Immunosuppressive tumor microenvironment in gastric signet-ring cell carcinoma

Gastric signet-ring cell carcinoma(GSRCC)is a subtype of gastric cancer with distinct phenotype and high risk of peritoneal metastasis.Studies have shown that early GSRCC has a good prognosis,while advanced GSRCC is insensitive to radiotherapy,chemotherapy or immune checkpoint blockade therapy.With technological advancement of single-cell RNA sequencing analysis and cytometry by time of flight mass cytometry,more detailed atlas of tumor microenvironment(TME)in GSRCC and its association with prognosis could be investigated extensively.Recently,two single-cell RNA sequencing studies revealed that GSRCC harbored a unique TME,manifested as highly immunosuppressive,leading to high immune escape.The TME of advanced GSRCC was enriched for immunosuppressive factors,including the loss of CXCL13+-cluster of differentiation 8+-Tex cells and declined clonal crosstalk among populations of T and B cells.In addition,GSRCC was mainly infiltrated by follicular B cells.The increased proportion of SRCC was accompanied by a decrease in mucosaassociated lymphoid tissue-derived B cells and a significant increase in follicular B cells,which may be one of the reasons for the poor prognosis of GSRCC.By understanding the relationship between immunosuppressive TME and poor prognosis in GSRCC and the underlying mechanism,more effective immunotherapy strategies and improved treatment outcomes of GSRCC can be anticipated.

Wrecking neutrophil extracellular traps and antagonizing cancer-associated neurotransmitters by interpenetrating network hydrogels prevent postsurgical cancer relapse and metastases

Tumor-promoting niche after incomplete surgery resection(SR)can lead to more aggressive local progression and distant metastasis with augmented angiogenesis-immunosuppressive tumor microenvironment(TME).Herein,elevated neutrophil extracellular traps(NETs)and cancer-associated neurotransmitters(CANTs,e.g.,catecholamines)are firstly identified as two of the dominant inducements.Further,an injectable fibrin-alginate hydrogel with high tissue adhesion has been constructed to specifically co-deliver NETs inhibitor(DNase I)-encapsulated PLGA nanoparticles and an unselectiveβ-adrenergic receptor blocker(propranolol).The two components(i.e.,fibrin and alginate)can respond to two triggers(thrombin and Ca2+,respectively)in postoperative bleeding to gelate,shaping into an interpenetrating network(IPN)featuring high strength.The continuous release of DNase I and PR can wreck NETs and antagonize catecholamines to decrease microvessel density,blockade myeloid-derived suppressor cells,secrete various proinflammatory cytokines,potentiate natural killer cell function and hamper cytotoxic T cell exhaustion.The reprogrammed TME significantly suppress locally residual and distant tumors,induce strong immune memory effects and thus inhibit lung metastasis.Thus,targetedly degrading NETs and blocking CANTs enabled by this in-situ IPN-based hydrogel drug depot provides a simple and efficient approach against SR-induced cancer recurrence and metastasis.

BRAF_(V600E)mutant colorectal cancer cells mediate local immunosuppressive microenvironment through exosomal long noncoding RNAs

