associated with malignant-related pathways and poor prognosis. Furthermore, spindle assembly abnormal protein 6 homolog (SASS6) was identified as a key gene, which accurately predicted the immune-desert subtype. Prognostic analysis as well as in vitro and in vivo experiments further demonstrated that SASS6 was closely associated with tumor prognosis, proliferation, and migration. CONCLUSIONS: The ratio of resident to exhausted CD4 + T cells shows promise as a potential biomarker for HCC prognosis and immunotherapy response and SASS6 may serve as a biomarker and therapeutic target for prognostic assessment of HCC.

Pingyangmycin-loaded drug-eluting beads transarterial embolisation for giant cavernous haemangioma of the liver: A case report.

Purpose: Cavernous haemangioma of the liver (CHL) is the most common venous malformation of the liver. Surgical resection is considered the gold standard for large symptomatic haemangiomas. Transarterial embolisation has demonstrated acceptable efficacy with lower rates of morbidity and mortality. We report the first case of a 59-year-old man with a giant CHL treated using pingyangmycin drug-eluting bead transarterial embolisation (DEB-TACE). Material and methods: A 59-year-old man presented to our hospital with cough and sputum, most probably related to the mass effect of the haemangioma and secondary lung collapse. Computed tomography (CT) revealed a 187.5 mm × 142.7 mm cavernous haemangioma located in the right lobe of the liver. He underwent DEB-TACE, and a 2.6-F microcatheter was used to selectively catheterise the right hepatic artery. One vial of 300-500-µm CalliSpheres microspheres loaded with 8-mg pingyangmycin and two vials of 100-300-µm microspheres were injected through the microcatheter until the disappearance of CHL staining. Results: The patient experienced mild abdominal pain on the second day after embolisation. A reduction in CHL size to 106.7 × 141.3 mm was observed on the 1.1-month follow-up CT. We performed a second similar DEB-TACE, which resulted in further size reduction to 83.1 × 50.1 mm, as detected on the follow-up CT at 4.6 months. At the 8.7-month follow-up, his clinical symptoms improved with no cough or sputum and the CHL size further reduced to 63.2 × 55.8 mm. Conclusion: We report the first case of a giant CHL treated using DEB-TACE. Although DEB-TACE may be an effective and safe alternative for treating of giant CHL, an in vitro study on the efficient loading and binding of pingyangmycin with microspheres and more comparative studies with larger samples are required to further confirm its safety and efficacy.

Associations Between Cardiovascular Health (Life's Essential 8) and Mental Disorders.

BACKGROUND: Mental health was closely associated with cardiovascular disease (CVD). We aimed to investigate the association between cardiovascular health (CVH), as defined by Life's Essential 8 (LE8), and the presence of depression and anxiety. HYPOTHESIS: We hypothesized that CVH, as defined by LE8, was negatively associated with the prevalence of depression and anxiety. METHODS: A cross-sectional study was conducted on participants (≥ 20 years old) from the National Health and Nutrition Examination Survey (NHANES). The LE8 score (ranging from 0 to 100) was composed of the health behavior score and the health factor score, which were further categorized into three levels as follows: low (0-49), moderate (50-79), and high (80-100). Weighted multivariable logistic regressions and restricted cubic splines were utilized to assess the association between LE8 and mental disorders. RESULTS: Among the 13 028 participants included in this research, 1206 were determined to have depression symptoms and 2947 were determined to have anxiety symptoms. In the weighted and adjusted model, LE8 was negatively associated with the prevalence of depression (odds ratio [OR], 95% confidence interval [CI]: 0.61, 0.58-0.65) and anxiety (OR, 95% CI: 0.78, 0.75-0.81). Furthermore, a nonlinear dose-response relationship was observed between LE8 and anxiety. CONCLUSIONS: CVH defined by the LE8 was independently and negatively associated with the prevalence of depression and anxiety. Interventions targeting LE8 components may improve both CVH and mental health.

Graphene oxide-loaded rapamycin coating on airway stents inhibits stent-related granulation tissue hyperplasia.

