Wilm′s tumor gene1肽疫苗Galinpepimut-S在肿瘤免疫治疗中的应用

目的为Wilm′s tumor gene1(WT1)肽疫苗Galinpepimut-S(GPS)用于肿瘤免疫治疗的后续研究提供参考。方法采用计算机检索中国知网、PubMed等数据库自建库起至2022年12月的肿瘤免疫治疗相关文献,总结GPS在肿瘤免疫治疗中的应用现状。结果GPS能激发自身免疫系统,对WT1抗原产生强烈免疫反应而发挥抗肿瘤作用,在卵巢癌、恶性胸膜间皮瘤、急性髓系白血病、多发性骨髓瘤的治疗中均显示出较好的疗效。结论以GPS为代表的肿瘤疫苗是未来肿瘤治疗的重要方向,需进一步进行临床研究,以获取更多数据。

Association of tumor budding with clinicopathological features and prognostic value in stage III-IV colorectal cancer

BACKGROUND Tumor budding(TB)has emerged as a promising independent prognostic biomarker in colorectal cancer(CRC).The prognostic role of TB has been extensively studied and currently affects clinical decision making in patients with stage I and II CRC.However,existing prognostic studies on TB in stage III CRC have been confined to small retrospective cohort studies.Consequently,this study investigated the correlation among TB categories,clinicopathological features,and prognosis in stage III-IV CRC to further enhance the precision and individualization of treatment through refined prognostic risk stratification.AIM To analyze the relationship between TB categories and clinicopathological characteristics and assess their prognostic value in stage III-IV CRC to further refine the prognostic risk stratification of stage III-IV CRC.METHODS The clinical data of 547 CRC patients were collected for this retrospective study.Infiltration at the front edge of the tumor buds was counted according to the 2016 International Tumor Budding Consensus Conference guidelines.RESULTS Multivariate Cox proportional hazards regression analysis demonstrated that chemotherapy(P=0.004),clinical stage IV(P<0.001),≥4 regional lymph node metastases(P=0.004),left-sided colonic cancer(P=0.040),and Bd 2-3(P=0.002)were independent prognostic factors in patients with stage III-IV CRC.Moreover,the density of tumor infiltrating lymphocytes was higher in Bd 1 than in Bd 2-3,both in the tumor stroma and its invasive margin.CONCLUSION TB has an independent predictive prognostic value in patients with stage III-IV CRC.It is recommended to complete the TB report of stage III-IV CRC cases in the standardized pathological report to further refine risk stratification.

Comprehensive review of hepatocellular carcinoma with portal vein tumor thrombus:State of art and future perspectives

Background:Despite advances in the diagnosis of patients with hepatocellular carcinoma(HCC),70%-80%of patients are diagnosed with advanced stage disease.Portal vein tumor thrombus(PVTT)is among the most ominous signs of advanced stage disease and has been associated with poor survival if untreated.Data sources:A systematic search of MEDLINE(PubMed),Embase,Cochrane Library and Database for Systematic Reviews(CDSR),Google Scholar,and National Institute for Health and Clinical Excellence(NICE)databases until December 2022 was conducted using free text and MeSH terms:hepatocellular carcinoma,portal vein tumor thrombus,portal vein thrombosis,vascular invasion,liver and/or hepatic resection,liver transplantation,and systematic review.Results:Centers of surgical excellence have reported promising results related to the individualized surgical management of portal thrombus versus arterial chemoembolization or systemic chemotherapy.Critical elements to the individualized surgical management of HCC and portal thrombus include precise classification of the portal vein tumor thrombus,accurate identification of the subgroups of patients who may benefit from resection,as well as meticulous surgical technique.This review addressed five specific areas:(a)formation of PVTT;(b)classifications of PVTT;(c)controversies related to clinical guidelines;(d)surgical treatments versus non-surgical approaches;and(e)characterization of surgical techniques correlated with classifications of PVTT.Conclusions:Current evidence from Chinese and Japanese high-volume centers demonstrated that patients with HCC and associated PVTT can be managed with surgical resection with acceptable results.

