Dysfunction of anti-tumor immune responses is crucial for cancer progression. Immune checkpoint blockade(ICB), which can potentiate T cell responses, is an effective strategy for the normalization of host anti-tumor i...Dysfunction of anti-tumor immune responses is crucial for cancer progression. Immune checkpoint blockade(ICB), which can potentiate T cell responses, is an effective strategy for the normalization of host anti-tumor immunity. In recent years, immune checkpoints, expressed on both tumor cells and immune cells, have been identified;some of them have exhibited potential druggability and have been approved by the US Food and Drug Administration(FDA) for clinical treatment. However, limited responses and immune-related adverse events(ir AEs) cannot be ignored. This review outlines the development and applications of ICBs, potential strategies for overcoming resistance, and future directions for ICB-based cancer immunotherapy.展开更多
During the past three decades,studies have shown that tumor cells could"manipulate"host immunity to escape the immune defenses in the tumor microenvironment.One of the most important underlying mechanisms is...During the past three decades,studies have shown that tumor cells could"manipulate"host immunity to escape the immune defenses in the tumor microenvironment.One of the most important underlying mechanisms is immune-suppression regulated by programmed cell death-1 or its ligand 1(PD-1/PD-L1),which makes PD-1/PD-L1 blockadea promising target of cancer immune-therapy.Tumors could suppress immuno-response of T cells by activating PD-1/PD-L1 signaling pathway.Therefore,inhibiting the interaction between PD-1 and PD-L1 could reconstitute the enduring antitumor immunity in the tumor microenvironment via enhancing the T-cell response,there after augmenting the endogenous antitumor force of the immune system.Along these lines,inhibitors of PD-1/PD-L1 has been applied in multiple clinical trials against various types of tumors.Recent studies indicated that PD-1/PD-L1 blockade have demonstrated high efficacy and safety against melanoma,lung,kidney and several other solid tumors,as well as hematological malignancies.Nevertheless,the efficacy of this checkpoint blockade approach is not universal.Some investigation suggested that lack of responses to anti-PD-1/PD-L1 therapy of patients without PD-1/PD-L1 over-expression was expected.In this review,we summarize the history and current understanding of multiple intrinsic and extrinsic mechanisms via which PD-1/PD-L1 is regulated and research advances in preclinical/clinical aspects of PD-1/PD-L1,as well as significance and perspectives regarding the PD-1/PD-L1 blockade in immune-antitumor therapy.展开更多
Background:Gastric cancer(GC)continues to pose a significant global health challenge due to its high rates of incidence and mortality,with the majority of cases identified at advanced stages.Immunotherapy,particularly...Background:Gastric cancer(GC)continues to pose a significant global health challenge due to its high rates of incidence and mortality,with the majority of cases identified at advanced stages.Immunotherapy,particularly immune checkpoint blockades(ICBs),has demonstrated considerable therapeutic potential;however,many patients do not exhibit a favorable response.As a result,constructing a predictive model to assess ICBs'responsiveness is essential for enhancing treatment outcomes.Methods:Using consensus clustering based on anoikis-related gene expression,GC patients were stratified into two subclusters.Differences in tumor immune microenvironment,ICB resistance,genomic alterations,methylation profiles,and transcriptional networks were analyzed.A machine learning-based strategy was employed to develop a consensus anoikis-related gene signature(ARGS).Potential therapeutic targets were identified through single-cell RNA sequencing(scRNA-seq),and validation was conducted using multiplex immunofluorescence and immunohistochemistry in an in-house cohort(n=28),including 14 ICB responders and 14 nonresponders.Results:The anoikis-resistant cluster(Cluster A)was associated with poorer survival,immunosuppressive infiltration,lower tumor mutation burden,and ICB resistance.ScRNA-seq revealed high fibroblast and endothelial infiltration,with GLI3+cancer-associated fibroblasts suggesting Hedgehog pathway involvement.The ARGS model effectively stratified patients,with elevated scores associ-ated with immunotherapy resistance,enhanced AR characteristics,and poorer clinical outcomes.展开更多
The synergistic approach of combining photodynamic immunotherapy with endogenous clearance of PD-L1 immune checkpoint blockade therapy holds promise for enhancing survival outcomes in glioblastoma(GBM)patients.The obs...The synergistic approach of combining photodynamic immunotherapy with endogenous clearance of PD-L1 immune checkpoint blockade therapy holds promise for enhancing survival outcomes in glioblastoma(GBM)patients.The observed upregulation of O-GlcNAc glycolysis in tumors may contribute to the stabilization of endogenous PD-L1 protein,facilitating tumor immune evasion.This study presents a pH-adapted excited state intramolecular proton transfer(ESIPT)-isomerizedβ-ketoamide-based covalent organic framework(COF)nanoplatform(denoted as OT@COF-RVG).Temozolomide(TMZ)and OSMI-4(O-GlcNAc transferase inhibitor)were integrated into COF cavities,then modified on the surface with polyethylene glycol and the rabies virus peptide RVG-29,showing potential for sensitizing TMZ chemotherapy and initiating photodynamic therapy(PDT).By inhibiting O-GlcNAc and promoting lysosomal degradation of PD-L1,OT@COF-RVG enhanced the effectiveness of immune checkpoint blockade(ICB)therapy.Additionally,treatment with OT@COF-RVG led to a notable elevation in reactive oxygen species(ROS)levels,thereby re-establishing an immunostimulatory state,inducing immunogenic cell death(ICD).In summary,our research unveiled a correlation between O-GlcNAc in GBM and the evasion of immune responses by tumors,while showcasing the potential of OT@COF-RVG in reshaping the immunosuppressive microenvironment of GBM and offering a more effective approach to immunotherapy in clinical settings.展开更多
The authors regret to note that the affiliations in the above paper were incorrect.The correct author affiliations should be:Lijin Chen a,b,1,Yingying Li b,1,Hong Zhao c,1,Jinyuan Huangb,Huimeng Yan b,Xiaoyan Lin b,∗∗...The authors regret to note that the affiliations in the above paper were incorrect.The correct author affiliations should be:Lijin Chen a,b,1,Yingying Li b,1,Hong Zhao c,1,Jinyuan Huangb,Huimeng Yan b,Xiaoyan Lin b,∗∗,Bin Zhao a,∗a Quanzhou First Hospital Affiliated to Fujian Medical University,Quanzhou,Fujian 362000,China.展开更多
