The present study assessed the efficacy and safety of thoracic radiotherapy(TRT)following first-line chemotherapy or chemoimmunotherapy in patients with extensive-stage small cell lung cancer(ES-SCLC),focusing on the ...The present study assessed the efficacy and safety of thoracic radiotherapy(TRT)following first-line chemotherapy or chemoimmunotherapy in patients with extensive-stage small cell lung cancer(ES-SCLC),focusing on the influence of different TRT timing strategies(consolidative vs.salvage)on survival rates.We retrospectively analyzed a total of 54 patients with ES-SCLC treated between January 2019 and July 2022.Patients receiving consolidative TRT(cTRT)within three months after completion of first-line treatment were compared with those receiving salvage TRT(sTRT)after disease progression.The primary endpoints were overall survival(OS),progression-free survival(PFS),locoregional-free survival(LRFS),and distant metastasis-free survival(DMFS);the secondary endpoint included safety.The cTRT group(n=41)showed significantly longer median OS(26.6 vs.14.8 months,P=0.048),PFS(12.9 vs.3.5 months,P<0.0001),and DMFS(10.7 vs.3.4 months,P=0.0044)than the sTRT group(n=13).Multivariate analysis revealed that cTRT was an independent,favorable prognostic factor.No significant differences in OS or LRFS were observed between high-dose(≥50 Gy)and low-dose(<50 Gy)TRT.Hematologic and respiratory toxicities were the most frequently reported adverse events,with acceptable tolerability.In conclusion,cTRT after chemoimmunotherapy significantly improves survival outcomes for ES-SCLC patients,and low-dose TRT may be a suitable option.展开更多
Chemoimmunotherapy has the potential to enhance chemotherapy and modulate the immunosuppressive tumor microenvironment by activating immunogenic cell death(ICD),making it a promising strategy for clinical application....Chemoimmunotherapy has the potential to enhance chemotherapy and modulate the immunosuppressive tumor microenvironment by activating immunogenic cell death(ICD),making it a promising strategy for clinical application.Alantolactone(A)was found to augment the anticancer efficacy of paclitaxel(P)at a molar ratio of 1:0.5(P:A)through induction of more potent ICD via modulation of STAT3 signaling pathways.Nano drug delivery systems can synergistically combine natural drugs with conventional chemotherapeutic agents,thereby enhancing multi-drug chemoimmunotherapy.To improve tumor targeting ability and bioavailability of hydrophobic drugs,an amphiphilic prodrug conjugate(HA-PTX)was chemically modified with paclitaxel(PTX)and hyaluronic acid(HA)as a backbone.Based on this concept,CD44-targeted nanodrugs(A@HAP NPs)were developed for co-delivery of A and P in colorectal cancer treatment,aiming to achieve synergistic toxicity-based chemo-immunotherapy.The uniform size and high drug loading capacity of A@HAP NPs facilitated their accumulation within tumors through enhanced permeability and retention effect as well as HA-mediated targeting,providing a solid foundation for subsequent synergistic therapy and immunoregulation.In vitro and in vivo studies demonstrated that A@HAP NPs exhibited potent cytotoxicity against tumor cells while also remodeling the immune-suppressive tumor microenvironment by promoting antigen presentation and inducing dendritic cell maturation,thus offering a novel approach for colorectal cancer chemoimmunotherapy.展开更多
Esophageal squamous cell carcinoma(ESCC)remains a highly aggressive ma-lignancy with limited effective therapeutic options for patients with locally advanced unresectable disease.The study by Wei et al,featured in thi...Esophageal squamous cell carcinoma(ESCC)remains a highly aggressive ma-lignancy with limited effective therapeutic options for patients with locally advanced unresectable disease.The study by Wei et al,featured in this issue,highlights the potential of induction chemoimmunotherapy followed by definitive radiotherapy or concurrent chemoradiotherapy to improve treatment outcomes in this challenging patient population.This retrospective analysis of 132 patients demonstrates promising results,including a median progression-free survival of 14.2 months and overall survival of 19.9 months,alongside an acceptable safety profile.Notably,the study identifies the effectiveness of induction therapy and maintenance immunotherapy as key prognostic factors,emphasizing the syner-gistic potential of integrating immune checkpoint inhibitors with radiotherapy.While these findings are encouraging,they require further validation through prospective trials,along with biomarker-based and immune response studies,to refine patient selection and maximize therapeutic benefits.This editorial explores the implications of this research,its impact on clinical practice,and future di-rections for advancing the treatment landscape of ESCC.展开更多
Background:Non-small cell lung cancer(NSCLC)is the cancer with the highest incidence and mortality rate worldwide.This study aimed to investigate the predictive value of clinicopathological and radiological characteri...Background:Non-small cell lung cancer(NSCLC)is the cancer with the highest incidence and mortality rate worldwide.This study aimed to investigate the predictive value of clinicopathological and radiological characteristics for event-free survival(EFS),major pathological response(MPR),and pathological complete response(pCR)in patients with NSCLC undergoing neoadjuvant chemoimmunotherapy.Methods:A retrospective analysis was performed on the clinical data of 180 patients with NSCLC who received neoadjuvant chemoimmunotherapy between October 2019 and December 2023.The primary endpoint was EFS,and the secondary endpoint was the pathological response rate.Fisher exact test and the nonparametricMann-Whitney U test were used to compare categorical and continuous data between the pCR/MPR and non-pCR/non-MPR groups.The Kaplan-Meier method was used to estimate EFS curves,and Cox regression analysis was performed to compare the differences in EFS between patients with or without pCR or MPR.Results:Sex(p=0.004),smoking history(p=0.025),and clinical stage(p=0.002)were identified as predictors of pCR and MPR.In our study,pCR was observed in 38.12%and MPR in 44.75%of the patients.Through the multivariate logistic regression model,age and pathological response were found to predict the 1-and 2-year EFS rates,demonstrating satisfactory predictive power(area under the curve,0.866 and 0.736,respectively).Patients with pCR or MPR exhibited longer EFS compared with those without pCR or MPR,as determined by Cox analysis.Conclusions:Sex,smoking history,and clinical stage were identified as predictors of pCR and MPR in patients with NSCLC.Survival analysis revealed that age and pathological response were key prognostic factors for EFS.展开更多