New roles of tumor-derived exosomes in tumor microenvironment

Throughout tumorigenesis, the co-evolution of tumor cells and their surrounding microenvironment leads to the development of malignant phenotypes. Cellular communication within the tumor microenvironment(TME) plays a critical role in influencing various aspects of tumor progression, including invasion and metastasis. The release of exosomes, a type of extracellular vesicle, by most cell types in the body, is an essential mediator of intercellular communication. A growing body of research indicates that tumor-derived exosomes(TDEs) significantly expedite tumor progression through multiple mechanisms, inducing epithelial-mesenchymal transition and macrophage polarization, enhancing angiogenesis, and aiding in the immune evasion of tumor cells. Herein, we describe the formation and characteristics of the TME, and summarize the contents of TDEs and their diverse functions in modulating tumor development. Furthermore, we explore potential applications of TDEs in tumor diagnosis and treatment.

Calculus bovis inhibits M2 tumor-associated macrophage polarization via Wnt/β-catenin pathway modulation to suppress liver cancer

BACKGROUND Calculus bovis(CB),used in traditional Chinese medicine,exhibits anti-tumor effects in various cancer models.It also constitutes an integral component of a compound formulation known as Pien Tze Huang,which is indicated for the treatment of liver cancer.However,its impact on the liver cancer tumor microenvironment,particularly on tumor-associated macrophages(TAMs),is not well understood.AIM To elucidate the anti-liver cancer effect of CB by inhibiting M2-TAM polarization via Wnt/β-catenin pathway modulation.METHODS This study identified the active components of CB using UPLC-Q-TOF-MS,evaluated its anti-neoplastic effects in a nude mouse model,and elucidated the underlying mechanisms via network pharmacology,transcriptomics,and molecular docking.In vitro assays were used to investigate the effects of CB-containing serum on HepG2 cells and M2-TAMs,and Wnt pathway modulation was validated by real-time reverse transcriptase-polymerase chain reaction and Western blot analysis.RESULTS This study identified 22 active components in CB,11 of which were detected in the bloodstream.Preclinical investigations have demonstrated the ability of CB to effectively inhibit liver tumor growth.An integrated approach employing network pharmacology,transcriptomics,and molecular docking implicated the Wnt signaling pathway as a target of the antineoplastic activity of CB by suppressing M2-TAM polarization.In vitro and in vivo experiments further confirmed that CB significantly hinders M2-TAM polarization and suppresses Wnt/β-catenin pathway activation.The inhibitory effect of CB on M2-TAMs was reversed when treated with the Wnt agonist SKL2001,confirming its pathway specificity.CONCLUSION This study demonstrated that CB mediates inhibition of M2-TAM polarization through the Wnt/β-catenin pathway,contributing to the suppression of liver cancer growth.

Advancements in medical treatment for pancreatic neuroendocrine tumors:A beacon of hope

This editorial highlights the remarkable advancements in medical treatment strategies for pancreatic neuroendocrine tumors(pan-NETs),emphasizing tailored approaches for specific subtypes.Cytoreductive surgery and somatostatin analogs(SSAs)play pivotal roles in managing tumors,while palliative options such as molecular targeted therapy,peptide receptor radionuclide therapy,and chemotherapy are reserved for SSA-refractory patients.Gastrinomas,insul-inomas,glucagonomas,carcinoid tumors and VIPomas necessitate distinct thera-peutic strategies.Understanding the genetic basis of pan-NETs and exploring immunotherapies could lead to promising avenues for future research.This review underscores the evolving landscape of pan-NET treatment,offering renewed hope and improved outcomes for patients facing this complex disease.