Amplifying“eat me signal”during tumor immunogenic cell death(ICD)cascade is crucial for tumor immunotherapy.Inspired by the indispensable role of adenosine triphosphate(ATP,a necessary“eat me signal”for ICD),a ver...Amplifying“eat me signal”during tumor immunogenic cell death(ICD)cascade is crucial for tumor immunotherapy.Inspired by the indispensable role of adenosine triphosphate(ATP,a necessary“eat me signal”for ICD),a versatile ICD amplifier was developed for chemotherapy-sensitized immunotherapy.Doxorubicin(DOX),ATP and ferrous ions(Fe^(2+))were co-assembled into nanosized amplifier(ADO-Fe)throughπ‒πstacking and coordination effect.Meanwhile,phenylboric acid-polyethylene glycol-phenylboric acid(PBA-PEG-PBA)was modified on the surface of ADO-Fe(denoted as PADO-Fe)by the virtue of d-ribose unit of ATP.PADO-Fe could display active targetability against tumor cells via sialic acid/PBA interaction.In acidic microenvironment,PBA-PEG-PBA would dissociate from amplifier.Moreover,high H_(2)O_(2)concentration would induce hydroxyl radical(·OH)and oxygen(O_(2))generation through Fenton reaction by Fe^(2+).DOX and ATP would be released from the amplifier,which could induce ICD effect and“ICD adjuvant”to amplify this process.Together with programmed death ligands 1(PD-L1)checkpoint blockade immunotherapy,PADO-Fe could not only activate immune response against primary tumor,but also strong abscopal effect against distant tumor.Our simple and multifunctional ICD amplifier opens a new window for enhancing ICD effect and immune checkpoint blockade therapy.展开更多
The use of checkpoint-blockade antibodies is still restricted in several malignancies due to the modest efficacy,despite considerable success in anti-tumor immunotherapy.The poor response of cancer cells to immune des...The use of checkpoint-blockade antibodies is still restricted in several malignancies due to the modest efficacy,despite considerable success in anti-tumor immunotherapy.The poor response of cancer cells to immune destruction is an essential contributor to the failure of checkpoint therapy.We hypothesized that combining checkpoint therapy with natural-product chemosensitizer could enhance immune response.Herein,a targeted diterpenoid derivative was integrated with the checkpoint blockade(anti-CTLA-4)to improve immunotherapy using thermo sensitive liposomes as carriers.In vivo,the liposomes enabled the co-delivery of the two drug payloads into the tumor.Consequently,the regulatory T cell proliferation was restrained,the cytotoxic T cell infiltration was enhanced,and the profound immunotherapeutic effect was achieved.In addition,the immunotherapeutic effect of another clinically used checkpoint antibody,anti-PD-1,also benefited from the diterpenoid derivative.Of note,our mechanism study revealed that the targeted diterpenoid derivative increased the sensitivity of cancer cells to immune attack via THBS1 downregulation and the resultant destruction of THBS1-CD47 interaction.Collectively,co-delivering THBS1 inhibitor and checkpoint blockade is promising to boost cancer immunotherapy.We first time discovered that THBS1 suppression could strengthen checkpoint therapy.展开更多
Metastases of uveal melanoma(UM)spread predominantly to the liver.Due to low response rates to systemic therapies,liver-directed therapies(LDT)are commonly used for tumor control.The impact of LDT on the response to s...Metastases of uveal melanoma(UM)spread predominantly to the liver.Due to low response rates to systemic therapies,liver-directed therapies(LDT)are commonly used for tumor control.The impact of LDT on the response to systemic treatment is unknown.A total of 182 patients with metastatic UM treated with immune checkpoint blockade(ICB)were included in this analysis.Patients were recruited from prospective skin cancer centers and the German national skin cancer registry(ADOReg)of the German Dermatologic Cooperative Oncology Group(DeCOG).Two cohorts were compared:patients with LDT(cohort A,n=78)versus those without LDT(cohort B,n=104).Data were analyzed for response to treatment,progression-free survival(PFS),and overall survival(OS).The median OS was significantly longer in cohort A than in cohort B(20.1 vs.13.8 months;P=0.0016)and a trend towards improved PFS was observed for cohort A(3.0 vs.2.5 months;P=0.054).The objective response rate to any ICB(16.7%vs.3.8%,P=0.0073)and combined ICB(14.1%vs.4.5%,P=0.017)was more favorable in cohort A.Our data suggest that the combination of LDT with ICB may be associated with a survival benefit and higher treatment response to ICB in patients with metastatic UM.展开更多
The therapeutic efficacy of programmed cell death protein 1/programmed cell death-ligand 1(PD-1/PD-L1)blockade immunotherapy is extremely dampened by complex immunosuppressive mechanisms including regulatory T cells(T...The therapeutic efficacy of programmed cell death protein 1/programmed cell death-ligand 1(PD-1/PD-L1)blockade immunotherapy is extremely dampened by complex immunosuppressive mechanisms including regulatory T cells(Treg),M2 macrophages(M2),and prostaglandin E2(PGE2).The pivotal roles of PGE2 have been recognized by directly inactivating CD8+T cells and indirectly inducing Treg and M2.Therefore,PGE2 abolishment through inactivating cyclooxygenase-2(COX-2)could be robust to sensitize tumour toward anti-PD-1/PD-L1 immunotherapy,which has gone into clinical trials.However,exploring this promising strategy in nanomedicine to enhance immunotherapy remains unrevealed.The key challenge to synergistically combine COX-2 inhibition and anti-PD-1/PD-L1 lies in the different pharmacokinetic profiles and the spatial obstacles since PD-1/PD-L1 interaction occurs extracellularly and COX-2 locates intracellularly.Thus,the programmed release nanoparticles(termed as Cele-BMS-NPs)are rationally designed,which are composed of pH-sensitive human serum albumin derivative,BMS-202 compound as PD-1/PD-L1 inhibitor,glutathione(GSH)-activatable prodrug of celecoxib(COX-2 inhibitor).The in vitro experiments demonstrate that this smart Cele-BMS-NPs could extracellularly release BMS-202 under the acidic tumour microenvironment,and the intracellularly release of celecoxib in response to the elevated GSH concentration inside tumour cells.After systemic administration,the intratumoral infiltration of CD8+T cells is significantly enhanced and meanwhile immunosuppressive M2,Treg,and PGE2 are reduced,thereby eliciting the anti-tumour immune responses toward low immunogenic tumours and postsurgical tumour recurrences.展开更多
Immune checkpoint blockade(ICB) has been regarded as one promising approach for tumor immunotherapy. Here, we report a functional nanoplatform based on generation 5(G5) poly(amidoamine)(PAMAM)dendrimer-entrapped gold ...Immune checkpoint blockade(ICB) has been regarded as one promising approach for tumor immunotherapy. Here, we report a functional nanoplatform based on generation 5(G5) poly(amidoamine)(PAMAM)dendrimer-entrapped gold nanoparticles(Au DENPs) as a nonviral vector to deliver programmed death-ligand 1(PDL1) small interfering RNA(siPD-L1) for subsequent PD-L1 gene silencing-mediated tumor immunotherapy. In this work,G5 dendrimers with amine termini were partially decorated with methoxy polyethylene glycol(m PEG) on their periphery,entrapped Au NPs within their interiors, and were eventually labeled with fluorescamine. The generated functional Au DENPs possess desired dispersibility in water and colloidal stability, satisfactory cytocompatibility after complexation with siPD-L1, and efficient gene delivery performance. Strikingly, the functional Au DENPs enabled the delivery of siPDL1 to cancer cells to efficiently knock down the PD-L1 protein expression, thus boosting the ICB-based immunotherapy of a xenografted melanoma mouse tumor model with a tumor inhibition efficiency much higher than the PD-L1 antibody.The immune responses were also well demonstrated by downregulation of PD-L1 protein on the tumor cell surface and abundant distribution of CD8+and CD4+T cells in the infiltrating tumor tissue and spleen organ. The developed functional dendrimer-based nanoplatform may be promising to boost ICB-based immunotherapy of other tumor types.展开更多