BACKGROUND Non-small cell lung cancer(NSCLC)is the primary form of lung cancer,and the combination of chemotherapy with immunotherapy offers promising treatment options for patients suffering from this disease.However...BACKGROUND Non-small cell lung cancer(NSCLC)is the primary form of lung cancer,and the combination of chemotherapy with immunotherapy offers promising treatment options for patients suffering from this disease.However,the emergence of drug resistance significantly limits the effectiveness of these therapeutic strategies.Consequently,it is imperative to devise methods for accurately detecting and evaluating the efficacy of these treatments.AIM To identify the metabolic signatures associated with neutrophil extracellular traps(NETs)and chemoimmunotherapy efficacy in NSCLC patients.METHODS In total,159 NSCLC patients undergoing first-line chemoimmunotherapy were enrolled.We first investigated the characteristics influencing clinical efficacy.Circulating levels of NETs and cytokines were measured by commercial kits.Liquid chromatography tandem mass spectrometry quantified plasma metabolites,and differential metabolites were identified.Least absolute shrinkage and selection operator,support vector machine-recursive feature elimination,and random forest algorithms were employed.By using plasma metabolic profiles and machine learning algorithms,predictive metabolic signatures were established.RESULTS First,the levels of circulating interleukin-8,neutrophil-to-lymphocyte ratio,and NETs were closely related to poor efficacy of first-line chemoimmunotherapy.Patients were classed into a low NET group or a high NET group.A total of 54 differential plasma metabolites were identified.These metabolites were primarily involved in arachidonic acid and purine metabolism.Three key metabolites were identified as crucial variables,including 8,9-epoxyeicosatrienoic acid,L-malate,and bis(monoacylglycerol)phosphate(18:1/16:0).Using metabolomic sequencing data and machine learning methods,key metabolic signatures were screened to predict NET level as well as chemoimmunotherapy efficacy.CONCLUSION The identified metabolic signatures may effectively distinguish NET levels and predict clinical benefit from chemoimmunotherapy in NSCLC patients.展开更多
Although notable progress has been made on novel cancer treatments,the overall survival rate and therapeutic effects are still unsatisfactory for cancer patients.Chemoimmunotherapy,combining chemotherapeutics and immu...Although notable progress has been made on novel cancer treatments,the overall survival rate and therapeutic effects are still unsatisfactory for cancer patients.Chemoimmunotherapy,combining chemotherapeutics and immunotherapeutic drugs,has emerged as a promising approach for cancer treatment,with the advantages of cooperating two kinds of treatment mechanism,reducing the dosage of the drug and enhancing therapeutic effect.Moreover,nano-based drug delivery system(NDDS)was applied to encapsulate chemotherapeutic agents and exhibited outstanding properties such as targeted delivery,tumor microenvironment response and site-specific release.Several nanocarriers have been approved in clinical cancer chemotherapy and showed significant improvement in therapeutic efficiency compared with traditional formulations,such as liposomes(Doxil R,Lipusu R),nanoparticles(Abraxane R)and micelles(Genexol-PM R).The applications of NDDS to chemoimmunotherapy would be a powerful strategy for future cancer treatment,which could greatly enhance the therapeutic efficacy,reduce the side effects and optimize the clinical outcomes of cancer patients.Herein,the current approaches of cancer immunotherapy and chemoimmunotherapy were discussed,and recent advances of NDDS applied for chemoimmunotherapy were further reviewed.展开更多
AIM: To investigate the association of plasma levels of interleukin(IL)-6 and-8 with Wilms' tumor 1(WT1)-specific immune responses and clinical outcomes in patients with pancreatic ductal adenocarcinoma(PDA) treat...AIM: To investigate the association of plasma levels of interleukin(IL)-6 and-8 with Wilms' tumor 1(WT1)-specific immune responses and clinical outcomes in patients with pancreatic ductal adenocarcinoma(PDA) treated with dendritic cells(DCs) pulsed with three types of major histocompatibility complex classⅠand Ⅱ-restricted WT1 peptides combined with chemotherapy.METHODS: During the entire treatment period, plasma levels of IL-6 and-8 were analyzed by ELISA. The induction of WT1-specific immune responses was assessed using the WT1 peptide-specific delayed-type hypersensitivity(DTH) test.RESULTS: Three of 7 patients displayed strong WT1-DTH reactions throughout long-term vaccination with significantly decreased levels of IL-6/-8 after vaccinations compared with the levels prior to treatment. Moreover, overall survival(OS) was significantly longer in PDA patients with low plasma IL-6 levels(< 2 pg/m L) after 5 vaccinations than in patients with high plasma IL-6 levels(≥ 2 pg/m L)(P = 0.025). After disease progression, WT1-DTH reactions decreased severely and were ultimately negative at the terminal stage of cancer. The decreased levels of IL-6/-8 observed throughout long-term vaccination were associated with WT1-specific DTH reactions and long-term OS.CONCLUSION: Prolonged low levels of plasma IL-6/-8 in PDA patients may be a prognostic marker for the clinical outcomes of chemoimmunotherapy.展开更多
Metastatic lung cancer continues to cause a high number of deaths due to high malignancy and poor prognosis,and the efficacy of typical chemotherapy or immunotherapy is less than ideal due to the low pulmonary accumul...Metastatic lung cancer continues to cause a high number of deaths due to high malignancy and poor prognosis,and the efficacy of typical chemotherapy or immunotherapy is less than ideal due to the low pulmonary accumulation and targeting of therapeutics.Here,a submicron-sized biomimetic liposome was formulated for the lung-targeted co-delivery of bacterial superantigen and paclitaxel.Recombinant staphylococcal enterotoxin C2(rSEC2),a bacterial superantigen,was expressed with the Escherichia coli system and showed potent immunostimulatory activities to mediate tumor cell death.The submicron-sized(w800 nm)biomimetic liposomes,namely 4T1 cell membrane-hybrid rSEC2 paclitaxel liposomes(TSPLs),exhibited high lung-accumulation efficiency and tumor homologous effect due to the suitable particle size and membrane hybridization of cancer cell membranes with phospholipids.Intravenous TSPLs remarkably inhibited metastatic lung cancer with limited systemic immune responses.TSPLs reversed the immunosuppressive state and increased the proportion of local CD4^(+) and CD8^(+) T cells in the lung;moreover,paclitaxel increased tumor cell apoptosis and reduced tumor burden.In summary,the high lung cancer targeting was achieved by particle size control and cell membrane hybridization,and the highly efficient anticancer effect was achieved by the co-delivery of superantigens and chemotherapeutic drugs.展开更多
To the Editor:Lung cancer,specifically lung adenocarcinoma(LUAD),is one of the primary cause of cancer-related mortality globally.[1,2]Nevertheless,only a small subset of individuals with LUAD have derived clinical be...To the Editor:Lung cancer,specifically lung adenocarcinoma(LUAD),is one of the primary cause of cancer-related mortality globally.[1,2]Nevertheless,only a small subset of individuals with LUAD have derived clinical benefits from chemoimmunotherapy in either first-line or subsequent treatment settings.Both programmed death-ligand 1(PDL1)expression and tumor mutational burden(TMB)have proven inadequate in accurately predicting treatment outcomes in these scenarios.[3]Consequently,there exists a pressing necessity to identify a reliable biomarker to inform treatment decisions.展开更多
Metastatic lung cancer remains a formidable adversary in oncology,accounting for a staggering global mortality burden due to its high malignancy and poor prognosis^(1).In recent years,the integration of chemotherapy a...Metastatic lung cancer remains a formidable adversary in oncology,accounting for a staggering global mortality burden due to its high malignancy and poor prognosis^(1).In recent years,the integration of chemotherapy and immunotherapy has emerged as a promising strategy for synergize killing of tumor cell^(2).展开更多