Mycobacterium smegmatis enhances shikonin-induced immunogenic cell death—an efficient in situ tumor vaccine strategy

Tumor vaccines are a promising avenue in cancer immunotherapy.Despite the progress in targeting specific immune epitopes,tumor cells lacking these epitopes can evade the treatment.Here,we aimed to construct an efficient in situ tumor vaccine called Vac-SM,utilizing shikonin(SKN)to induce immunogenic cell death(ICD)and Mycobacterium smegmatis as an immune adjuvant to enhance in situ tumor vaccine efficacy.SKN showed a dose-dependent and time-dependent cytotoxic effect on the tumor cell line and induced ICD in tumor cells as evidenced by the CCK-8 assay and the detection of the expression of relevant indicators,respectively.Compared with the control group,the in situ Vac-SM injection in mouse subcutaneous metastatic tumors significantly inhibited tumor growth and distant tumor metastasis,while also improving survival rates.Mycobacterium smegmatis effectively induced maturation and activation of bone marrow-derived dendritic cells(DCs),and in vivo tumor-draining lymph nodes showed an increased maturation of DCs and a higher proportion of effector memory T-cell subsets with the Vac-SM treatment,based on flow cytometry analysis results.Collectively,the Vac-SM vaccine effectively induces ICD,improves antigen presentation by DCs,activates a specific systemic antitumor T-cell immune response,exhibits a favorable safety profile,and holds the promise for clinical translation for local tumor immunotherapy.

Circulating tumor DNA in liquid biopsy: Current diagnostic limitation

With the rapid development of science and technology,cell-free DNA(cfDNA)is rapidly becoming an important biomarker for tumor diagnosis,monitoring and prognosis,and this cfDNA-based liquid biopsy technology has great potential to become an important part of precision medicine.cfDNA is the total amount of free DNA in the systemic circulation,including DNA fragments derived from tumor cells and all other somatic cells.Tumor cells release fragments of DNA into the bloodstream,and this source of cfDNA is called circulating tumor DNA(ctDNA).cfDNA detection has become a major focus in the field of tumor research in recent years,which provides a new opportunity for non-invasive diagnosis and prognosis of cancer.In this paper,we discuss the limitations of the study on the origin and dynamics analysis of ctDNA,and how to solve these problems in the future.Although the future faces major challenges,it also con-tains great potential.

Double-nylon purse-string suture in closing postoperative wounds following endoscopic resection of large(≥3 cm)gastric submucosal tumors

BACKGROUND Endoscopic full-thickness resection(EFTR)of gastric submucosal tumors(SMTs)is safe and effective;however,postoperative wound management is equally important.Literature on suturing following EFTR for large(≥3 cm)SMTs is scarce and limited.AIM To evaluate the efficacy and clinical value of double-nylon purse-string suture in closing postoperative wounds following EFTR of large(≥3 cm)SMTs.METHODS We retrospectively analyzed the data of 85 patients with gastric SMTs in the fundus of the stomach or in the lesser curvature of the gastric body whose wounds were treated with double-nylon purse-string sutures after successful tumor resection at the Endoscopy Center of Renmin Hospital of Wuhan University.The operative,postoperative,and follow-up conditions of the patients were evaluated.RESULTS All tumors were completely resected using EFTR.36(42.35%)patients had tumors located in the fundus of the stomach,and 49(57.65%)had tumors located in the body of the stomach.All patients underwent suturing with double-nylon sutures after EFTR without laparoscopic assistance or further surgical treatment.Postoperative fever and stomach pain were reported in 13(15.29%)and 14(16.47%)patients,respectively.No serious adverse events occurred during the intraoperative or postoperative periods.A postoperative review of all patients revealed no residual or recurrent lesions.CONCLUSION Double-nylon purse-string sutures can be used to successfully close wounds that cannot be completely closed with a single nylon suture,especially for large(≥3 cm)EFTR wounds in SMTs.

Metformin and pancreatic neuroendocrine tumors:A systematic review and meta-analysis