The disease burden related to hepatocellular carcinoma(HCC) is increasing. Most HCC patients are diagnosed at the advanced stage and multikinase inhibitors have been the only treatment choice for them. Recently, the a...The disease burden related to hepatocellular carcinoma(HCC) is increasing. Most HCC patients are diagnosed at the advanced stage and multikinase inhibitors have been the only treatment choice for them. Recently, the approval of immune checkpoint inhibitors(ICIs) has provided a new therapeutic strategy for HCC. It is noteworthy that the positive outcomes of the phase Ⅲ clinical trial IMBrave150 [atezolizumab(anti-programmed cell death ligand 1 antibody) combined with bevacizumab(anti-vascular endothelial growth factor monoclonal antibody)],showed that overall survival and progression-free survival were significantly better with sorafenib. This combination therapy has become the new standard therapy for advanced HCC and has also attracted more attention in the treatment of HCC with anti-angiogenesis-immune combination therapy. Currently, the synergistic antitumor efficacy of this combination has been shown in many preclinical and clinical studies. In this review, we discuss the mechanism and clinical application of anti-angiogenics and immunotherapy in HCC, outline the relevant mechanism and rationality of the combined application of antiangiogenics and ICIs, and point out the existing challenges of the combination therapy.展开更多
Early studies shed light on the immune suppression of immune checkpoint molecules in the cancer microenvironment,with later studies applying immune checkpoint blockade(ICB)in treatment of various malignancies.Despite ...Early studies shed light on the immune suppression of immune checkpoint molecules in the cancer microenvironment,with later studies applying immune checkpoint blockade(ICB)in treatment of various malignancies.Despite the encouraging efficacy of ICBs in a substantial subset of cancer patients,the treatment response varies.Gene mutations of both tumor cells and immune cells in the tumor microenvironment have recently been identified as potential predictors of the ICB response.Recent developments in gene expression profiling of tumors have allowed identification of a panel of mutated genes that may affect tumor cell response to ICB treatment.In this review,we discuss the association of the ICB response with gene expression and mutation profiles in tumor cells,which it is hoped will help to optimize the clinical application of ICBs in cancer patients.展开更多
Immune checkpoint blockade(ICB)therapy targeting PD-L1 via monoclonal antibody(m Ab)has shown extensive clinical benefits in the diverse types of advanced malignancies.However,most patients are completely refractory t...Immune checkpoint blockade(ICB)therapy targeting PD-L1 via monoclonal antibody(m Ab)has shown extensive clinical benefits in the diverse types of advanced malignancies.However,most patients are completely refractory to ICB therapy owing to the PD-L1 recycling mechanism.Herein,we propose photo-induced crosslinked and anti-PD-L1 peptide incorporated liposomes(immune checkpoint blockade liposomes;ICB-LPs)to promote PD-L1 multivalent binding for inducing lysosomal degradation of PD-L1 in tumor cells.The ICB-LPs are prepared by formulation of DC_(8,9)PC with photo-polymerized diacetylenic moiety,1,2-dipalmitoylphosphatidylcholine(DPPC)and anti-PD-L1peptide(D-form NYSKPTDRQYHF)-conjugated DSPE-PEG_(2k)(anti-PD-L1-DSPE-PEG_(2k))in a molar ratio of 45:45:10,followed by cross-linking of liposomal bilayer upon UV irradiation.The 10 mol% antiPD-L1-DSPE-PEG_(2k)incorporated ICB-LPs have a nano-sized lipid bilayer structure with an average diameter of 137.7±1.04 nm,showing a high stability in serum condition.Importantly,the ICB-LPs efficiently promote the multivalent binding with PD-L1 on the tumor cell membrane,which are endocytosed with aim to deliver PD-L1 to the lysosomes,wherein the durable PD-L1 degradation is observed for72 h,in contrast to anti PD-L1 m Abs showing the rapid PD-L1 recycling within 9 h.The in vitro coculture experiments with CD8^(+)T cells show that ICB-LPs effectively enhance the T cell-mediated antitumor immune responses against tumor cells by blocking the PD-L1/PD-1 axis.When ICB-LPs are intravenously injected into colon tumor-bearing mice,they efficiently accumulate within the targeted tumor tissues via both passive and active tumor targeting,inducing a potent T cell-mediated antitumor immune response by effective and durable PD-L1 degradation.Collectively,this study demonstrates the superior antitumor efficacy of crosslinked and anti-PD-L1 peptide incorporated liposome formulation that promotes PD-L1 multivalent binding for trafficking of PD-L1 toward the lysosomes instead of the recycling endosomes.展开更多
Cancer immunotherapies, which train the natural immune system to specifically kill tumor cells while sparing the healthy cells,have helped revolutionize cancer treatments and demonstrated promising clinical therapeuti...Cancer immunotherapies, which train the natural immune system to specifically kill tumor cells while sparing the healthy cells,have helped revolutionize cancer treatments and demonstrated promising clinical therapeutic benefits for decades. However, the therapeutic outcome of immunotherapies, even for the most successful immune checkpoint blockade(ICB) therapy, remains unsatisfactory in the clinical practice, mainly due to the low immunogenicity of solid tumors and its immunosuppressive tumor microenvironment(TME). Notably, several cancer treatment modalities, including chemotherapy, radiotherapy, and phototherapy, have been revealed to evoke tumor immunogenicity and reverse immunosuppressive TME via inducing immunogenic cell death(ICD) of tumor cells, which synergistically sensitized tumors to ICB therapy. Nanomedicines have been extensively applied to augment ICD-inducing treatment modalities and potentiate ICB therapeutic efficacy therapy due to the opportune convergence of immunotherapy and nanotechnology. Here, we discuss the recent advances in nanomedicine-mediated ICD and its combination with ICB therapy.展开更多