Chemotherapeutics can induce immunogenic cell death(ICD)in tumor cells,offering new possibilities for cancer therapy.However,the efficiency of the immune response generated is insufficient due to the inhibitory nature...Chemotherapeutics can induce immunogenic cell death(ICD)in tumor cells,offering new possibilities for cancer therapy.However,the efficiency of the immune response generated is insufficient due to the inhibitory nature of the tumor microenvironment(TME).Here,we developed a pH/reactive oxygen species(ROS)dual-response system to enhance chemoimmunotherapy for melanoma.The system productively accumulated in tumors by specific binding of phenylboronic acid(PBA)to sialic acids(SA).The nanoparticles(NPs)rapidly swelled and released quercetin(QUE)and doxorubicin(DOX)upon the stimulation of tumor microenvironment(TME).The in vitro and in vivo results consistently demonstrated that the NPs improved anti-tumor efficacy and prolonged survival of mice,significantly enhancing the effects of the combination.Our study revealed DOX was an ICD inducer,stimulating immune responses and promoting maturation of dendritic cells(DCs).Additionally,QUE served as a TME regulator by inhibiting the cyclooxygenase-2(COX2)-prostaglandin E2(PGE2)axis,which influenced various immune cells,including increasing cytotoxic T cells(CLTs)infiltration,promoting M1 macrophage polarization,and reducing regulatory T cells(Tregs)infiltration.The combination synergistically facilitated chemoimmunotherapy efficacy by remodeling the immunosuppressive microenvironment.This work presents a promising strategy to increase anti-tumor efficiency of chemotherapeutic agents.展开更多
Glycolysis-related lactic acid overproduction creates an“ion-trapping”barrier and immunosuppressive tumor microenvironment that compromise effective intratumoral drug delivery and therapy.Therefore,normalization of ...Glycolysis-related lactic acid overproduction creates an“ion-trapping”barrier and immunosuppressive tumor microenvironment that compromise effective intratumoral drug delivery and therapy.Therefore,normalization of tumor microenvironment via lactic acid neutralization can be a promising avenue for overcoming this therapeutic hurdle.In this study,the flexible liposomes loaded with sodium bicarbonate(NaHCO_(3)@Flip)were used as a nano-adjuvant to boost chemoimmunotherapy.Their effects on assisting DOXIL and anti-programmed cell death protein 1(PD-1)therapy were investigated.NaHCO_(3)@Flip achieved deep tumor penetration,with the ability to neutralize lactic acid and normalize the acidic tumor microenvironment.NaHCO_(3)@Flip is biosafe and can enhance cellular uptake efficiency of doxorubicin(DOX)by overcoming the ion-trapping barrier and amplify immunogenic cell death induced by DOX.The combination therapy of liposomal DOX and NaHCO_(3)@Flip demonstrated enhanced inhibition of tumor growth.NaHCO_(3)@Flip can also synergize with PD-1 antibody therapy.NaHCO_(3)@Flip has the potential to serve as a therapeutic adjuvant for boosting chemoimmunotherapy by overcoming the ion-trapping effect and normalizing the tumor microenvironment.展开更多
Patients with chronic lymphocytic leukemia(CLL)have differing clinical outcomes.Recent advances integrating multi-omic data have uncovered molecular subtypes in CLL with different prognostic implications and may allow...Patients with chronic lymphocytic leukemia(CLL)have differing clinical outcomes.Recent advances integrating multi-omic data have uncovered molecular subtypes in CLL with different prognostic implications and may allow better prediction of therapy response.While finite-duration chemoimmunotherapy(CIT)has enabled deep responses and prolonged duration of responses in the past,the advent of novel targeted therapy for the treatment of CLL has dramatically changed the therapeutic landscape.In this review,we discuss the latest genomic,transcriptomic,and epigenetic alterations regarded as major drivers of resistance to CIT in CLL.Further advances in genomic medicine will allow for better prediction of response to therapy and provide the basis for rational selection of therapy for long-term remissions with minimal toxicity.展开更多
BACKGROUND Primary testicular lymphoma(PTL)is a rare,aggressive malignancy,representing a small fraction of testicular tumors and non-Hodgkin lymphomas,yet it is the most common testicular malignancy in older men.Diff...BACKGROUND Primary testicular lymphoma(PTL)is a rare,aggressive malignancy,representing a small fraction of testicular tumors and non-Hodgkin lymphomas,yet it is the most common testicular malignancy in older men.Diffuse large B-cell lymphoma(DLBCL),which is typically the aggressive subtype,dominates PTL and shows diffuse B-cell infiltration.Venous tumor thrombus,uncommon in lymphomas,is uniquely reported in this case of testicular DLBCL with gonadal vein involvement.CASE SUMMARY A 62-year-old man presented with a two-month history of painless left testicular swelling and stiffness.Diagnostic imaging[ultrasonography,computed tomography(CT),and 18F-fluorodeoxyglucose positron emission tomography/CT(18FFDG-PET/CT)]revealed bilateral testicular masses and a gonadal vein tumor thrombus(SUVmax 16.5).Left orchiectomy confirmed DLBCL with CD20,Bcl-2,and MUM1 positivity(Ki-67:approximately 80%).The disease was staged as Ann Arbor stage IVA(International Prognostic Index score 3,high-intermediate risk).The patient received Rituximab,Polatuzumab Vedotin,Cyclophosphamide,Epirubicin,and Prednisolone chemotherapy,completing the first cycle with good tolerability.No adverse events were reported,and follow-up is ongoing to assess long-term outcomes.This case highlights the diagnostic utility of 18F-FDGPET/CT and the importance of multidisciplinary management in rare PTL presentations with tumor thrombus.CONCLUSION This case demonstrates the diagnostic complexities of PTL with gonadal vein tumor thrombus,underscoring the importance of considering lymphoma in elderly patients with testicular masses and venous involvement.A multi-disciplinary team including urologists,hematologists,and radiation oncologists is needed to ensure appropriate therapy.展开更多
Many conventional chemotherapeutics play an immune-modulating effect by inducing immunogenic cell death(ICD)in tumor cells.However,they hardly arouse strong antitumor immune response because the immunosuppressive lymp...Many conventional chemotherapeutics play an immune-modulating effect by inducing immunogenic cell death(ICD)in tumor cells.However,they hardly arouse strong antitumor immune response because the immunosuppressive lymphocytes are present in the tumor microenvironment.These immunosuppressive lymphocytes include regulatory T cells(Tregs)and myeloid-derived suppressor cells(MDSCs).We used a low dose of doxorubicin(DOX)to induce ICD in combination with immune regulator 1-methylDL-tryptophan(1 MT)to suppress indoleamine 2,3-dioxygenase and overcome Treg-and MDSCassociated immune suppression.By co-encapsulation of DOX and 1 MT into a reduction-responsive polypeptide nanogel,the drugs were simultaneously released in the tumor cells and synergistically performed antitumor efficacy.After treatment,recruitment of Tregs and MDSCs was inhibited,and the frequency of tumor-infiltrating CD8+T cells was remarkably enhanced.These results demonstrated that the chemoimmunotherapy strategy effectively suppressed tumor growth without causing evident adverse effects,indicating its great potential in clinical cancer therapy.展开更多