BACKGROUND BRAF^(V600E) mutated colorectal cancer(CRC)is prone to peritoneal and distant lymph node metastasis and this correlates with a poor prognosis.The BRAF^(V600E) mutation is closely related to the formation of an immunosuppressive microenvironment.However,the correlation between BRAF^(V600E) mutation and changes in local immune microenvironment of CRC is not clear.AIM To explore the effect and mechanism of BRAF^(V600E) mutant on the immune microenvironment of CRC.METHODS Thirty patients with CRC were included in this study:20 in a control group and 10 in a treatment group.The density of microvessels and microlymphatic vessels,and M2 subtype macrophages in tumor tissues were detected by immunohistochemistry.Screening and functional analysis of exosomal long noncoding RNAs(lncRNAs)were performed by transcriptomics.The proliferation and migration of human umbilical vein endothelial cells(HUVECs)and human lymphatic endothelial cells(HLECs)were detected by CCK-8 assay and scratch test,respectively.The tube-forming ability of endothelial cells was detected by tube formation assay.The macrophage subtypes were obtained by flow cytometry.The expression of vascular endothelial growth factor(VEGF)-A,basic fibroblast growth factor(bFGF),transforming growth factor(TGF)-β1,VEGF-C,claudin-5,occludin,zonula occludens(ZO)-1,fibroblast activation protein,andα-smooth muscle actin was assessed by western blot analysis.The levels of cytokines interleukin(IL)-6,TGF-β1,and VEGF were assessed by enzyme-linked immunosorbent assay.RESULTS BRAF^(V600E) mutation was positively correlated with the increase of preoperative serum carbohydrate antigen 19-9(P<0.05),and with poor tumor tissue differentiation in CRC(P<0.01).Microvascular density and microlymphatic vessel density in BRAF^(V600E) mutant CRC tissues were higher than those in BRAF wildtype CRC(P<0.05).The number of CD163+M2 macrophages in BRAF^(V600E) mutant CRC tumor tissue was markedly increased(P<0.05).Compared with exosomes from CRC cells with BRAF gene silencing,the expression of 13 lncRNAs and 192 mRNAs in the exosomes from BRAF^(V600E) mutant CRC cells was upregulated,and the expression of 22 lncRNAs and 236 mRNAs was downregulated(P<0.05).The biological functions and signaling pathways predicted by differential lncRNA target genes and differential mRNAs were closely related to angiogenesis,tumor cell proliferation,differentiation,metabolism,and changes in the microenvironment.The proliferation,migration,and tube formation ability of HUVECs and HLECs induced by exosomes in the 1627 cell group(HT29 cells with BRAF gene silencing)was greatly reduced compared with the HT29 cell group(P<0.05).Compared with the HT29 cell group,the expression levels of VEGF-A,bFGF,TGF-β1,and VEGF-C in the exosomes derived from 1627 cells were reduced.The expression of ZO-1 in HUVECs,and claudin-5,occludin,and ZO-1 in HLECs of the 1627 cell group was higher.Compared with the 1627 cell group,the exosomes of the HT29 cell group promoted the expression of CD163 in macrophages(P<0.05).IL-6 secretion by macrophages in the HT29 cell group was markedly elevated(P<0.05),whereas TGF-β1 was decreased(P<0.05).The levels of IL-6,TGF-β1,and VEGF secreted by fibroblasts in the 1627 cell group decreased,compared with the HT29 cell group(P<0.05).CONCLUSION BRAF^(V600E) mutant CRC cells can reach the tumor microenvironment by releasing exosomal lncRNAs,and induce the formation of an immunosuppressive microenvironment.

Smart drug delivery systems to overcome drug resistance in cancer immunotherapy

Cancer immunotherapy,a therapeutic approach that inhibits tumors by activating or strengthening anti-tumor immunity,is currently an important clinical strategy for cancer treatment;however,tumors can develop drug resistance to immune surveillance,resulting in poor response rates and low therapeutic efficacy.In addition,changes in genes and signaling pathways in tumor cells prevent susceptibility to immunotherapeutic agents.Furthermore,tumors create an immunosuppressive microenvironment via immunosuppressive cells and secrete molecules that hinder immune cell and immune modulator infiltration or induce immune cell malfunction.To address these challenges,smart drug delivery systems(SDDSs)have been developed to overcome tumor cell resistance to immunomodulators,restore or boost immune cell activity,and magnify immune responses.To combat resistance to small molecules and monoclonal antibodies,SDDSs are used to co-deliver numerous therapeutic agents to tumor cells or immunosuppressive cells,thus increasing the drug concentration at the target site and improving efficacy.Herein,we discuss how SDDSs overcome drug resistance during cancer immunotherapy,with a focus on recent SDDS advances in thwarting drug resistance in immunotherapy by combining immunogenic cell death with immunotherapy and reversing the tumor immunosuppressive microenvironment.SDDSs that modulate the interferon signaling pathway and improve the efficacy of cell therapies are also presented.Finally,we discuss potential future SDDS perspectives in overcoming drug resistance in cancer immunotherapy.We believe that this review will contribute to the rational design of SDDSs and development of novel techniques to overcome immunotherapy resistance.