The blocking of the immune checkpoint pathway with antibodies,especially targeting to programmed death-1/programmed death ligand-1(PD-1/PD-L1)pathway,was currently a widely used treatment strategy in clinical practice...The blocking of the immune checkpoint pathway with antibodies,especially targeting to programmed death-1/programmed death ligand-1(PD-1/PD-L1)pathway,was currently a widely used treatment strategy in clinical practice.However,the shortcomings of PD-L1 antibodies were constantly exposed with the deepening of its research and their therapeutic effect was limited by the translocation and redistribution of intracellular PD-L1.Herein,we proposed to improve immune checkpoint blockade therapy by using liposomes-coated CaO_(2)(CaO_(2)@Lipo)nanoparticles to inhibit the de novo biosynthesis of PD-L1.CaO_(2)@Lipo would produce oxygen and reduce hypoxia-inducible factor-1α(HIF-1α)level,which then downregulated the expression of PD-L1.Our in vitro and in vivo results have confirmed CaO_(2)@Lipo promoted the degradation of HIF-1αand then downregulated the expression of PD-L1 in cancer cells for avoiding immune escape.Furthermore,to mimicking the clinical protocol of anti-PD-L1 antibodies+chemo-drugs,CaO_(2)@Lipo was combined with doxorubicin(DOX)to investigate the tumor inhibition efficiency.We found CaO_(2)@Lipo enhanced DOX-induced immunogenic cell death(ICD)effect,which then promoted the infiltration of T cells,strengthened the blocking effect,thus provided an effective means to overcome the traditional immune checkpoint blockade treatment.展开更多
Primary and secondary resistance to immune checkpoint blockade(ICB)reduces its efficacy.The mechanisms underlying immunotherapy resistance are highly complex.In non-small cell lung cancer(NSCLC),these mechanisms are p...Primary and secondary resistance to immune checkpoint blockade(ICB)reduces its efficacy.The mechanisms underlying immunotherapy resistance are highly complex.In non-small cell lung cancer(NSCLC),these mechanisms are primarily associated with the loss of programmed cell death-ligand 1(PD-L1)expression,genetic mutations,circular RNA axis and transcription factor regulation,antigen presentation disorders,and dysregulation of signaling pathways.Additionally,alterations in the tumor microenvironment(TME)play a pivotal role in driving immunotherapy resistance.Primary resistance is mainly attributed to TME alterations,including mutations and comutations,modulation of T cell infiltration,enrichment of M2 tumor-associated macrophages(M2-TAMs)and mucosal-associated invariant T(MAIT)cells,vascular endothelial growth factor(VEGF),and pulmonary fibrosis.Acquired resistance mainly stems from changes in cellular infiltration patterns leading to“cold”or“hot”tumors,altered interferon(IFN)signaling pathway expression,involvement of extracellular vesicles(EVs),and oxidative stress responses,as well as post-treatment gene mutations and circadian rhythm disruption(CRD).This review presents an overview of various mechanisms underlying resistance to ICB,elucidates the alterations in the TME during primary,adaptive,and acquired resistance,and discusses existing strategies for overcoming ICB resistance.展开更多
Epithelial-mesenchymal plasticity(EMP)of cancer cells contributes to cancer cell heterogeneity,and it is well established that EMP is a critical determinant of acquired resistance to cancer treatment modalities includ...Epithelial-mesenchymal plasticity(EMP)of cancer cells contributes to cancer cell heterogeneity,and it is well established that EMP is a critical determinant of acquired resistance to cancer treatment modalities including radiation therapy,chemotherapy,and targeted therapies.Here,we aimed to explore how EMP contributes to cancer cell camouflage,allowing an ever-changing population of cancer cells to pass under the radar of our immune system and consequently compromise the effect of immune checkpoint blockade therapies.The ultimate clinical benefit of any combination regimen is evidenced by the sum of the drug-induced alterations observed in the variety of cellular populations composing the tumor immune microenvironment.The finely-tuned molecular crosstalk between cancer and immune cells remains to be fully elucidated,particularly for the spectrum of malignant cells along the epithelial to mesenchymal axis.High-dimensional single cell analyses of specimens collected in ongoing clinical studies is becoming a key contributor to our understanding of these interactions.This review will explore to what extent targeting EMP in combination with immune checkpoint inhibition represents a promising therapeutic avenue within the overarching strategy to reactivate a halting cancer-immunity cycle and establish a robust host immune response against cancer cells.Therapeutic strategies currently in clinical development will be discussed.展开更多
Esophageal squamous cell carcinoma(ESCC)remains a daunting global health concern.It is marked by aggressive progression and poor survival.While immunotherapy has emerged as a promising treatment modality,both primary ...Esophageal squamous cell carcinoma(ESCC)remains a daunting global health concern.It is marked by aggressive progression and poor survival.While immunotherapy has emerged as a promising treatment modality,both primary and acquired resistance continue to limit its clinical impact,leaving many patients without durable benefits(e.g.,CheckMate-648,ESCORT-1st).This review explains resistance mechanisms and suggests new strategies to improve outcomes.These mechanisms include immunosuppressive cells(Treg cells,myeloid-derived suppressor cells),inhibitory cytokines,molecular alterations involving programmed death 1/programmed death-ligand 1 signaling,and impaired antigen presentation.We also highlight key clinical trials—for example,CheckMate-648 and ESCORT-1st—that reveal both the potential and pitfalls of current immune checkpoint blockade strategies,underscoring the need for robust predictive biomarkers.Moreover,we examine cutting-edge tactics to overcome resistance,including combination regimens,tumor microenvironment remodeling,and tailored treatment approaches rooted in the patient’s unique genomic and immunologic landscape.展开更多
Dear Editor,Lymphocyte activation gene 3(LAG3),the third established target for immune checkpoint blockade therapy,suppresses T cell function by binding to major histocompatibility complex classⅡ(MHCⅡ).Despite its s...Dear Editor,Lymphocyte activation gene 3(LAG3),the third established target for immune checkpoint blockade therapy,suppresses T cell function by binding to major histocompatibility complex classⅡ(MHCⅡ).Despite its significant therapeutic potential in cancer immunotherapy and the substantial attention it has received from academia and industry,the molecular mechanisms of LAG3-mediated immunosuppression remain poorly understood,primarily because of its unique ligand-binding characteristics and intracellular domains[1].展开更多
基金supported by the National Key Research and Development Program of China(No.2022YFE0102100)the National Natural Science Foundation of China(Nos.U22A20307 and 81930041)。
文摘Dysfunction of anti-tumor immune responses is crucial for cancer progression. Immune checkpoint blockade(ICB), which can potentiate T cell responses, is an effective strategy for the normalization of host anti-tumor immunity. In recent years, immune checkpoints, expressed on both tumor cells and immune cells, have been identified;some of them have exhibited potential druggability and have been approved by the US Food and Drug Administration(FDA) for clinical treatment. However, limited responses and immune-related adverse events(ir AEs) cannot be ignored. This review outlines the development and applications of ICBs, potential strategies for overcoming resistance, and future directions for ICB-based cancer immunotherapy.