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 ...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(Zn^(2+))-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.展开更多
Triple-negative breast cancer(TNBC)due to lack of clear target and notorious“cold”tumor microenvironment(TME)is one of the most intractable and lethal malignancies.Tuning“cold”TME into“hot”becomes an emerging th...Triple-negative breast cancer(TNBC)due to lack of clear target and notorious“cold”tumor microenvironment(TME)is one of the most intractable and lethal malignancies.Tuning“cold”TME into“hot”becomes an emerging therapeutic strategy to TNBC.Herewith,we report that integrin-targeting micellar gemcitabine and paclitaxel(ATN-mG/P,ATN sequence:Ac-PhScNK-NH2)cooperating with polymersomal CpG(NanoCpG)effectively“heated up”and treated TNBC.ATN-mG/P exhibited greatly boosted apoptotic activity in 4T1 cells,induced potent immunogenic cell death(ICD),and efficiently stimulated maturation of bone marrow-derived dendritic cells(BMDCs).Remarkably,in a postoperative TNBC model,ATN-mG/P combining with NanoCpG promoted strong anti-cancer immune responses,showing a greatly augmented proportion of mature DCs and CD8^(+)T cells while reduced immune-suppressive myeloid-derived suppressor cells(MDSCs)and regulatory T cells(T_(reg)),which led to complete inhibition of lung metastasis and 60%mice tumor-free.The co-delivery of gemcitabine and paclitaxel at desired ratio in combination with NanoCpG provides a unique platform for potent chemoimmunotherapy of“cold”tumors like TNBC.展开更多
Background Immune cell heterogenicity is known to determine the therapeutic response to cancer progression.Neoadjuvant chemoimmunotherapy(NACI)has shown clinical benefits in some patients with advanced head and neck s...Background Immune cell heterogenicity is known to determine the therapeutic response to cancer progression.Neoadjuvant chemoimmunotherapy(NACI)has shown clinical benefits in some patients with advanced head and neck squamous cell carcinoma(HNSCC),but the underlying mechanism behind this clinical response is unknown.The efficacy of NACI needs to be potentiated by identifying accurate biomarkers to predict clinical responses.Here,we attempted to identify molecules predicting NACI response in advanced HNSCC.Methods We performed combined single-cell RNA sequencing(scRNA-seq)and multiplex immunofluorescence(mIHC)staining with tumor samples derived from NACI-treated HNSCC patients to identify a new tumor-infiltrating cell(TIL)subtype,CD103^(+)CD8^(+)TILs,associated with clinical response,while both in vitro and in vivo assays were carried out to determine its antitumor efficiency.The regulatory mechanism of the CD103^(+)CD8^(+)TILs population was examined by performing cell-cell interaction analysis of the scRNA-seq data and spatial analysis of the mIHC images.Results We established intratumoral CD103^(+)CD8^(+)TILs density as a determinant of NACI efficacy in cancers.Our scRNA-seq results indicated that the population of CD103^(+)CD8^(+)TILs was dramatically increased in the responders of NACI-treated HNSCC patients,while mIHC analysis confirmed the correlation between intratumoral CD103^(+)CD8^(+)TILs density and NACI efficacy in HNSCC patients.Further receiver operating characteristic curve analysis defined this TIL subset as a potent marker to predict patient response to NACI.Functional assays showed that CD103^(+)CD8^(+)TILs were tumor-reactive T cells,while programmed cell death protein-1(PD-1)blockade enhanced CD103^(+)CD8^(+)TILs cytotoxicity against tumor growth in vivo.Mechanistically,targeting the triggering receptor expressed on myeloid cells 2-positive(TREM2^(+))macrophages might enhance the population of CD103^(+)CD8^(+)TILs and facilitate antitumor immunity during NACI treatment.Conclusions Our study highlights the impact of intratumoral CD103^(+)CD8^(+)TILs density on NACI efficacy in different cancers,while the efforts to elevate its population warrant further clinical investigation.展开更多
Chemoimmunotherapy has been approved as standard treatment for triple-negative breast cancer(TNBC),but the clinical outcomes remain unsatisfied.Abnormal epigenetic regulation is associated with acquired drug resistanc...Chemoimmunotherapy has been approved as standard treatment for triple-negative breast cancer(TNBC),but the clinical outcomes remain unsatisfied.Abnormal epigenetic regulation is associated with acquired drug resistance and T cell exhaustion,which is a critical factor for the poor response to chemoimmunotherapy in TNBC.Herein,macrophage-camouflaged nanoinducers co-loaded with paclitaxel(PTX)and decitabine(DAC)(P/D-mMSNs)were prepared in combination with PD-1 blockade therapy,hoping to improve the efficacy of chemoimmunotherapy through the demethylation of tumor tissue.Camouflage of macrophage vesicle confers P/D-mMSNs with tumor-homing properties.First,DAC can achieve demethylation of tumor tissue and enhance the sensitivity of tumor cells to PTX.Subsequently,PTX induces immunogenic death of tumor cells,promotes phagocytosis of dead cells by dendritic cells,and recruits cytotoxic T cells to infiltrate tumors.Finally,DAC reverses T cell depletion and facilitates immune checkpoint blockade therapy.P/D-mMSNs may be a promising candidate for future drug delivery design and cancer combination therapy in TNBC.展开更多
A novel hybrid model combining a convolutional neural network(CNN)and a low-complexity Transformer network is introduced for predicting lung cancer response to neoadjuvant chemoimmunotherapy using computed tomography ...A novel hybrid model combining a convolutional neural network(CNN)and a low-complexity Transformer network is introduced for predicting lung cancer response to neoadjuvant chemoimmunotherapy using computed tomography scans.This approach is crucial as it assists clinicians in identifying patients likely to benefit from treatment and in assessing their prognosis.The model employs channel splitting to minimize parameter count.It then leverages both CNN for local feature extraction and a streamlined Transformer for global feature comprehension.To enhance efficiency,a novel self-attention mechanism is implemented,focusing on feature aggregation and element-wise multiplication.To address the different semantic meanings of features,an attention-based module is designed to seamlessly integrate features from both networks,employing a process of coarse fusion,attention computation,and fine fusion.When evaluated with data from 232 lung cancer patients who have undergone neoadjuvant chemoimmunotherapy,the model demonstrates exceptional performance,achieving a Dice score of 47.04%and a 95.00%Hausdorff distance of 25.12 mm,outperforming existing methods.Additionally,it has only 2.91×106 parameters and 52.95×109 floating point operations.Moreover,the model’s predictive accuracy in tumor diameter estimation is beneficial for treatment planning.Its robustness is further validated through its application in stroke lesion prediction,indicating its broad applicability.展开更多
基金supported by the Young Talents Program of Jiangsu Cancer Hospital(Grant No.QL201802)the Science and Technology Development Fund of Jiangsu Cancer Hospital(Grant No.ZL202105).