Enhancing cancer immunotherapy:Nanotechnology-mediated immunotherapy overcoming immunosuppression

Immunotherapy is an important cancer treatment method that offers hope for curing cancer patients.While immunotherapy has achieved initial success,a major obstacle to its widespread adoption is the inability to benefit the majority of patients.The success or failure of immunotherapy is closely linked to the tumor’s immune microenvironment.Recently,there has been significant attention on strategies to regulate the tumor immune microenvironment in order to stimulate anti-tumor immune responses in cancer immunotherapy.The distinctive physical properties and design flexibility of nanomedicines have been extensively utilized to target immune cells(including tumor-associated macrophages(TAMs),T cells,myeloid-derived suppressor cells(MDSCs),and tumor-associated fibroblasts(TAFs)),offering promising advancements in cancer immunotherapy.In this article,we have reviewed treatment strategies aimed at targeting various immune cells to regulate the tumor immune microenvironment.The focus is on cancer immunotherapy models that are based on nanomedicines,with the goal of inducing or enhancing anti-tumor immune responses to improve immunotherapy.It is worth noting that combining cancer immunotherapy with other treatments,such as chemotherapy,radiotherapy,and photodynamic therapy,can maximize the therapeutic effects.Finally,we have identified the challenges that nanotechnology-mediated immunotherapy needs to overcome in order to design more effective nanosystems.

Cellular senescence and metabolic reprogramming:Unraveling the intricate crosstalk in the immunosuppressive tumor microenvironment

The intrinsic oncogenic mechanisms and properties of the tumor microenvironment(TME)have been extensively investigated.Primary features of the TME include metabolic reprogramming,hypoxia,chronic inflammation,and tumor immunosuppression.Previous studies suggest that senescence-associated secretory phenotypes that mediate intercellular information exchange play a role in the dynamic evolution of the TME.Specifically,hypoxic adaptation,metabolic dysregulation,and phenotypic shifts in immune cells regulated by cellular senescence synergistically contribute to the development of an immunosuppressive microenvironment and chronic inflammation,thereby promoting the progression of tumor events.This review provides a comprehensive summary of the processes by which cellular senescence regulates the dynamic evolution of the tumor-adapted TME,with focus on the complex mechanisms underlying the relationship between senescence and changes in the biological functions of tumor cells.The available findings suggest that components of the TME collectively contribute to the progression of tumor events.The potential applications and challenges of targeted cellular senescence-based and combination therapies in clinical settings are further discussed within the context of advancing cellular senescence-related research.

CaCO3-Assisted Preparation of pH-Responsive Immune-Modulating Nanoparticles for Augmented Chemo-Immunotherapy

Due to the negative roles of tumor microenvironment(TME)in compromising therapeutic responses of various cancer therapies,it is expected that modulation of TME may be able to enhance the therapeutic responses during cancer treatment.Herein,we develop a concise strategy to prepare pH-responsive nanoparticles via the CaCO3-assisted double emulsion method,thereby enabling effective co-encapsulation of both doxorubicin(DOX),an immunogenic cell death(ICD)inducer,and alkylated NLG919(aNLG919),an inhibitor of indoleamine 2,3-dioxygenase 1(IDO1).The obtained DOX/aNLG919-loaded CaCO3 nanoparticles(DNCaNPs)are able to cause effective ICD of cancer cells and at the same time restrict the production of immunosuppressive kynurenine by inhibiting IDO1.Upon intravenous injection,such DNCaNPs show efficient tumor accumulation,improved tumor penetration of therapeutics and neutralization of acidic TME.As a result,those DNCaNPs can elicit effective anti-tumor immune responses featured in increased density of tumor-infiltrating CD8+cytotoxic T cells as well as depletion of immunosuppressive regulatory T cells(Tregs),thus effectively suppressing the growth of subcutaneous CT26 and orthotopic 4T1 tumors on the Balb/c mice through combined chemotherapy&immunotherapy.This study presents a compendious strategy for construction of pH-responsive nanoparticles,endowing significantly enhanced chemo-immunotherapy of cancer by overcoming the immunosuppressive TME.