BACKGROUND Most patients with advanced pancreatic neuroendocrine tumors(pNETs)die due to tumor progression.Therefore,identifying new therapies with low toxicity and good tolerability to use concomitantly with the established pNET treatment is relevant.In this perspective,metformin is emerging as a molecule of interest.Retrospective studies have described metformin,a widely used agent for the treatment of patients with type 2 diabetes mellitus(T2DM),to be effective in modulating different tumor-related events,including cancer incidence,recurrence and survival by inhibiting mTOR phosphorylation.This systematic review evaluates the role of T2DM and metformin in the insurgence and post-treatment outcomes in patients with pNET.AIM To systematically analyze and summarize evidence related to the diagnostic and prognostic value of T2DM and metformin for predicting the insurgence and posttreatment outcomes of pNET.METHODS A systematic review of the published literature was undertaken,focusing on the role of T2DM and metformin in insurgence and prognosis of pNET,measured through outcomes of tumor-free survival(TFS),overall survival and progression free survival.RESULTS A total of 13 studies(5674 patients)were included in this review.Analysis of 809 pNET cases from five retrospective studies(low study heterogeneity with I^(2)=0%)confirms the correlation between T2DM and insurgence of pNET(OR=2.13,95%CI=1.56-4.55;P<0.001).The pooled data from 1174 pNET patients showed the correlation between T2DM and post-treatment TFS in pNET patients(hazard ratio=1.84,95%CI=0.78-2.90;P<0.001).The study heterogeneity was intermediate,with I^(2)=51%.A few studies limited the possibility of performing pooled analysis in the setting of metformin;therefore,results were heterogeneous,with no statistical relevance to the use of this drug in the diagnosis and prognosis of pNET.CONCLUSION T2DM represents a risk factor for the insurgence of pNET and is a significant predictor of poor post-treatment TFS of pNET patients.Unfortunately,a few studies with heterogeneous results limited the possibility of exploring the effect of metformin in the diagnosis and prognosis of pNET.

Tumor deposits in axillary adipose tissue in patients with breast cancer:Do they matter?

Tumor deposits(TDs)are defined as discrete,irregular clusters of tumor cells lying in the soft tissue adjacent to but separate from the primary tumor,and are usually found in the lymphatic drainage area of the primary tumor.By definition,no residual lymph node structure should be identified in these tumor masses.At present,TDs are mainly reported in colorectal cancer,with a few reports in gastric cancer.There are very few reports on breast cancer(BC).For TDs,current dominant theories suggest that these are the result of lymph node metastasis of the tumor with complete destruction of the lymph nodes by the tumor tissue.Even some pathologists classify a TD as two lymph node metastases for calculation.Some pathologists also believe that TDs belong to the category of disseminated metastasis.Therefore,regardless of the origin,TDs are an indicator of poor prognosis.Moreover,for BC,sentinel lymph node biopsy is generally used at present.Whether radical axillary lymph node dissection should be adopted for BC with TDs in axillary lymph nodes is still inconclusive.The present commentary of this clinical issue has certain guiding significance.It is aimed to increase the awareness of the scientific community towards this under-recognized problem in BC pathology.

LATS1 Promotes B-ALL Tumorigenesis by Regulating YAP1 Phosphorylation and Subcellular Localization

Objective YAP1 plays a dual role as an oncogene and tumor suppressor gene in several tumors;differentiating between these roles may depend on the YAP1 phosphorylation pattern.The specific function of YAP1 in B cell acute lymphoblastic leukemia(B-ALL),however,is currently unclear.Thus,in the present study,the role of YAP1 in B-ALL was investigated using relevant cell lines and patient datasets.Methods The effects of shRNA-mediated knockdown on YAP1 and LATS1 levels in the NALM6 and MOLT-4 cell lines were examined using Western blotting,quantitative real-time polymerase chain reaction,flow cytometry,immunostaining,and nude mouse subcutaneous tumorigenesis experiments.Gene expression levels of Hippo pathway-related molecules before and after verteporfin(VP)treatment were compared using RNA-Seq to identify significant Hippo pathway-related genes in NALM6 cells.Results Patients with ALL showing high YAP1 expression and low YAP1-Ser127 phosphorylation levels had worse prognoses than those with low YAP1 protein expression and high YAP1-Ser127 phosphorylation levels.YAP1-Ser127 phosphorylation levels were lower in NALM6 cells than in MOLT-4 and control cells;YAP1 was distributed in the nuclei in NALM6 cells.Knockdown of YAP1 inhibited MOLT-4 and NALM6 cell proliferation and arrested the NALM6 cell cycle in the G0/G1 phase.Before and after VP treatment,the expression of the upstream gene LATS1 was upregulated;its overexpression promoted YAP1-Ser127 phosphorylation.Further,YAP1 was distributed in the plasma.Conclusion LATS1 may downregulate YAP1-Ser127 phosphorylation and maintain B-ALL cell function;thus,VP,which targets this axis,may serve as a new therapeutic method for improving the outcomes for B-ALL patients.