文摘The present study assessed the efficacy and safety of thoracic radiotherapy(TRT)following first-line chemotherapy or chemoimmunotherapy in patients with extensive-stage small cell lung cancer(ES-SCLC),focusing on the influence of different TRT timing strategies(consolidative vs.salvage)on survival rates.We retrospectively analyzed a total of 54 patients with ES-SCLC treated between January 2019 and July 2022.Patients receiving consolidative TRT(cTRT)within three months after completion of first-line treatment were compared with those receiving salvage TRT(sTRT)after disease progression.The primary endpoints were overall survival(OS),progression-free survival(PFS),locoregional-free survival(LRFS),and distant metastasis-free survival(DMFS);the secondary endpoint included safety.The cTRT group(n=41)showed significantly longer median OS(26.6 vs.14.8 months,P=0.048),PFS(12.9 vs.3.5 months,P<0.0001),and DMFS(10.7 vs.3.4 months,P=0.0044)than the sTRT group(n=13).Multivariate analysis revealed that cTRT was an independent,favorable prognostic factor.No significant differences in OS or LRFS were observed between high-dose(≥50 Gy)and low-dose(<50 Gy)TRT.Hematologic and respiratory toxicities were the most frequently reported adverse events,with acceptable tolerability.In conclusion,cTRT after chemoimmunotherapy significantly improves survival outcomes for ES-SCLC patients,and low-dose TRT may be a suitable option.
基金supported by Zhejiang Provincial Natural Science Foundation(LYY22H300001,LGF22H150016)Wenzhou Municipal Science and Technology Bureau(Y20210212)+2 种基金Application Basic Research Project of Liaoning Provincial Department of Science and Technology(2023JH2/101700072)Zhejiang Medical Doctor Association(YS2022-2-001)Health innovation talents program(Longfa Kou)from Health Commission of Zhejiang Province.
文摘Chemoimmunotherapy has the potential to enhance chemotherapy and modulate the immunosuppressive tumor microenvironment by activating immunogenic cell death(ICD),making it a promising strategy for clinical application.Alantolactone(A)was found to augment the anticancer efficacy of paclitaxel(P)at a molar ratio of 1:0.5(P:A)through induction of more potent ICD via modulation of STAT3 signaling pathways.Nano drug delivery systems can synergistically combine natural drugs with conventional chemotherapeutic agents,thereby enhancing multi-drug chemoimmunotherapy.To improve tumor targeting ability and bioavailability of hydrophobic drugs,an amphiphilic prodrug conjugate(HA-PTX)was chemically modified with paclitaxel(PTX)and hyaluronic acid(HA)as a backbone.Based on this concept,CD44-targeted nanodrugs(A@HAP NPs)were developed for co-delivery of A and P in colorectal cancer treatment,aiming to achieve synergistic toxicity-based chemo-immunotherapy.The uniform size and high drug loading capacity of A@HAP NPs facilitated their accumulation within tumors through enhanced permeability and retention effect as well as HA-mediated targeting,providing a solid foundation for subsequent synergistic therapy and immunoregulation.In vitro and in vivo studies demonstrated that A@HAP NPs exhibited potent cytotoxicity against tumor cells while also remodeling the immune-suppressive tumor microenvironment by promoting antigen presentation and inducing dendritic cell maturation,thus offering a novel approach for colorectal cancer chemoimmunotherapy.
基金Supported by National Science Centre,Poland,No.2021/43/B/NZ5/03345.
文摘Esophageal squamous cell carcinoma(ESCC)remains a highly aggressive ma-lignancy with limited effective therapeutic options for patients with locally advanced unresectable disease.The study by Wei et al,featured in this issue,highlights the potential of induction chemoimmunotherapy followed by definitive radiotherapy or concurrent chemoradiotherapy to improve treatment outcomes in this challenging patient population.This retrospective analysis of 132 patients demonstrates promising results,including a median progression-free survival of 14.2 months and overall survival of 19.9 months,alongside an acceptable safety profile.Notably,the study identifies the effectiveness of induction therapy and maintenance immunotherapy as key prognostic factors,emphasizing the syner-gistic potential of integrating immune checkpoint inhibitors with radiotherapy.While these findings are encouraging,they require further validation through prospective trials,along with biomarker-based and immune response studies,to refine patient selection and maximize therapeutic benefits.This editorial explores the implications of this research,its impact on clinical practice,and future di-rections for advancing the treatment landscape of ESCC.
基金Supported by a grant from Beijing Municipal PublicWelfare Development and Reform Pilot Project for Medical Research Institutes(PWD&RPP-MRI,No.JYY2023-14).
文摘Background:Non-small cell lung cancer(NSCLC)is the cancer with the highest incidence and mortality rate worldwide.This study aimed to investigate the predictive value of clinicopathological and radiological characteristics for event-free survival(EFS),major pathological response(MPR),and pathological complete response(pCR)in patients with NSCLC undergoing neoadjuvant chemoimmunotherapy.Methods:A retrospective analysis was performed on the clinical data of 180 patients with NSCLC who received neoadjuvant chemoimmunotherapy between October 2019 and December 2023.The primary endpoint was EFS,and the secondary endpoint was the pathological response rate.Fisher exact test and the nonparametricMann-Whitney U test were used to compare categorical and continuous data between the pCR/MPR and non-pCR/non-MPR groups.The Kaplan-Meier method was used to estimate EFS curves,and Cox regression analysis was performed to compare the differences in EFS between patients with or without pCR or MPR.Results:Sex(p=0.004),smoking history(p=0.025),and clinical stage(p=0.002)were identified as predictors of pCR and MPR.In our study,pCR was observed in 38.12%and MPR in 44.75%of the patients.Through the multivariate logistic regression model,age and pathological response were found to predict the 1-and 2-year EFS rates,demonstrating satisfactory predictive power(area under the curve,0.866 and 0.736,respectively).Patients with pCR or MPR exhibited longer EFS compared with those without pCR or MPR,as determined by Cox analysis.Conclusions:Sex,smoking history,and clinical stage were identified as predictors of pCR and MPR in patients with NSCLC.Survival analysis revealed that age and pathological response were key prognostic factors for EFS.
基金the National Natural Science Foundation of Hunan Province,No.2023JJ60039Natural Science Foundation of Hunan Province National Health Commission,No.B202303027655+3 种基金Natural Science Foundation of Changsha Science and Technology Bureau,No.Kq2208150Wu Jieping Foundation of China,No.320.6750.2022-22-59,320.6750.2022-17-41Guangdong Association of Clinical Trials(GACT)/Chinese Thoracic Oncology Group(CTONG)and Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer,No.2017B030314120.