文摘During the past three decades,studies have shown that tumor cells could"manipulate"host immunity to escape the immune defenses in the tumor microenvironment.One of the most important underlying mechanisms is immune-suppression regulated by programmed cell death-1 or its ligand 1(PD-1/PD-L1),which makes PD-1/PD-L1 blockadea promising target of cancer immune-therapy.Tumors could suppress immuno-response of T cells by activating PD-1/PD-L1 signaling pathway.Therefore,inhibiting the interaction between PD-1 and PD-L1 could reconstitute the enduring antitumor immunity in the tumor microenvironment via enhancing the T-cell response,there after augmenting the endogenous antitumor force of the immune system.Along these lines,inhibitors of PD-1/PD-L1 has been applied in multiple clinical trials against various types of tumors.Recent studies indicated that PD-1/PD-L1 blockade have demonstrated high efficacy and safety against melanoma,lung,kidney and several other solid tumors,as well as hematological malignancies.Nevertheless,the efficacy of this checkpoint blockade approach is not universal.Some investigation suggested that lack of responses to anti-PD-1/PD-L1 therapy of patients without PD-1/PD-L1 over-expression was expected.In this review,we summarize the history and current understanding of multiple intrinsic and extrinsic mechanisms via which PD-1/PD-L1 is regulated and research advances in preclinical/clinical aspects of PD-1/PD-L1,as well as significance and perspectives regarding the PD-1/PD-L1 blockade in immune-antitumor therapy.
基金National Science and Technology Major Project,Grant/Award Number:2024ZD0533300Excellent Doctor Program of Zhongnan Hospital of Wuhan University,Grant/Award Number:ZNYB2021009。
文摘Background:Gastric cancer(GC)continues to pose a significant global health challenge due to its high rates of incidence and mortality,with the majority of cases identified at advanced stages.Immunotherapy,particularly immune checkpoint blockades(ICBs),has demonstrated considerable therapeutic potential;however,many patients do not exhibit a favorable response.As a result,constructing a predictive model to assess ICBs'responsiveness is essential for enhancing treatment outcomes.Methods:Using consensus clustering based on anoikis-related gene expression,GC patients were stratified into two subclusters.Differences in tumor immune microenvironment,ICB resistance,genomic alterations,methylation profiles,and transcriptional networks were analyzed.A machine learning-based strategy was employed to develop a consensus anoikis-related gene signature(ARGS).Potential therapeutic targets were identified through single-cell RNA sequencing(scRNA-seq),and validation was conducted using multiplex immunofluorescence and immunohistochemistry in an in-house cohort(n=28),including 14 ICB responders and 14 nonresponders.Results:The anoikis-resistant cluster(Cluster A)was associated with poorer survival,immunosuppressive infiltration,lower tumor mutation burden,and ICB resistance.ScRNA-seq revealed high fibroblast and endothelial infiltration,with GLI3+cancer-associated fibroblasts suggesting Hedgehog pathway involvement.The ARGS model effectively stratified patients,with elevated scores associ-ated with immunotherapy resistance,enhanced AR characteristics,and poorer clinical outcomes.
基金supported by grants from the Natural Science Foundation of Jiangxi Province(No.20232BAB206085 and 20224BAB216074 for TFY,No.20232BAB216084 for LY)Postdoctoral Research Foundation of China(No.2022M721452 for TFY)。
文摘The synergistic approach of combining photodynamic immunotherapy with endogenous clearance of PD-L1 immune checkpoint blockade therapy holds promise for enhancing survival outcomes in glioblastoma(GBM)patients.The observed upregulation of O-GlcNAc glycolysis in tumors may contribute to the stabilization of endogenous PD-L1 protein,facilitating tumor immune evasion.This study presents a pH-adapted excited state intramolecular proton transfer(ESIPT)-isomerizedβ-ketoamide-based covalent organic framework(COF)nanoplatform(denoted as OT@COF-RVG).Temozolomide(TMZ)and OSMI-4(O-GlcNAc transferase inhibitor)were integrated into COF cavities,then modified on the surface with polyethylene glycol and the rabies virus peptide RVG-29,showing potential for sensitizing TMZ chemotherapy and initiating photodynamic therapy(PDT).By inhibiting O-GlcNAc and promoting lysosomal degradation of PD-L1,OT@COF-RVG enhanced the effectiveness of immune checkpoint blockade(ICB)therapy.Additionally,treatment with OT@COF-RVG led to a notable elevation in reactive oxygen species(ROS)levels,thereby re-establishing an immunostimulatory state,inducing immunogenic cell death(ICD).In summary,our research unveiled a correlation between O-GlcNAc in GBM and the evasion of immune responses by tumors,while showcasing the potential of OT@COF-RVG in reshaping the immunosuppressive microenvironment of GBM and offering a more effective approach to immunotherapy in clinical settings.
文摘The authors regret to note that the affiliations in the above paper were incorrect.The correct author affiliations should be:Lijin Chen a,b,1,Yingying Li b,1,Hong Zhao c,1,Jinyuan Huangb,Huimeng Yan b,Xiaoyan Lin b,∗∗,Bin Zhao a,∗a Quanzhou First Hospital Affiliated to Fujian Medical University,Quanzhou,Fujian 362000,China.
基金the financial support of Natural Science Foundation of China (Nos. 82104108, 82073797, 81874305 and 81773668)China Postdoctoral Science Foundation (2021M693869)Liaoning Natural Science Foundation for Planned Project (2021JH6/10500161, China)
文摘Amplifying“eat me signal”during tumor immunogenic cell death(ICD)cascade is crucial for tumor immunotherapy.Inspired by the indispensable role of adenosine triphosphate(ATP,a necessary“eat me signal”for ICD),a versatile ICD amplifier was developed for chemotherapy-sensitized immunotherapy.Doxorubicin(DOX),ATP and ferrous ions(Fe^(2+))were co-assembled into nanosized amplifier(ADO-Fe)throughπ‒πstacking and coordination effect.Meanwhile,phenylboric acid-polyethylene glycol-phenylboric acid(PBA-PEG-PBA)was modified on the surface of ADO-Fe(denoted as PADO-Fe)by the virtue of d-ribose unit of ATP.PADO-Fe could display active targetability against tumor cells via sialic acid/PBA interaction.In acidic microenvironment,PBA-PEG-PBA would dissociate from amplifier.Moreover,high H_(2)O_(2)concentration would induce hydroxyl radical(·OH)and oxygen(O_(2))generation through Fenton reaction by Fe^(2+).DOX and ATP would be released from the amplifier,which could induce ICD effect and“ICD adjuvant”to amplify this process.Together with programmed death ligands 1(PD-L1)checkpoint blockade immunotherapy,PADO-Fe could not only activate immune response against primary tumor,but also strong abscopal effect against distant tumor.Our simple and multifunctional ICD amplifier opens a new window for enhancing ICD effect and immune checkpoint blockade therapy.