Sequential delivery of PD-1/PD-L1 blockade peptide and IDO inhibitor for immunosuppressive microenvironment remodeling via an MMP-2 responsive dual-targeting liposome

Intelligent responsive drug delivery system opens up new avenues for realizing safer and more effective combination immunotherapy.Herein,a kind of tumor cascade-targeted responsive liposome(NLG919@Lip-pep1)is developed by conjugating polypeptide inhibitor of PD-1 signal pathway(AUNP-12),which is also a targeted peptide that conjugated with liposome carrier through matrix metalloproteinase-2(MMP-2)cleavable peptide(GPLGVRGD).This targeted liposome is prepared through a mature preparation process,and indoleamine-2,3-dioxygenase(IDO)inhibitor NLG919 was encapsulated into it.Moreover,mediated by the enhanced permeability and retention effect(EPR effect)and AUNP-12,NLG919@Lip-pep1 first targets the cells that highly express PD-L1 in tumor tissues.At the same time,the over-expressed MMP-2 in the tumor site triggers the dissociation of AUNP-12,thus realizing the precise block of PD-1 signal pathway,and restoring the activity of T cells.The exposure of secondary targeting moduleⅡVRGDC-NLG919@Lip mediated tumor cells targeting,and further relieved the immunosuppressive microenvironment.Overall,this study offers a potentially appealing paradigm of a high efficiency,low toxicity,and simple intelligent responsive drug delivery system for targeted drug delivery in breast cancer,which can effectively rescue and activate the body's anti-tumor immune response and furthermore achieve effective treatment of metastatic breast cancer.

Dual-responsive supramolecular photodynamic nanomedicine with activatable immunomodulation for enhanced antitumor therapy

A major challenge facing photodynamic therapy(PDT) is that the activity of the immuneinduced infiltrating CD8^(+)T cells is subject to the regulatory T lymphocytes(Tregs), leaving the tumor at risk of recurrence and metastasis after the initial ablation. To augment the antitumor response and reprogram the immunosuppressive tumor microenvironment(TME), a supramolecular photodynamic nanoparticle(DACss) is constructed by the host-guest interaction between demethylcantharidin-conjugated β-cyclodextrin(DMC-CD) and amantadine-terminated disulfide-conjugated FFVLGGGC peptide with chlorin e6 decoration(Ad-ss-pep-Ce6) to achieve intelligent delivery of photosensitizer and immunomodulator for breast cancer treatment. The acid-labile β-carboxamide bond of DMC-CD is hydrolyzed in response to the acidic TME, resulting in the localized release of DMC and subsequent inhibition of Tregs.The guest molecule Ad-ss-pep-Ce6 can be cleaved by a high level of intracellular GSH, reducing photosensitizer toxicity and increasing photosensitizer retention in the tumor. With a significant increase in the CTL/Treg ratio, the combination of Ce6-based PDT and DMC-mediated immunomodulation adequately achieved spatiotemporal regulation and remodeling of the TME, as well as improved primary tumor and in situ lung metastasis suppression with the aid of PD-1 antibody.

SOX17-mediated immune evasion in early colorectal cancer:From pre-malignant adaptation to tumor progression

One of the hallmarks of cancer is its inherently immunosuppressive microenvironment,which strategically manipulates surrounding immune cells,signaling molecules,and structural components to shield cancer cells from immune attacks and foster tumor progression1.Such tumor microenvironment is characterized by the presence of immunosuppressive entities such as tumor-associated macrophages,T cells,tumor-associated neutrophils,and myeloid-derived suppressor cells(MDSCs),as well as metabolic alterations like hypoxia2 and elevated lactate levels3.

Biomimetic“Gemini nanoimmunoregulators”orchestrated for boosted photoimmunotherapy by spatiotemporally modulating PD-L1 and tumor-associated macrophages