文摘BACKGROUND Non-small cell lung cancer(NSCLC)is the primary form of lung cancer,and the combination of chemotherapy with immunotherapy offers promising treatment options for patients suffering from this disease.However,the emergence of drug resistance significantly limits the effectiveness of these therapeutic strategies.Consequently,it is imperative to devise methods for accurately detecting and evaluating the efficacy of these treatments.AIM To identify the metabolic signatures associated with neutrophil extracellular traps(NETs)and chemoimmunotherapy efficacy in NSCLC patients.METHODS In total,159 NSCLC patients undergoing first-line chemoimmunotherapy were enrolled.We first investigated the characteristics influencing clinical efficacy.Circulating levels of NETs and cytokines were measured by commercial kits.Liquid chromatography tandem mass spectrometry quantified plasma metabolites,and differential metabolites were identified.Least absolute shrinkage and selection operator,support vector machine-recursive feature elimination,and random forest algorithms were employed.By using plasma metabolic profiles and machine learning algorithms,predictive metabolic signatures were established.RESULTS First,the levels of circulating interleukin-8,neutrophil-to-lymphocyte ratio,and NETs were closely related to poor efficacy of first-line chemoimmunotherapy.Patients were classed into a low NET group or a high NET group.A total of 54 differential plasma metabolites were identified.These metabolites were primarily involved in arachidonic acid and purine metabolism.Three key metabolites were identified as crucial variables,including 8,9-epoxyeicosatrienoic acid,L-malate,and bis(monoacylglycerol)phosphate(18:1/16:0).Using metabolomic sequencing data and machine learning methods,key metabolic signatures were screened to predict NET level as well as chemoimmunotherapy efficacy.CONCLUSION The identified metabolic signatures may effectively distinguish NET levels and predict clinical benefit from chemoimmunotherapy in NSCLC patients.
基金supported by the National Natural Science Foundation of China(No.81974498,No.81773652)。
文摘Although notable progress has been made on novel cancer treatments,the overall survival rate and therapeutic effects are still unsatisfactory for cancer patients.Chemoimmunotherapy,combining chemotherapeutics and immunotherapeutic drugs,has emerged as a promising approach for cancer treatment,with the advantages of cooperating two kinds of treatment mechanism,reducing the dosage of the drug and enhancing therapeutic effect.Moreover,nano-based drug delivery system(NDDS)was applied to encapsulate chemotherapeutic agents and exhibited outstanding properties such as targeted delivery,tumor microenvironment response and site-specific release.Several nanocarriers have been approved in clinical cancer chemotherapy and showed significant improvement in therapeutic efficiency compared with traditional formulations,such as liposomes(Doxil R,Lipusu R),nanoparticles(Abraxane R)and micelles(Genexol-PM R).The applications of NDDS to chemoimmunotherapy would be a powerful strategy for future cancer treatment,which could greatly enhance the therapeutic efficacy,reduce the side effects and optimize the clinical outcomes of cancer patients.Herein,the current approaches of cancer immunotherapy and chemoimmunotherapy were discussed,and recent advances of NDDS applied for chemoimmunotherapy were further reviewed.
基金Grants-in-Aid for Scientific Research(C)from the Ministry of Education,Culture,Sports,Science and Technology of Japan
文摘AIM: To investigate the association of plasma levels of interleukin(IL)-6 and-8 with Wilms' tumor 1(WT1)-specific immune responses and clinical outcomes in patients with pancreatic ductal adenocarcinoma(PDA) treated with dendritic cells(DCs) pulsed with three types of major histocompatibility complex classⅠand Ⅱ-restricted WT1 peptides combined with chemotherapy.METHODS: During the entire treatment period, plasma levels of IL-6 and-8 were analyzed by ELISA. The induction of WT1-specific immune responses was assessed using the WT1 peptide-specific delayed-type hypersensitivity(DTH) test.RESULTS: Three of 7 patients displayed strong WT1-DTH reactions throughout long-term vaccination with significantly decreased levels of IL-6/-8 after vaccinations compared with the levels prior to treatment. Moreover, overall survival(OS) was significantly longer in PDA patients with low plasma IL-6 levels(< 2 pg/m L) after 5 vaccinations than in patients with high plasma IL-6 levels(≥ 2 pg/m L)(P = 0.025). After disease progression, WT1-DTH reactions decreased severely and were ultimately negative at the terminal stage of cancer. The decreased levels of IL-6/-8 observed throughout long-term vaccination were associated with WT1-specific DTH reactions and long-term OS.CONCLUSION: Prolonged low levels of plasma IL-6/-8 in PDA patients may be a prognostic marker for the clinical outcomes of chemoimmunotherapy.
基金partially supported by the Medical Innovation Research Project(23SWAQ12)National Natural Science Foundation of China(82404486)Beijing Natural Science Foundation(L232085,China).
文摘Metastatic lung cancer continues to cause a high number of deaths due to high malignancy and poor prognosis,and the efficacy of typical chemotherapy or immunotherapy is less than ideal due to the low pulmonary accumulation and targeting of therapeutics.Here,a submicron-sized biomimetic liposome was formulated for the lung-targeted co-delivery of bacterial superantigen and paclitaxel.Recombinant staphylococcal enterotoxin C2(rSEC2),a bacterial superantigen,was expressed with the Escherichia coli system and showed potent immunostimulatory activities to mediate tumor cell death.The submicron-sized(w800 nm)biomimetic liposomes,namely 4T1 cell membrane-hybrid rSEC2 paclitaxel liposomes(TSPLs),exhibited high lung-accumulation efficiency and tumor homologous effect due to the suitable particle size and membrane hybridization of cancer cell membranes with phospholipids.Intravenous TSPLs remarkably inhibited metastatic lung cancer with limited systemic immune responses.TSPLs reversed the immunosuppressive state and increased the proportion of local CD4^(+) and CD8^(+) T cells in the lung;moreover,paclitaxel increased tumor cell apoptosis and reduced tumor burden.In summary,the high lung cancer targeting was achieved by particle size control and cell membrane hybridization,and the highly efficient anticancer effect was achieved by the co-delivery of superantigens and chemotherapeutic drugs.
基金National Natural Science Foundation of China(Nos.82373425 and 82372722)Medical Innovation Research Special Project of the Science and Technology Commission of Shanghai Municipality(No.23Y11904200)+3 种基金Shanghai Innovative Medical Device Application Demonstration Project 2023(No.23SHS02600)"Science and Technology Innovation Action Plan"Medical Innovation Research Special Project of Shanghai(No.21Y11913500)key project of the Medical and Health Technology Development Research Center of the National Health Commission(No.WKZX2023CX030003)Shanghai Key Laboratory Open Project(No.STCSM 22DZ2229005)
文摘To the Editor:Lung cancer,specifically lung adenocarcinoma(LUAD),is one of the primary cause of cancer-related mortality globally.[1,2]Nevertheless,only a small subset of individuals with LUAD have derived clinical benefits from chemoimmunotherapy in either first-line or subsequent treatment settings.Both programmed death-ligand 1(PDL1)expression and tumor mutational burden(TMB)have proven inadequate in accurately predicting treatment outcomes in these scenarios.[3]Consequently,there exists a pressing necessity to identify a reliable biomarker to inform treatment decisions.
文摘Metastatic lung cancer remains a formidable adversary in oncology,accounting for a staggering global mortality burden due to its high malignancy and poor prognosis^(1).In recent years,the integration of chemotherapy and immunotherapy has emerged as a promising strategy for synergize killing of tumor cell^(2).
基金We acknowledge the support from the National Science Fund for Excellent Young Scholars(No.82022070)the Regional Innovation and Development Joint Fund(No.U20A20411).