Tumor necrosis factor-stimulated gene-6 ameliorates early brain injury after subarachnoid hemorrhage by suppressing NLRC4 inflammasome-mediated astrocyte pyroptosis

Subarachnoid hemorrhage is associated with high morbidity and mortality and lacks effective treatment.Pyroptosis is a crucial mechanism underlying early brain injury after subarachnoid hemorrhage.Previous studies have confirmed that tumor necrosis factor-stimulated gene-6(TSG-6)can exert a neuroprotective effect by suppressing oxidative stress and apoptosis.However,no study to date has explored whether TSG-6 can alleviate pyroptosis in early brain injury after subarachnoid hemorrhage.In this study,a C57BL/6J mouse model of subarachnoid hemorrhage was established using the endovascular perforation method.Our results indicated that TSG-6 expression was predominantly detected in astrocytes,along with NLRC4 and gasdermin-D(GSDMD).The expression of NLRC4,GSDMD and its N-terminal domain(GSDMD-N),and cleaved caspase-1 was significantly enhanced after subarachnoid hemorrhage and accompanied by brain edema and neurological impairment.To explore how TSG-6 affects pyroptosis during early brain injury after subarachnoid hemorrhage,recombinant human TSG-6 or a siRNA targeting TSG-6 was injected into the cerebral ventricles.Exogenous TSG-6 administration downregulated the expression of NLRC4 and pyroptosis-associated proteins and alleviated brain edema and neurological deficits.Moreover,TSG-6 knockdown further increased the expression of NLRC4,which was accompanied by more severe astrocyte pyroptosis.In summary,our study revealed that TSG-6 provides neuroprotection against early brain injury after subarachnoid hemorrhage by suppressing NLRC4 inflammasome activation-induced astrocyte pyroptosis.

Imaging, pathology, and diagnosis of solitary fibrous tumor of the pancreas: A case report and review of literature

BACKGROUND A solitary fibrous tumor(SFT)is often located in the pleura,while SFT of the pancreas is extremely rare.Here,we report a case of SFT of the pancreas and discuss imaging,histopathology,and immunohistochemistry for accurate diagnosis and treatment.CASE SUMMARY A 54-year-old man presented to our hospital with pancreatic occupancy for over a month.There were no previous complaints of discomfort.His blood pressure was normal.Blood glucose,tumor markers,and enhanced computed tomography(CT)suggested a malignant tumor.Because the CT appearance of pancreatic cancer varies,we could not confirm the diagnosis;therefore,we performed endoscopic ultrasound-guided fine-needle biopsy(EUS-FNB).Pathology and immunohistochemistry were consistent with SFT of the pancreas.The posto-perative pathology and immunohistochemistry were consistent with the puncture results.The patient presented for a follow-up examination one month after discharge with no adverse effects.CONCLUSION Other diseases must be excluded in patients with a pancreatic mass that cannot be diagnosed.CT and pathological histology have diagnostic value for pancreatic tumors.Endoscopic puncture biopsy under ultrasound can help diagnose pancreatic masses that cannot be diagnosed preoperatively.Surgery is an effective treatment for SFT of the pancreas;however,long-term follow-up is strongly recommended because of the possibility of malignant transformation of the tumor.

Mechanisms of tumor immunosuppressive microenvironment formation in esophageal cancer

As a highly invasive malignancy,esophageal cancer(EC)is a global health issue,and was the eighth most prevalent cancer and the sixth leading cause of cancerrelated death worldwide in 2020.Due to its highly immunogenic nature,emerging immunotherapy approaches,such as immune checkpoint blockade,have demonstrated promising efficacy in treating EC;however,certain limitations and challenges still exist.In addition,tumors may exhibit primary or acquired resistance to immunotherapy in the tumor immune microenvironment(TIME);thus,understanding the TIME is urgent and crucial,especially given the importance of an immunosuppressive microenvironment in tumor progression.The aim of this review was to better elucidate the mechanisms of the suppressive TIME,including cell infiltration,immune cell subsets,cytokines and signaling pathways in the tumor microenvironment of EC patients,as well as the downregulated expression of major histocompatibility complex molecules in tumor cells,to obtain a better understanding of the differences in EC patient responses to immunotherapeutic strategies and accurately predict the efficacy of immunotherapies.Therefore,personalized treatments could be developed to maximize the advantages of immunotherapy.