A novel strategy of not only stimulating the immune cycle but also modulating the immunosuppressive tumor microenvironment is of vital importance to efficient cancer immunotherapy.Here,a new type of spatiotemporal biomimetic“Gemini nanoimmunoregulators”was engineered to activate robust systemic photoimmunotherapy by integrating the triple-punch of amplified immunogenic cell death(ICD),tumor-associated macrophages(TAMs)phenotype reprogramming and programmed cell death ligand 1(PD-L1)degradation.The“Gemini nanoimmunoregulators”PM@RM-T7 and PR@RM-M2 were constructed by taking the biocompatible mesoporous polydopamine(mPDA)as nanovectors to deliver metformin(Met)and toll-like receptor 7/8 agonist resiquimod(R848)to cancer cells and TAMs by specific biorecognition via wrapping of red blood cell membrane(RM)inlaid with T7or M2 peptides.mPDA/Met@RM-T7(abbreviated as PM@RM-T7)was constructed to elicit an amplified in situ ICD effect through the targeted PTT and effectively stimulated the anticancer immunity.Meanwhile,PD-L1 on the remaining cancer cells was degraded by the burst metformin to prevent immune evasion.Subsequently,mPDA/R848@RM-M2(abbreviated as PR@RM-M2)specifically recognized TAMs and reset the phenotype from M2 to M1 state,thus disrupting the immunosuppressive microenvironment and further boosting the function of cytotoxic T lymphocytes.This pair of sister nanoimmunoregulators cooperatively orchestrated the comprehensive anticancer activity,which remarkably inhibited the growth of primary and distant 4T1 tumors and prevented malignant metastasis.This study highlights the spatiotemporal cooperative modalities using multiple nanomedicines and provides a new paradigm for efficient cancer immunotherapy against metastatic-prone tumors.

Targeted nanomedicines remodeling immunosuppressive tumor microenvironment for enhanced cancer immunotherapy

Cancer immunotherapy has significantly flourished and revolutionized the limited conventional tumor therapies,on account of its good safety and long-term memory ability.Discouragingly,low patient response rates and potential immune-related side effects make it rather challenging to literally bring immunotherapy from bench to bedside.However,it has become evident that,although the immunosuppressive tumor microenvironment(TME)plays a pivotal role in facilitating tumor progression and metastasis,it also provides various potential targets for remodeling the immunosuppressive TME,which can consequently bolster the effectiveness of antitumor response and tumor suppression.Additionally,the particular characteristics of TME,in turn,can be exploited as avenues for designing diverse precise targeting nanomedicines.In general,it is of urgent necessity to deliver nanomedicines for remodeling the immunosuppressive TME,thus improving the therapeutic outcomes and clinical translation prospects of immunotherapy.Herein,we will illustrate several formation mechanisms of immunosuppressive TME.More importantly,a variety of strategies concerning remodeling immunosuppressive TME and strengthening patients'immune systems,will be reviewed.Ultimately,we will discuss the existing obstacles and future perspectives in the development of antitumor immunotherapy.Hopefully,the thriving bloom of immunotherapy will bring vibrancy to further exploration of comprehensive cancer treatment.

Reverse immune suppressive microenvironment in tumor draining lymph nodes to enhance anti-PD1 immunotherapy via nanovaccine complexed microneedle

The maturation of dendritic cells(DCs)and infiltration effector T cells in tumor-draining lymph node(tdLN)and tumor tissue are crucial for immunotherapy.Despite constructive progresses have been made with anti-programmed death-1(anti-PD1)checkpoint blockade for immunotherapy,the efficacy of PD1/PD-L1 therapy deserves to be improved.Here,we constructed a novel transfersomes based nanovaccine complexed microneedles to enhance anti-PD1 immunotherapy via transdermal immunization for skin tumor therapy.Transfersomes were functionalized with DCs targeting moietyαCD40,co-encapsulated with antigens and adjuvant poly I:C.Moreover,transdermal administration promoted accumulation in tumor-draining lymph nodes(tdLN),which could facilitate cellular uptake,activate DCs maturation and enhance Th1 immune responses.Using a mouse melanoma model,combined therapy of such nanovaccine complexed microneedles with pembrolizumab(αPD1)was able to enhance cytotoxic T lymphocytes activation,promote infiltration and reduce regulatory T cells frequency in tdLN and tumor tissues,which achieved reversion of the immunosuppressive microenvironment into immune activation.This study highlighted the potential of transfersomes based nanovaccines complexed microneedles as an attractive platform for tumor immunotherapy.