文摘Chemotherapeutics can induce immunogenic cell death(ICD)in tumor cells,offering new possibilities for cancer therapy.However,the efficiency of the immune response generated is insufficient due to the inhibitory nature of the tumor microenvironment(TME).Here,we developed a pH/reactive oxygen species(ROS)dual-response system to enhance chemoimmunotherapy for melanoma.The system productively accumulated in tumors by specific binding of phenylboronic acid(PBA)to sialic acids(SA).The nanoparticles(NPs)rapidly swelled and released quercetin(QUE)and doxorubicin(DOX)upon the stimulation of tumor microenvironment(TME).The in vitro and in vivo results consistently demonstrated that the NPs improved anti-tumor efficacy and prolonged survival of mice,significantly enhancing the effects of the combination.Our study revealed DOX was an ICD inducer,stimulating immune responses and promoting maturation of dendritic cells(DCs).Additionally,QUE served as a TME regulator by inhibiting the cyclooxygenase-2(COX2)-prostaglandin E2(PGE2)axis,which influenced various immune cells,including increasing cytotoxic T cells(CLTs)infiltration,promoting M1 macrophage polarization,and reducing regulatory T cells(Tregs)infiltration.The combination synergistically facilitated chemoimmunotherapy efficacy by remodeling the immunosuppressive microenvironment.This work presents a promising strategy to increase anti-tumor efficiency of chemotherapeutic agents.
基金the National Key Research and Development Program of China(2021YFC400600,2022YFE0203600)the National Natural Science Foundation of China(81925035 and 82341232)+4 种基金the Future Network(083GJHZ2023012FN)Grand Challenges(083GJHZ2023021GC)of the International Partnership Program of the Chinese Academyof Sciences,CAS President’s International Fellowship Initiative(2024VBB0004)High-level Innovative Research Institute(2021B0909050003)from Department of ScienceTechnology of Guangdong ProvinceZhongshan Municipal Bureau of Science and Technology(LJ2021001 and CXTD2022011).
文摘Glycolysis-related lactic acid overproduction creates an“ion-trapping”barrier and immunosuppressive tumor microenvironment that compromise effective intratumoral drug delivery and therapy.Therefore,normalization of tumor microenvironment via lactic acid neutralization can be a promising avenue for overcoming this therapeutic hurdle.In this study,the flexible liposomes loaded with sodium bicarbonate(NaHCO_(3)@Flip)were used as a nano-adjuvant to boost chemoimmunotherapy.Their effects on assisting DOXIL and anti-programmed cell death protein 1(PD-1)therapy were investigated.NaHCO_(3)@Flip achieved deep tumor penetration,with the ability to neutralize lactic acid and normalize the acidic tumor microenvironment.NaHCO_(3)@Flip is biosafe and can enhance cellular uptake efficiency of doxorubicin(DOX)by overcoming the ion-trapping barrier and amplify immunogenic cell death induced by DOX.The combination therapy of liposomal DOX and NaHCO_(3)@Flip demonstrated enhanced inhibition of tumor growth.NaHCO_(3)@Flip can also synergize with PD-1 antibody therapy.NaHCO_(3)@Flip has the potential to serve as a therapeutic adjuvant for boosting chemoimmunotherapy by overcoming the ion-trapping effect and normalizing the tumor microenvironment.
文摘Patients with chronic lymphocytic leukemia(CLL)have differing clinical outcomes.Recent advances integrating multi-omic data have uncovered molecular subtypes in CLL with different prognostic implications and may allow better prediction of therapy response.While finite-duration chemoimmunotherapy(CIT)has enabled deep responses and prolonged duration of responses in the past,the advent of novel targeted therapy for the treatment of CLL has dramatically changed the therapeutic landscape.In this review,we discuss the latest genomic,transcriptomic,and epigenetic alterations regarded as major drivers of resistance to CIT in CLL.Further advances in genomic medicine will allow for better prediction of response to therapy and provide the basis for rational selection of therapy for long-term remissions with minimal toxicity.
文摘BACKGROUND Primary testicular lymphoma(PTL)is a rare,aggressive malignancy,representing a small fraction of testicular tumors and non-Hodgkin lymphomas,yet it is the most common testicular malignancy in older men.Diffuse large B-cell lymphoma(DLBCL),which is typically the aggressive subtype,dominates PTL and shows diffuse B-cell infiltration.Venous tumor thrombus,uncommon in lymphomas,is uniquely reported in this case of testicular DLBCL with gonadal vein involvement.CASE SUMMARY A 62-year-old man presented with a two-month history of painless left testicular swelling and stiffness.Diagnostic imaging[ultrasonography,computed tomography(CT),and 18F-fluorodeoxyglucose positron emission tomography/CT(18FFDG-PET/CT)]revealed bilateral testicular masses and a gonadal vein tumor thrombus(SUVmax 16.5).Left orchiectomy confirmed DLBCL with CD20,Bcl-2,and MUM1 positivity(Ki-67:approximately 80%).The disease was staged as Ann Arbor stage IVA(International Prognostic Index score 3,high-intermediate risk).The patient received Rituximab,Polatuzumab Vedotin,Cyclophosphamide,Epirubicin,and Prednisolone chemotherapy,completing the first cycle with good tolerability.No adverse events were reported,and follow-up is ongoing to assess long-term outcomes.This case highlights the diagnostic utility of 18F-FDGPET/CT and the importance of multidisciplinary management in rare PTL presentations with tumor thrombus.CONCLUSION This case demonstrates the diagnostic complexities of PTL with gonadal vein tumor thrombus,underscoring the importance of considering lymphoma in elderly patients with testicular masses and venous involvement.A multi-disciplinary team including urologists,hematologists,and radiation oncologists is needed to ensure appropriate therapy.
基金supported by the National Natural Science Foundation of China(51973216,51873207,51803006,51833010,51673190,and 51603204)the Science and Technology Development Program of Jilin Province(20200404182YY)+1 种基金the Youth Talents Promotion Project of Jilin Province(181909)the Youth Innovation Promotion Association of Chinese Academy of Sciences(2019005)。
文摘Many conventional chemotherapeutics play an immune-modulating effect by inducing immunogenic cell death(ICD)in tumor cells.However,they hardly arouse strong antitumor immune response because the immunosuppressive lymphocytes are present in the tumor microenvironment.These immunosuppressive lymphocytes include regulatory T cells(Tregs)and myeloid-derived suppressor cells(MDSCs).We used a low dose of doxorubicin(DOX)to induce ICD in combination with immune regulator 1-methylDL-tryptophan(1 MT)to suppress indoleamine 2,3-dioxygenase and overcome Treg-and MDSCassociated immune suppression.By co-encapsulation of DOX and 1 MT into a reduction-responsive polypeptide nanogel,the drugs were simultaneously released in the tumor cells and synergistically performed antitumor efficacy.After treatment,recruitment of Tregs and MDSCs was inhibited,and the frequency of tumor-infiltrating CD8+T cells was remarkably enhanced.These results demonstrated that the chemoimmunotherapy strategy effectively suppressed tumor growth without causing evident adverse effects,indicating its great potential in clinical cancer therapy.