Transcatheter arterial chemoembolization combined with PD-1 inhibitors and Lenvatinib for hepatocellular carcinoma with portal vein tumor thrombus

BACKGROUND Hepatocellular carcinoma(HCC)patients complicated with portal vein tumor thrombus(PVTT)exhibit poor prognoses and treatment responses.AIM To investigate efficacies and safety of the combination of PD-1 inhibitor,transcatheter arterial chemoembolization(TACE)and Lenvatinib in HCC subjects comorbid with PVTT.METHODS From January 2019 to December 2020,HCC patients with PVTT types Ⅰ-Ⅳ were retrospectively enrolled at Beijing Ditan Hospital.They were distributed to either the PTL or TACE/Lenvatinib(TL)group.The median progression-free survival(mPFS)was set as the primary endpoint,while parameters like median overall survival,objective response rate,disease control rate(DCR),and toxicity level served as secondary endpoints.RESULTS Forty-one eligible patients were finally recruited for this study and divided into the PTL(n=18)and TL(n=23)groups.For a median follow-up of 21.8 months,the DCRs were 88.9%and 60.9%in the PTL and TL groups(P=0.046),res-pectively.Moreover,mPFS indicated significant improvement(HR=0.25;P<0.001)in PTL-treated patients(5.4 months)compared to TL-treated(2.7 months)patients.There were no treatment-related deaths or differences in adverse events in either group.CONCLUSION A triplet regimen of PTL was safe and well-tolerated as well as exhibited favorable efficacy over the TL regimen for advanced-stage HCC patients with PVTT types Ⅰ-Ⅳ.

Unraveling the enigma:A comprehensive review of solid pseudopapillary tumor of the pancreas

Solid pseudopapillary tumor of the pancreas(SPTP)is a rare neoplasm predom-inantly observed in young females.Pathologically,CTNNB1 mutations,β-catenin nuclear accumulation,and subsequent Wnt-signaling pathway activation are the leading molecular features.Accurate preoperative diagnosis often relies on imaging techniques and endoscopic biopsies.Surgical resection remains the mainstay treatment.Risk models,such as the Fudan Prognostic Index,show promise as predictive tools for assessing the prognosis of SPTP.Establishing three types of metachronous liver metastasis can be beneficial in tailoring individu-alized treatment and follow-up strategies.Despite advancements,challenges persist in understanding its etiology,establishing standardized treatments for unresectable or metastatic diseases,and developing a widely recognized grading system.This comprehensive review aims to elucidate the enigma by consolidating current knowledge on the epidemiology,clinical presentation,pathology,molecular characteristics,diagnostic methods,treatment options,and prognostic factors.

The action mechanism by which C1q/tumor necrosis factor-related protein-6 alleviates cerebral ischemia/reperfusion injury in diabetic mice

Studies have shown that C1q/tumor necrosis factor-related protein-6 (CTRP6) can alleviate renal ischemia/reperfusion injury in mice. However, its role in the brain remains poorly understood. To investigate the role of CTRP6 in cerebral ischemia/reperfusion injury associated with diabetes mellitus, a diabetes mellitus mouse model of cerebral ischemia/reperfusion injury was established by occlusion of the middle cerebral artery. To overexpress CTRP6 in the brain, an adeno-associated virus carrying CTRP6 was injected into the lateral ventricle. The result was that oxygen injury and inflammation in brain tissue were clearly attenuated, and the number of neurons was greatly reduced. In vitro experiments showed that CTRP6 knockout exacerbated oxidative damage, inflammatory reaction, and apoptosis in cerebral cortical neurons in high glucose hypoxia-simulated diabetic cerebral ischemia/reperfusion injury. CTRP6 overexpression enhanced the sirtuin-1 signaling pathway in diabetic brains after ischemia/reperfusion injury. To investigate the mechanism underlying these effects, we examined mice with depletion of brain tissue-specific sirtuin-1. CTRP6-like protection was achieved by activating the sirtuin-1 signaling pathway. Taken together, these results indicate that CTRP6 likely attenuates cerebral ischemia/reperfusion injury through activation of the sirtuin-1 signaling pathway.