Fucoidan-functionalized activated platelet-hitchhiking micelles simultaneously track tumor cells and remodel the immunosuppressive microenvironment for efficient metastatic cancer treatment

Tumor metastasis is responsible for most mortality in cancer patients, and remains a challenge in clinical cancer treatment. Platelets can be recruited and activated by tumor cells, then adhere to circulating tumor cells(CTCs) and assist tumor cells extravasate in distant organs. Therefore, nanoparticles specially hitchhiking on activated platelets are considered to have excellent targeting ability for primary tumor, CTCs and metastasis in distant organs. However, the activated tumor-homing platelets will release transforming growth factor-β(TGF-β), which promotes tumor metastasis and forms immunosuppressive microenvironment. Therefore, a multitalent strategy is needed to balance the accurate tumor tracking and alleviate the immunosuppressive signals. In this study, a fucoidan-functionalized micelle(FD/DOX) was constructed, which could efficiently adhere to activated platelets through P-selectin.Compared with the micelle without P-selectin targeting effect, FD/DOX had increased distribution in both tumor tissue and metastasis niche, and exhibited excellent anti-tumor and anti-metastasis efficacy on 4 T1 spontaneous metastasis model. In addition, due to the contribution of fucoidan, FD/DOXtreatment was confirmed to inhibit the expression of TGF-β, thereby stimulating anti-tumor immune response and reversing the immunosuppressive microenvironment. The fucoidan-functionalized activated platelets-hitchhiking micelle was promising for the metastatic cancer treatment.

Anti-PD-L1 antibody enhances curative effect of cryoablation via antibody-dependent cell-mediated cytotoxicity mediating PD-L1^(high)CD11b^(+)cells elimination in hepatocellular carcinoma

Cryoablation(CRA)and microwave ablation(MWA)are two main local treatments for hepatocellular carcinoma(HCC).However,which one is more curative and suitable for combining with immunotherapy is still controversial.Herein,CRA induced higher tumoral PD-L1 expression and more T cells infiltration,but less PD-L1^(high)CD11b^(+)myeloid cells infiltration than MWA in HCC.Furthermore,CRA had better curative effect than MWA for anti-PD-L1 combination therapy in mouse models.Mechanistically,anti-PD-L1 antibody facilitated infiltration of CD8^(+)T cells by enhancing the secretion of CXCL9 from cDC1 cells after CRA therapy.On the other hand,anti-PD-L1 antibody promoted the infiltration of NK cells to eliminate PD-L1^(high)CD11b^(+)myeloid cells by antibody-dependent cell-mediated cytotoxicity(ADCC)effect after CRA therapy.Both aspects relieved the immunosuppressive microenvironment after CRA therapy.Notably,the wild-type PD-L1 Avelumab(Bavencio),compared to the mutant PD-L1 atezolizumab(Tecentriq),was better at inducing the ADCC effect to target PD-L1^(high)CD11b^(+)myeloid cells.Collectively,our study uncovered the novel insights that CRA showed superior curative effect than MWA in combining with anti-PD-L1 antibody by strengthening CTL/NK cell immune responses,which provided a strong rationale for combining CRA and PD-L1 blockade in the clinical treatment for HCC.

Tumor-responsive dynamic nanoassemblies for boosted photoimmunotherapy

Photoimmunotherapy(PIT)is an emerging therapeutic approach that integrates phototherapy and immunotherapy to eliminate primary tumors under an appropriate dosage of local light irradiation,while simultaneously preventing tumor metastasis and recurrence by activating the host antitumor immune response.Tumor-responsive dynamic nanoassemblies(TDNs)have evolved from being a mere curiosity to a promising platform for high-performance PIT.However,the dynamic nano-bio interaction between TDNs and tumor microenvironment remains poorly understood,which shall be critical for precise control of TDNs assembling/disassembling behavior and superior PIT efficacy.To deepen the understanding of the structure–function relationship of TDNs,this review introduces the rational design,nano-bio interactions,and controllable functionalities of cutting-edge TDNs for enhanced PIT.Moreover,the synergetic mechanism between TDNs-based PIT and immunomodulatory agents-mediated immunomodulation is particularly emphasized.Finally,the challenges and future perspectives in this emerging field are assessed.