OBJECTIVES: Our objective was to explore the safety and efficacy of a graphene oxide-loaded rapamycin-coated self-expandable metallic airway stent (GO@RAPA-SEMS) in a rabbit model. METHODS: The dip coating method was used to develop a GO@RAPA-SEMS and a poly(lactic-co-glycolic)-acid loaded rapamycin-coated self-expandable metallic airway stent (PLGA@RAPA-SEMS). The surface structure was evaluated using a scanning electronic microscope. The in vitro drug-release profiles of the 2 stents were explored and compared. In the animal study, a total of 45 rabbits were randomly divided into 3 groups and underwent 3 kinds of stent placements. Computed tomography was performed to evaluate the degree of stenosis at 1, 2 and 3 months after the stent operation. Five rabbits in each group were sacrificed after the computed tomography scan. The stented trachea and blood were collected for further pathological analysis and laboratory testing. RESULTS: The in vitro drug-release study revealed that GO@RAPA-SEMS exhibited a sudden release on the first day and maintained a certain release rate on the 14th day. The PLGA@RAPA-SEMS exhibited a longer sustained release time. All 45 rabbits underwent successful stent placement. Pathological results indicated that the granulation tissue thickness in the GO@RAPA-SEMS group was less than that in the PLGA@RAPA-SEMS group. The TUNEL and hypoxia-inducible factor-1α staining results support the fact that the granulation inhibition effect in the GO@RAPA-SEMS group was greater than that in the PLGA@RAPA-SEMS group. CONCLUSIONS: GO@RAPA-SEMS effectively inhibited stent-related granulation tissue hyperplasia.

Molecular subtypes of colorectal cancer in the era of precision oncotherapy: Current inspirations and future challenges.

BACKGROUND: Colorectal cancer (CRC) is among the most hackneyed malignancies. Even patients with identical clinical symptoms and the same TNM stage still exhibit radically different clinical outcomes after receiving equivalent treatment regimens, indicating extensive heterogeneity of CRC. Myriad molecular subtypes of CRC have been exploited for decades, including the most compelling consensus molecular subtype (CMS) classification that has been broadly applied for patient stratification and biomarker-drug combination formulation. Encountering barriers to clinical translation, however, CMS classification fails to fully reflect inter- or intra-tumor heterogeneity of CRC. As a consequence, addressing heterogeneity and precisely managing CRC patients with unique characteristics remain arduous tasks for clinicians. REVIEW: In this review, we systematically summarize molecular subtypes of CRC and further elaborate on their clinical applications, limitations, and future orientations. CONCLUSION: In recent years, exploration of subtypes through cell lines, animal models, patient-derived xenografts (PDXs), organoids, and clinical trials contributes to refining biological insights and unraveling subtype-specific therapies in CRC. Therapeutic interventions including nanotechnology, clustered regulatory interspaced short palindromic repeat/CRISPR-associated nuclease 9 (CRISPR/Cas9), gut microbiome, and liquid biopsy are powerful tools with the possibility to shift the immunologic landscape and outlook for CRC precise medicine.

Molecular subtypes of ischemic heart disease based on circadian rhythm.

Coronary atherosclerotic heart disease (CAD) is among the most prevalent chronic diseases globally. Circadian rhythm disruption (CRD) is closely associated with the progression of various diseases. However, the precise role of CRD in the development of CAD remains to be elucidated. The Circadian rhythm disruption score (CRDscore) was employed to quantitatively assess the level of CRD in CAD samples. Our investigation revealed a significant association between high CRDscore and adverse prognosis in CAD patients, along with a substantial correlation with CAD progression. Remarkably distinct CRDscore distributions were also identified among various subtypes. In summary, we have pioneered the revelation of the relationship between CRD and CAD at the single-cell level and established reliable markers for the development, treatment, and prognosis of CAD. A deeper understanding of these mechanisms may offer new possibilities for incorporating "the therapy of coronary heart disease based circadian rhythm" into personalized medical treatment regimens.

Cell Membrane Hybrid Lipid Nanovesicles Enhance Innate Immunity for Synergistic Immunotherapy by Promoting Immunogenic Cell Death and cGAS Activation.

Immunotherapy shows great therapeutic potential for long-term protection against tumor relapse and metastasis. Innate immune sensors, such as cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING), dissolve DNA and induce type I interferon. Through activation of the cGAS/STING pathway, chemotherapy drugs and reversine (REV) may provide synergetic anti-tumor effects. Here, we prepared drug-loaded cell membrane hybrid lipid nanovesicles (LEVs) (designated LEV@DOX@REV) by fusion of cell membranes, phospholipids, doxorubicin (DOX), and REV, to realize accurate delivery to tumors and chemo-immunotherapy. The cell membranes of LEVs confer "homing" abilities. DOX can induce immunogenic cell death as a result of its specific immunomodulatory effects, which promotes the maturation of immune cells and improves the microenvironment of the immune system. REV is proven to efficiently activate cGAS/STING signaling, thereby enhancing the immune system. The antitumor efficacy of LEV@DOX@REV was evaluated in a 4T1 subcutaneous tumor xenograft model, a distant metastatic tumor model, and a liver metastatic tumor model. LEV@DOX@REV facilitated the infiltration of cytotoxic T lymphocytes within tumors, increased the secretion of proinflammatory cytokines, and modified the tumor microenvironment. In conclusion, LEV@DOX@REV displayed favorable antitumor effects and extended the survival of tumor-bearing mice. We therefore successfully developed nanoparticles capable of enhancing immune activation that have potential therapeutic applications for cancer immunotherapy.