Ferroptosis biomarkers predict tumor mutation burden's impact on prognosis in HER2-positive breast cancer

BACKGROUND Ferroptosis has recently been associated with multiple degenerative diseases.Ferroptosis induction in cancer cells is a feasible method for treating neoplastic diseases.However,the association of iron proliferation-related genes with prognosis in HER2+breast cancer(BC)patients is unclear.AIM To identify and evaluate fresh ferroptosis-related biomarkers for HER2+BC.METHODS First,we obtained the mRNA expression profiles and clinical information of HER2+BC patients from the TCGA and METABRIC public databases.A four gene prediction model comprising PROM2,SLC7A11,FANCD2,and FH was subsequently developed in the TCGA cohort and confirmed in the METABRIC cohort.Patients were stratified into high-risk and low-risk groups based on their median risk score,an independent predictor of overall survival(OS).Based on these findings,immune infiltration,mutations,and medication sensitivity were analyzed in various risk groupings.Additionally,we assessed patient prognosis by combining the tumor mutation burden(TMB)with risk score.Finally,we evaluated the expression of critical genes by analyzing single-cell RNA sequencing(scRNA-seq)data from malignant vs normal epithelial cells.RESULTS We found that the higher the risk score was,the worse the prognosis was(P<0.05).We also found that the immune cell infiltration,mutation,and drug sensitivity were different between the different risk groups.The highrisk subgroup was associated with lower immune scores and high TMB.Moreover,we found that the combination of the TMB and risk score could stratify patients into three groups with distinct prognoses.HRisk-HTMB patients had the worst prognosis,whereas LRisk-LTMB patients had the best prognosis(P<0.0001).Analysis of the scRNAseq data showed that PROM2,SLC7A11,and FANCD2 were significantly differentially expressed,whereas FH was not,suggesting that these genes are expressed mainly in cancer epithelial cells(P<0.01).CONCLUSION Our model helps guide the prognosis of HER2+breast cancer patients,and its combination with the TMB can aid in more accurate assessment of patient prognosis and provide new ideas for further diagnosis and treatment.

Tumor microenvironment reprogramming by nanomedicine to enhance the effect of tumor immunotherapy

With the rapid development of the fields of tumor biology and immunology, tumor immunotherapy has been used in clinical practice and has demonstrated significant therapeutic potential, particularly for treating tumors that do not respond to standard treatment options. Despite its advances, immunotherapy still has limitations, such as poor clinical response rates and differences in individual patient responses, largely because tumor tissues have strong immunosuppressive microenvironments. Many tumors have a tumor microenvironment (TME) that is characterized by hypoxia, low pH, and substantial numbers of immunosuppressive cells, and these are the main factors limiting the efficacy of antitumor immunotherapy. The TME is crucial to the occurrence, growth, and metastasis of tumors. Therefore, numerous studies have been devoted to improving the effects of immunotherapy by remodeling the TME. Effective regulation of the TME and reversal of immunosuppressive conditions are effective strategies for improving tumor immunotherapy. The use of multidrug combinations to improve the TME is an efficient way to enhance antitumor immune efficacy. However, the inability to effectively target drugs decreases therapeutic effects and causes toxic side effects. Nanodrug delivery carriers have the advantageous ability to enhance drug bioavailability and improve drug targeting. Importantly, they can also regulate the TME and deliver large or small therapeutic molecules to decrease the inhibitory effect of the TME on immune cells. Therefore, nanomedicine has great potential for reprogramming immunosuppressive microenvironments and represents a new immunotherapeutic strategy. Therefore, this article reviews strategies for improving the TME and summarizes research on synergistic nanomedicine approaches that enhance the efficacy of tumor immunotherapy.