基金the National Natural Science Foundation of China(Grant No.81730102,32271384)Shanghai Basic Research Program(Grant No.20JC1411702)Shanghai Science and Technology Program(Grant No.20ZR1456100).
文摘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(Zn^(2+))-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.
基金This work is supported by research grants from the National Natural Science Foundation of China(NSFC 52033006).
文摘Triple-negative breast cancer(TNBC)due to lack of clear target and notorious“cold”tumor microenvironment(TME)is one of the most intractable and lethal malignancies.Tuning“cold”TME into“hot”becomes an emerging therapeutic strategy to TNBC.Herewith,we report that integrin-targeting micellar gemcitabine and paclitaxel(ATN-mG/P,ATN sequence:Ac-PhScNK-NH2)cooperating with polymersomal CpG(NanoCpG)effectively“heated up”and treated TNBC.ATN-mG/P exhibited greatly boosted apoptotic activity in 4T1 cells,induced potent immunogenic cell death(ICD),and efficiently stimulated maturation of bone marrow-derived dendritic cells(BMDCs).Remarkably,in a postoperative TNBC model,ATN-mG/P combining with NanoCpG promoted strong anti-cancer immune responses,showing a greatly augmented proportion of mature DCs and CD8^(+)T cells while reduced immune-suppressive myeloid-derived suppressor cells(MDSCs)and regulatory T cells(T_(reg)),which led to complete inhibition of lung metastasis and 60%mice tumor-free.The co-delivery of gemcitabine and paclitaxel at desired ratio in combination with NanoCpG provides a unique platform for potent chemoimmunotherapy of“cold”tumors like TNBC.
基金supported by the National Natural Science Foundation of China(82272788,82072990,81903045,and 82072988)China Postdoctoral Science Foundation(2021M703692)+2 种基金Department of Health of Guangdong Province Science Foundation(A2022165 and A2021142)Guangzhou Municipal Science and Technology Project(202201011479)Guangdong Science and Technology Development Fund(2019A1515011867 and 2020A1515010405).
文摘Background Immune cell heterogenicity is known to determine the therapeutic response to cancer progression.Neoadjuvant chemoimmunotherapy(NACI)has shown clinical benefits in some patients with advanced head and neck squamous cell carcinoma(HNSCC),but the underlying mechanism behind this clinical response is unknown.The efficacy of NACI needs to be potentiated by identifying accurate biomarkers to predict clinical responses.Here,we attempted to identify molecules predicting NACI response in advanced HNSCC.Methods We performed combined single-cell RNA sequencing(scRNA-seq)and multiplex immunofluorescence(mIHC)staining with tumor samples derived from NACI-treated HNSCC patients to identify a new tumor-infiltrating cell(TIL)subtype,CD103^(+)CD8^(+)TILs,associated with clinical response,while both in vitro and in vivo assays were carried out to determine its antitumor efficiency.The regulatory mechanism of the CD103^(+)CD8^(+)TILs population was examined by performing cell-cell interaction analysis of the scRNA-seq data and spatial analysis of the mIHC images.Results We established intratumoral CD103^(+)CD8^(+)TILs density as a determinant of NACI efficacy in cancers.Our scRNA-seq results indicated that the population of CD103^(+)CD8^(+)TILs was dramatically increased in the responders of NACI-treated HNSCC patients,while mIHC analysis confirmed the correlation between intratumoral CD103^(+)CD8^(+)TILs density and NACI efficacy in HNSCC patients.Further receiver operating characteristic curve analysis defined this TIL subset as a potent marker to predict patient response to NACI.Functional assays showed that CD103^(+)CD8^(+)TILs were tumor-reactive T cells,while programmed cell death protein-1(PD-1)blockade enhanced CD103^(+)CD8^(+)TILs cytotoxicity against tumor growth in vivo.Mechanistically,targeting the triggering receptor expressed on myeloid cells 2-positive(TREM2^(+))macrophages might enhance the population of CD103^(+)CD8^(+)TILs and facilitate antitumor immunity during NACI treatment.Conclusions Our study highlights the impact of intratumoral CD103^(+)CD8^(+)TILs density on NACI efficacy in different cancers,while the efforts to elevate its population warrant further clinical investigation.
基金supported by National Natural Science Foundation of China(Nos.82173757,82173756)。
文摘Chemoimmunotherapy has been approved as standard treatment for triple-negative breast cancer(TNBC),but the clinical outcomes remain unsatisfied.Abnormal epigenetic regulation is associated with acquired drug resistance and T cell exhaustion,which is a critical factor for the poor response to chemoimmunotherapy in TNBC.Herein,macrophage-camouflaged nanoinducers co-loaded with paclitaxel(PTX)and decitabine(DAC)(P/D-mMSNs)were prepared in combination with PD-1 blockade therapy,hoping to improve the efficacy of chemoimmunotherapy through the demethylation of tumor tissue.Camouflage of macrophage vesicle confers P/D-mMSNs with tumor-homing properties.First,DAC can achieve demethylation of tumor tissue and enhance the sensitivity of tumor cells to PTX.Subsequently,PTX induces immunogenic death of tumor cells,promotes phagocytosis of dead cells by dendritic cells,and recruits cytotoxic T cells to infiltrate tumors.Finally,DAC reverses T cell depletion and facilitates immune checkpoint blockade therapy.P/D-mMSNs may be a promising candidate for future drug delivery design and cancer combination therapy in TNBC.
基金supported in part by the National Key Research and Development Program of China(No.2021YFF1201200)the Science and Technology Innovation Program of Hunan Province(No.2022RC1031),the Natural Science Foundation of Hunan Province(No.2023JJ50354)+1 种基金the Scientific Research Project of Hunan Education Department(No.24A0575)the High Performance Computing Center of Central South University.
文摘A novel hybrid model combining a convolutional neural network(CNN)and a low-complexity Transformer network is introduced for predicting lung cancer response to neoadjuvant chemoimmunotherapy using computed tomography scans.This approach is crucial as it assists clinicians in identifying patients likely to benefit from treatment and in assessing their prognosis.The model employs channel splitting to minimize parameter count.It then leverages both CNN for local feature extraction and a streamlined Transformer for global feature comprehension.To enhance efficiency,a novel self-attention mechanism is implemented,focusing on feature aggregation and element-wise multiplication.To address the different semantic meanings of features,an attention-based module is designed to seamlessly integrate features from both networks,employing a process of coarse fusion,attention computation,and fine fusion.When evaluated with data from 232 lung cancer patients who have undergone neoadjuvant chemoimmunotherapy,the model demonstrates exceptional performance,achieving a Dice score of 47.04%and a 95.00%Hausdorff distance of 25.12 mm,outperforming existing methods.Additionally,it has only 2.91×106 parameters and 52.95×109 floating point operations.Moreover,the model’s predictive accuracy in tumor diameter estimation is beneficial for treatment planning.Its robustness is further validated through its application in stroke lesion prediction,indicating its broad applicability.