Emerging resistance vs. losing response to immune check point inhibitors in renal cell carcinoma: two differing phenomena

The introduction of immune checkpoint inhibitor (ICI) has revolutionized the treatment of metastatic renal cell carcinoma (mRCC) and has dramatically improved the outcomes of patients. The use of monotherapy or combinations of ICIs targeting PD-1/PD-L1 and CTLA-4, as well as the addition of ICIs with tyrosine kinase inhibitors, has significantly enhanced the overall survival of mRCC patients. Despite these promising results, there remains a subset of patients who either do not respond to treatment (primary resistance) or develop resistance to therapy over time (acquired resistance). Understanding the mechanisms underlying the development of resistance to ICI treatment is crucial in the management of mRCC, as they can be used to identify new targets for innovative therapeutic strategies. Currently, there is an unmet need to develop new predictive and prognostic biomarkers that can aid in the development of personalized treatment options for mRCC patients. In this review, we summarize several mechanisms of ICI resistance in RCC, including alterations in tumor microenvironment, upregulation of alternative immune checkpoint pathways, and genetic and epigenetic changes. Additionally, we highlight potential strategies that can be used to overcome resistance, such as combination therapy, targeted therapy, and immune modulation.

Emerging role of natural products in cancer immunotherapy

Cancer immunotherapy has become a new generation of anti-tumor treatment,but its indications still focus on several types of tumors that are sensitive to the immune system.Therefore,effective strategies that can expand its indications and enhance its efficiency become the key element for the further development of cancer immunotherapy.Natural products are reported to have this effect on cancer immunotherapy,including cancer vaccines,immune-check points inhibitors,and adoptive immune-cells therapy.And the mechanism of that is mainly attributed to the remodeling of the tumorimmunosuppressive microenvironment,which is the key factor that assists tumor to avoid the recognition and attack from immune system and cancer immunotherapy.Therefore,this review summarizes and concludes the natural products that reportedly improve cancer immunotherapy and investigates the mechanism.And we found that saponins,polysaccharides,and flavonoids are mainly three categories of natural products,which reflected significant effects combined with cancer immunotherapy through reversing the tumor-immunosuppressive microenvironment.Besides,this review also collected the studies about nano-technology used to improve the disadvantages of natural products.All of these studies showed the great potential of natural products in cancer immunotherapy.

Nanomedicines modulating tumor immunosuppressive cells to enhance cancer immunotherapy

Cancer immunotherapy has veered the paradigm of cancer treatment.Despite recent advances in immunotherapy for improved antitumor efficacy,the complicated tumor microenvironment(TME)is highly immunosuppressive,yielding both astounding and unsatisfactory clinical successes.In this regard,clinical outcomes of currently available immunotherapy are confined to the varied immune systems owing in large part to the lack of understanding of the complexity and diversity of the immune context of the TME.Various advanced designs of nanomedicines could still not fully surmount the delivery barriers of the TME.The immunosuppressive TME may even dampen the efficacy of antitumor immunity.Recently,some nanotechnology-related strategies have been inaugurated to modulate the immunosuppressive cells within the tumor immune microenvironment(TIME)for robust immunotherapeutic responses.In this review,we will highlight the current understanding of the immunosuppressive TIME and identify disparate subclasses of TIME that possess an impact on immunotherapy,especially those unique classes associated with the immunosuppressive effect.The immunoregulatory cell types inside the immunosuppressive TIME will be delineated along with the existing and potential approaches for immunosuppressive cell modulation.After introducing the various strategies,we will ultimately outline both the novel therapeutic targets and the potential issues that affect the efficacy of TIME-based nanomedicines.

Cancer stem cell-targeted chimeric antigen receptor(CAR)-T cell therapy: Challenges and prospects

Cancer stem cells(CSCs)with their self-renewal ability are accepted as cells which initiate tumors.CSCs are regarded as interesting targets for novel anticancer therapeutic agents because of their association with tumor recurrence and resistance to conventional therapies,including radiotherapy and chemotherapy.Chimeric antigen receptor(CAR)-T cells are engineered T cells which express an artificial receptor specific for tumor associated antigens(TAAs)by which they accurately target and kill cancer cells.In recent years,CAR-T cell therapy has shown more efficiency in cancer treatment,particularly regarding blood cancers.The expression of specific markers such as TAAs on CSCs in varied cancer types makes them as potent tools for CAR-T cell therapy.Here we review the CSC markers that have been previously targeted with CAR-T cells,as well as the CSC markers that may be used as possible targets for CAR-T cell therapy in the future.Furthermore,we will detail the most important obstacles against CART cell therapy and suggest solutions.