基金supported by the National Natural Science Foundation of China(Nos.81872823,82073782 and 81973524)the Double First-Class(CPU2018PZQ13,China)of the CPU+4 种基金the Shanghai Science and Technology Committee(19430741500,China)the Key Laboratory of Modern Chinese Medicine Preparation of Ministry of Education of Jiangxi University of Traditional Chinese Medicine(zdsys-202103)the Project Program of State Key Laboratory of Natural Medicines,China Pharmaceutical University(No.SKLNMZZ202004)Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor(Guangxi Medical University),Ministry of Education(GKEKF202010)。
文摘The use of checkpoint-blockade antibodies is still restricted in several malignancies due to the modest efficacy,despite considerable success in anti-tumor immunotherapy.The poor response of cancer cells to immune destruction is an essential contributor to the failure of checkpoint therapy.We hypothesized that combining checkpoint therapy with natural-product chemosensitizer could enhance immune response.Herein,a targeted diterpenoid derivative was integrated with the checkpoint blockade(anti-CTLA-4)to improve immunotherapy using thermo sensitive liposomes as carriers.In vivo,the liposomes enabled the co-delivery of the two drug payloads into the tumor.Consequently,the regulatory T cell proliferation was restrained,the cytotoxic T cell infiltration was enhanced,and the profound immunotherapeutic effect was achieved.In addition,the immunotherapeutic effect of another clinically used checkpoint antibody,anti-PD-1,also benefited from the diterpenoid derivative.Of note,our mechanism study revealed that the targeted diterpenoid derivative increased the sensitivity of cancer cells to immune attack via THBS1 downregulation and the resultant destruction of THBS1-CD47 interaction.Collectively,co-delivering THBS1 inhibitor and checkpoint blockade is promising to boost cancer immunotherapy.We first time discovered that THBS1 suppression could strengthen checkpoint therapy.
文摘Metastases of uveal melanoma(UM)spread predominantly to the liver.Due to low response rates to systemic therapies,liver-directed therapies(LDT)are commonly used for tumor control.The impact of LDT on the response to systemic treatment is unknown.A total of 182 patients with metastatic UM treated with immune checkpoint blockade(ICB)were included in this analysis.Patients were recruited from prospective skin cancer centers and the German national skin cancer registry(ADOReg)of the German Dermatologic Cooperative Oncology Group(DeCOG).Two cohorts were compared:patients with LDT(cohort A,n=78)versus those without LDT(cohort B,n=104).Data were analyzed for response to treatment,progression-free survival(PFS),and overall survival(OS).The median OS was significantly longer in cohort A than in cohort B(20.1 vs.13.8 months;P=0.0016)and a trend towards improved PFS was observed for cohort A(3.0 vs.2.5 months;P=0.054).The objective response rate to any ICB(16.7%vs.3.8%,P=0.0073)and combined ICB(14.1%vs.4.5%,P=0.017)was more favorable in cohort A.Our data suggest that the combination of LDT with ICB may be associated with a survival benefit and higher treatment response to ICB in patients with metastatic UM.
基金support from The National Key R&D Program of China(No.2018YFA0903500)The Postdoctoral Science Fund of China(No.2017M622429)The National Natural Science Foundation of China(No.51703073)。
文摘The therapeutic efficacy of programmed cell death protein 1/programmed cell death-ligand 1(PD-1/PD-L1)blockade immunotherapy is extremely dampened by complex immunosuppressive mechanisms including regulatory T cells(Treg),M2 macrophages(M2),and prostaglandin E2(PGE2).The pivotal roles of PGE2 have been recognized by directly inactivating CD8+T cells and indirectly inducing Treg and M2.Therefore,PGE2 abolishment through inactivating cyclooxygenase-2(COX-2)could be robust to sensitize tumour toward anti-PD-1/PD-L1 immunotherapy,which has gone into clinical trials.However,exploring this promising strategy in nanomedicine to enhance immunotherapy remains unrevealed.The key challenge to synergistically combine COX-2 inhibition and anti-PD-1/PD-L1 lies in the different pharmacokinetic profiles and the spatial obstacles since PD-1/PD-L1 interaction occurs extracellularly and COX-2 locates intracellularly.Thus,the programmed release nanoparticles(termed as Cele-BMS-NPs)are rationally designed,which are composed of pH-sensitive human serum albumin derivative,BMS-202 compound as PD-1/PD-L1 inhibitor,glutathione(GSH)-activatable prodrug of celecoxib(COX-2 inhibitor).The in vitro experiments demonstrate that this smart Cele-BMS-NPs could extracellularly release BMS-202 under the acidic tumour microenvironment,and the intracellularly release of celecoxib in response to the elevated GSH concentration inside tumour cells.After systemic administration,the intratumoral infiltration of CD8+T cells is significantly enhanced and meanwhile immunosuppressive M2,Treg,and PGE2 are reduced,thereby eliciting the anti-tumour immune responses toward low immunogenic tumours and postsurgical tumour recurrences.
基金supported by the National Key R&D Program of China (2017YFE0196200)the National Natural Science Foundation of China (81761148028 and 21773026)+3 种基金the Science and Technology Commission of Shanghai Municipality (19XD1400100,205207130300,20DZ2254900 and 19410740200)support by FCT-Funda??o para a Ciência e a Tecnologia through the CQM Base Fund—UIDB/00674/2020Programmatic Fund—UIDP/00674/2020ARDITI-Agência Regional para o Desenvolvimento da Investiga??o Tecnologia e Inova??o,through the project M1420-01-0145-FEDER-000005—Centro de Química da Madeira—CQM+ (Madeira 14-20 Program)。
文摘Immune checkpoint blockade(ICB) has been regarded as one promising approach for tumor immunotherapy. Here, we report a functional nanoplatform based on generation 5(G5) poly(amidoamine)(PAMAM)dendrimer-entrapped gold nanoparticles(Au DENPs) as a nonviral vector to deliver programmed death-ligand 1(PDL1) small interfering RNA(siPD-L1) for subsequent PD-L1 gene silencing-mediated tumor immunotherapy. In this work,G5 dendrimers with amine termini were partially decorated with methoxy polyethylene glycol(m PEG) on their periphery,entrapped Au NPs within their interiors, and were eventually labeled with fluorescamine. The generated functional Au DENPs possess desired dispersibility in water and colloidal stability, satisfactory cytocompatibility after complexation with siPD-L1, and efficient gene delivery performance. Strikingly, the functional Au DENPs enabled the delivery of siPDL1 to cancer cells to efficiently knock down the PD-L1 protein expression, thus boosting the ICB-based immunotherapy of a xenografted melanoma mouse tumor model with a tumor inhibition efficiency much higher than the PD-L1 antibody.The immune responses were also well demonstrated by downregulation of PD-L1 protein on the tumor cell surface and abundant distribution of CD8+and CD4+T cells in the infiltrating tumor tissue and spleen organ. The developed functional dendrimer-based nanoplatform may be promising to boost ICB-based immunotherapy of other tumor types.
基金Guangdong Basic and Applied Basic Research Foundation,No.2019A1515110654the National Natural Science Foundation of China,No.82103448China Organ Transplantation Development Foundation,No.YZLC-2021-003.
文摘The disease burden related to hepatocellular carcinoma(HCC) is increasing. Most HCC patients are diagnosed at the advanced stage and multikinase inhibitors have been the only treatment choice for them. Recently, the approval of immune checkpoint inhibitors(ICIs) has provided a new therapeutic strategy for HCC. It is noteworthy that the positive outcomes of the phase Ⅲ clinical trial IMBrave150 [atezolizumab(anti-programmed cell death ligand 1 antibody) combined with bevacizumab(anti-vascular endothelial growth factor monoclonal antibody)],showed that overall survival and progression-free survival were significantly better with sorafenib. This combination therapy has become the new standard therapy for advanced HCC and has also attracted more attention in the treatment of HCC with anti-angiogenesis-immune combination therapy. Currently, the synergistic antitumor efficacy of this combination has been shown in many preclinical and clinical studies. In this review, we discuss the mechanism and clinical application of anti-angiogenics and immunotherapy in HCC, outline the relevant mechanism and rationality of the combined application of antiangiogenics and ICIs, and point out the existing challenges of the combination therapy.
基金This work is supported by the National Natural Science Foundation of China(No.81602492)the National Key Research and Development Program of China(No.2016YFA0201402).
文摘Early studies shed light on the immune suppression of immune checkpoint molecules in the cancer microenvironment,with later studies applying immune checkpoint blockade(ICB)in treatment of various malignancies.Despite the encouraging efficacy of ICBs in a substantial subset of cancer patients,the treatment response varies.Gene mutations of both tumor cells and immune cells in the tumor microenvironment have recently been identified as potential predictors of the ICB response.Recent developments in gene expression profiling of tumors have allowed identification of a panel of mutated genes that may affect tumor cell response to ICB treatment.In this review,we discuss the association of the ICB response with gene expression and mutation profiles in tumor cells,which it is hoped will help to optimize the clinical application of ICBs in cancer patients.
基金This work was partially funded by the Key R&D Programs of Shandong Province,China(Grant Nos.2018CXGC1411 and 2021CXGC010514).
文摘Cuproptosis shows enormous application prospects in lung metastasis treatment.However,the glycolysis,Cu^(+)efflux mechanisms,and insufficient lung drug accumulation severely restrict cuproptosis efficacy.Herein,an inhalable poly(2-(N-oxide-N,N-diethylamino)ethyl methacrylate)(OPDEA)-coated copper-based metal–organic framework encapsulating pyruvate dehydrogenase kinase 1 siRNA(siPDK)is constructed for mediating cuproptosis and subsequently promoting lung metastasis immunotherapy,namely OMP.After inhalation,OMP shows highly efficient lung accumulation and long-term retention,ascribing to the OPDEA-mediated pulmonary mucosa penetration.Within tumor cells,OMP is degraded to release Cu2+under acidic condition,which will be reduced to toxic Cu^(+)to induce cuproptosis under glutathione(GSH)regulation.Meanwhile,siPDK released from OMP inhibits intracellular glycolysis and adenosine-5ʹ-triphosphate(ATP)production,then blocking the Cu^(+)efflux protein ATP7B,thereby rendering tumor cells more sensitive to OMP-mediated cuproptosis.Moreover,OMP-mediated cuproptosis triggers immunogenic cell death(ICD)to promote dendritic cells(DCs)maturation and CD8^(+)T cells infiltration.Notably,OMP-induced cuproptosis up-regulates membrane-associated programmed cell death-ligand 1(PD-L1)expression and induces soluble PD-L1 secretion,and thus synergizes with anti-PD-L1 antibodies(aPD-L1)to reprogram immunosuppressive tumor microenvironment,finally yielding improved immunotherapy efficacy.Overall,OMP may serve as an efficient inhalable nanoplatform and afford preferable efficacy against lung metastasis through inducing cuproptosis and combining with aPD-L1.
基金supported by grants from the National Research Foundation(NRF)of Korea,funded by the Ministry of Science(NRF-2022M3H4A1A03067401 and NRF-2021R1C1C2005460,Republic of Korea)the Intramural Research Program of KIST。
文摘Immune checkpoint blockade(ICB)therapy targeting PD-L1 via monoclonal antibody(m Ab)has shown extensive clinical benefits in the diverse types of advanced malignancies.However,most patients are completely refractory to ICB therapy owing to the PD-L1 recycling mechanism.Herein,we propose photo-induced crosslinked and anti-PD-L1 peptide incorporated liposomes(immune checkpoint blockade liposomes;ICB-LPs)to promote PD-L1 multivalent binding for inducing lysosomal degradation of PD-L1 in tumor cells.The ICB-LPs are prepared by formulation of DC_(8,9)PC with photo-polymerized diacetylenic moiety,1,2-dipalmitoylphosphatidylcholine(DPPC)and anti-PD-L1peptide(D-form NYSKPTDRQYHF)-conjugated DSPE-PEG_(2k)(anti-PD-L1-DSPE-PEG_(2k))in a molar ratio of 45:45:10,followed by cross-linking of liposomal bilayer upon UV irradiation.The 10 mol% antiPD-L1-DSPE-PEG_(2k)incorporated ICB-LPs have a nano-sized lipid bilayer structure with an average diameter of 137.7±1.04 nm,showing a high stability in serum condition.Importantly,the ICB-LPs efficiently promote the multivalent binding with PD-L1 on the tumor cell membrane,which are endocytosed with aim to deliver PD-L1 to the lysosomes,wherein the durable PD-L1 degradation is observed for72 h,in contrast to anti PD-L1 m Abs showing the rapid PD-L1 recycling within 9 h.The in vitro coculture experiments with CD8^(+)T cells show that ICB-LPs effectively enhance the T cell-mediated antitumor immune responses against tumor cells by blocking the PD-L1/PD-1 axis.When ICB-LPs are intravenously injected into colon tumor-bearing mice,they efficiently accumulate within the targeted tumor tissues via both passive and active tumor targeting,inducing a potent T cell-mediated antitumor immune response by effective and durable PD-L1 degradation.Collectively,this study demonstrates the superior antitumor efficacy of crosslinked and anti-PD-L1 peptide incorporated liposome formulation that promotes PD-L1 multivalent binding for trafficking of PD-L1 toward the lysosomes instead of the recycling endosomes.
基金supported by the National Natural Science Foundation of China (Grant Nos. U22A20156, 52173121)the Open Project of Guangdong Province Key Laboratory of Biomedical Engineering (Grant No. GDKLBEM202203)。
文摘Cancer immunotherapies, which train the natural immune system to specifically kill tumor cells while sparing the healthy cells,have helped revolutionize cancer treatments and demonstrated promising clinical therapeutic benefits for decades. However, the therapeutic outcome of immunotherapies, even for the most successful immune checkpoint blockade(ICB) therapy, remains unsatisfactory in the clinical practice, mainly due to the low immunogenicity of solid tumors and its immunosuppressive tumor microenvironment(TME). Notably, several cancer treatment modalities, including chemotherapy, radiotherapy, and phototherapy, have been revealed to evoke tumor immunogenicity and reverse immunosuppressive TME via inducing immunogenic cell death(ICD) of tumor cells, which synergistically sensitized tumors to ICB therapy. Nanomedicines have been extensively applied to augment ICD-inducing treatment modalities and potentiate ICB therapeutic efficacy therapy due to the opportune convergence of immunotherapy and nanotechnology. Here, we discuss the recent advances in nanomedicine-mediated ICD and its combination with ICB therapy.
基金the National Natural Science Foundation of China(Nos.31971304,32271420,and 21977024)the Beijing-Tianjin-Hebei Basic Research Cooperation Project(No.19JCZDJC64100)+3 种基金Cross-disciplinary Project of Hebei University(No.DXK201916)One Hundred Talent Project of Hebei Province(No.E2018100002)Science Fund for Creative Research Groups of Nature Science Foundation of Hebei Province(No.B2021201038)Guangdong Basic and Applied Basic Research Foundation(No.2021B1515120065).
文摘The blocking of the immune checkpoint pathway with antibodies,especially targeting to programmed death-1/programmed death ligand-1(PD-1/PD-L1)pathway,was currently a widely used treatment strategy in clinical practice.However,the shortcomings of PD-L1 antibodies were constantly exposed with the deepening of its research and their therapeutic effect was limited by the translocation and redistribution of intracellular PD-L1.Herein,we proposed to improve immune checkpoint blockade therapy by using liposomes-coated CaO_(2)(CaO_(2)@Lipo)nanoparticles to inhibit the de novo biosynthesis of PD-L1.CaO_(2)@Lipo would produce oxygen and reduce hypoxia-inducible factor-1α(HIF-1α)level,which then downregulated the expression of PD-L1.Our in vitro and in vivo results have confirmed CaO_(2)@Lipo promoted the degradation of HIF-1αand then downregulated the expression of PD-L1 in cancer cells for avoiding immune escape.Furthermore,to mimicking the clinical protocol of anti-PD-L1 antibodies+chemo-drugs,CaO_(2)@Lipo was combined with doxorubicin(DOX)to investigate the tumor inhibition efficiency.We found CaO_(2)@Lipo enhanced DOX-induced immunogenic cell death(ICD)effect,which then promoted the infiltration of T cells,strengthened the blocking effect,thus provided an effective means to overcome the traditional immune checkpoint blockade treatment.
基金supported by grants from the Ministry of Science and Technology,RPC(No.2023YFC3503302)the Shanghai Municipal Commission of Science and Technology(No.22Y31920400)the National Natural Science Foundation of China(No.82474484).
文摘Primary and secondary resistance to immune checkpoint blockade(ICB)reduces its efficacy.The mechanisms underlying immunotherapy resistance are highly complex.In non-small cell lung cancer(NSCLC),these mechanisms are primarily associated with the loss of programmed cell death-ligand 1(PD-L1)expression,genetic mutations,circular RNA axis and transcription factor regulation,antigen presentation disorders,and dysregulation of signaling pathways.Additionally,alterations in the tumor microenvironment(TME)play a pivotal role in driving immunotherapy resistance.Primary resistance is mainly attributed to TME alterations,including mutations and comutations,modulation of T cell infiltration,enrichment of M2 tumor-associated macrophages(M2-TAMs)and mucosal-associated invariant T(MAIT)cells,vascular endothelial growth factor(VEGF),and pulmonary fibrosis.Acquired resistance mainly stems from changes in cellular infiltration patterns leading to“cold”or“hot”tumors,altered interferon(IFN)signaling pathway expression,involvement of extracellular vesicles(EVs),and oxidative stress responses,as well as post-treatment gene mutations and circadian rhythm disruption(CRD).This review presents an overview of various mechanisms underlying resistance to ICB,elucidates the alterations in the TME during primary,adaptive,and acquired resistance,and discusses existing strategies for overcoming ICB resistance.
基金This work was partly supported by the Research Council of Norway through its Centres of Excellence funding scheme,project number 223250(CCBIO affiliates)Lorens JB was supported by grants from the Norwegian Research Council(grant number 240130)+2 种基金Norwegian Cancer Society(grant number 190330)Engelsen AST was supported by the FRIPRO Mobility Grant Fellowship from the Research Council of Norway co-funded by the EU’s 7th Framework Programme’s Marie Skłodowska Curie Actions(MSCA COFUND,grant agreement number 608695)Support from Legat for Forskning av Kreftsykdommer fund at UIB and the Familien Blix fund to ASTE for this project is greatly appreciated.
文摘Epithelial-mesenchymal plasticity(EMP)of cancer cells contributes to cancer cell heterogeneity,and it is well established that EMP is a critical determinant of acquired resistance to cancer treatment modalities including radiation therapy,chemotherapy,and targeted therapies.Here,we aimed to explore how EMP contributes to cancer cell camouflage,allowing an ever-changing population of cancer cells to pass under the radar of our immune system and consequently compromise the effect of immune checkpoint blockade therapies.The ultimate clinical benefit of any combination regimen is evidenced by the sum of the drug-induced alterations observed in the variety of cellular populations composing the tumor immune microenvironment.The finely-tuned molecular crosstalk between cancer and immune cells remains to be fully elucidated,particularly for the spectrum of malignant cells along the epithelial to mesenchymal axis.High-dimensional single cell analyses of specimens collected in ongoing clinical studies is becoming a key contributor to our understanding of these interactions.This review will explore to what extent targeting EMP in combination with immune checkpoint inhibition represents a promising therapeutic avenue within the overarching strategy to reactivate a halting cancer-immunity cycle and establish a robust host immune response against cancer cells.Therapeutic strategies currently in clinical development will be discussed.
文摘Esophageal squamous cell carcinoma(ESCC)remains a daunting global health concern.It is marked by aggressive progression and poor survival.While immunotherapy has emerged as a promising treatment modality,both primary and acquired resistance continue to limit its clinical impact,leaving many patients without durable benefits(e.g.,CheckMate-648,ESCORT-1st).This review explains resistance mechanisms and suggests new strategies to improve outcomes.These mechanisms include immunosuppressive cells(Treg cells,myeloid-derived suppressor cells),inhibitory cytokines,molecular alterations involving programmed death 1/programmed death-ligand 1 signaling,and impaired antigen presentation.We also highlight key clinical trials—for example,CheckMate-648 and ESCORT-1st—that reveal both the potential and pitfalls of current immune checkpoint blockade strategies,underscoring the need for robust predictive biomarkers.Moreover,we examine cutting-edge tactics to overcome resistance,including combination regimens,tumor microenvironment remodeling,and tailored treatment approaches rooted in the patient’s unique genomic and immunologic landscape.
文摘Dear Editor,Lymphocyte activation gene 3(LAG3),the third established target for immune checkpoint blockade therapy,suppresses T cell function by binding to major histocompatibility complex classⅡ(MHCⅡ).Despite its significant therapeutic potential in cancer immunotherapy and the substantial attention it has received from academia and industry,the molecular mechanisms of LAG3-mediated immunosuppression remain poorly understood,primarily because of its unique ligand-binding characteristics and intracellular domains[1].
