NF-κB in biology and targeted therapy:new insights and translational implications

NF-κB signaling has been discovered for nearly 40 years.Initially,NF-κB signaling was identified as a pivotal pathway in mediating inflammatory responses.However,with extensive and in-depth investigations,researchers have discovered that its role can be expanded to a variety of signaling mechanisms,biological processes,human diseases,and treatment options.In this review,we first scrutinize the research process of NF-κB signaling,and summarize the composition,activation,and regulatory mechanism of NF-κB signaling.We investigate the interaction of NF-κB signaling with other important pathways,including PI3K/AKT,MAPK,JAK-STAT,TGF-β,Wnt,Notch,Hedgehog,and TLR signaling.The physiological and pathological states of NF-κB signaling,as well as its intricate involvement in inflammation,immune regulation,and tumor microenvironment,are also explicated.Additionally,we illustrate how NF-κB signaling is involved in a variety of human diseases,including cancers,inflammatory and autoimmune diseases,cardiovascular diseases,metabolic diseases,neurological diseases,and covID-19.Further,we discuss the therapeutic approaches targeting NF-κB signaling,including IKK inhibitors,monoclonal antibodies,proteasome inhibitors,nuclear translocation inhibitors,DNA binding inhibitors,TKls,non-coding RNAs,immunotherapy,and CAR-T.Finally,we provide an outlook for research in the field of NF-κB signaling.We hope to present a stereoscopic,comprehensive NF-κB signaling that will inform future research and clinical practice.

Efficacy and safety of PD-1 blockade plus long-course chemoradiotherapy in locally advanced rectal cancer(NECTAR):a multi-center phase 2 study

Adding PD-1 blockade in the neoadjuvant regimens for locally advanced rectal cancer(LARC)patients with microsatellite stable(MsS)/mismatch repair-proficient(pMMR)tumors is an attractive,but debatable strategy.This phase 2,multicenter,prospective,single-arm study enrolled patients from 6 centers from June 2021 to November 2022.Locally advanced rectal cancer(LARC,cT_(3-4a)N_(0)M_(0) and cT_(1-4a)N_(1-2)M_(0))patients aged≥18 years with the distance from distal border of tumor to anal verge≤10 cm(identified by Magnetic Resonance Imaging)were qualifed for inclusion.The patients received long-course radiotherapy(50 Gy/25 fractions,2 Gy/fraction,5 days/week)and three 21-day cycles capecitabine(850-1000 mg/m2,bid,po,day1-14)and three 21-day cycles tislelizumab(200 mg,iv.gtt,day8)as neoadjuvant.Total mesorectal excision(TME)was 6-12 weeks after the end of radiotherapy to achieve radical resection.A total of 50 patients were enrolled in this study.The pathological complete response rate was 40.0%[20/50,95%confidence interval(CI):27.61-53.82%],while 15(30.0%,95%CI:19.1-43.75%),9(18.0%,95%CI:9.77-30.8%),2(4.0%,95%CI:1.10-13.46%)patients respectively achieved grade 1,2,and 3 tumor regression.Treatment-related adverse events(TRAEs)occurred in 28(56.0%)LARC patients,including 26(52.0%)with grade I-II and 2(4.0%)with grade II(1 with grade 3 immune-related colitis and 1 with grade 3 rash).PD-1 blockade plus long-course chemoradiotherapy(CRT)showed promising therapeutic effects according to pathological complete response rate and is well-tolerated in LARC patients.A larger randomized controlled study is desired to further validate the above findings.

Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases

The human gastrointestinal tract is populated with a diverse microbial community.The vast genetic and metabolic potential of the gut microbiome underpins its ubiquity in nearly every aspect of human biology,including health maintenance,development,aging,and disease.The advent of new sequencing technologies and culture-independent methods has allowed researchers to move beyond correlative studies toward mechanistic explorations to shed light on microbiome–host interactions.Evidence has unveiled the bidirectional communication between the gut microbiome and the central nervous system,referred to as the“microbiota–gut–brain axis”.The microbiota–gut–brain axis represents an important regulator of glial functions,making it an actionable target to ameliorate the development and progression of neurodegenerative diseases.In this review,we discuss the mechanisms of the microbiota–gut–brain axis in neurodegenerative diseases.As the gut microbiome provides essential cues to microglia,astrocytes,and oligodendrocytes,we examine the communications between gut microbiota and these glial cells during healthy states and neurodegenerative diseases.Subsequently,we discuss the mechanisms of the microbiota–gut–brain axis in neurodegenerative diseases using a metabolite-centric approach,while also examining the role of gut microbiota-related neurotransmitters and gut hormones.Next,we examine the potential of targeting the intestinal barrier,blood–brain barrier,meninges,and peripheral immune system to counteract glial dysfunction in neurodegeneration.Finally,we conclude by assessing the pre-clinical and clinical evidence of probiotics,prebiotics,and fecal microbiota transplantation in neurodegenerative diseases.A thorough comprehension of the microbiota–gut–brain axis will foster the development of effective therapeutic interventions for the management of neurodegenerative diseases.

Ischemia-reperfusion injury:molecular mechanisms and therapeutic targets

Ischemia-reperfusion(I/R)injury paradoxically occurs during reperfusion following ischemia,exacerbating the initial tissue damage.The limited understanding of the intricate mechanisms underlying I/R injury hinders the development of effective therapeutic interventions.The Wnt signaling pathway exhibits extensive crosstalk with various other pathways,forming a network system of signaling pathways involved in I/R injury.This review article elucidates the underlying mechanisms involved in Wnt signaling,as well as the complex interplay between Wnt and other pathways,including Notch,phosphatidylinositol 3-kinase/protein kinase B,transforming growth factor-β,nuclear factor kappa,bone morphogenetic protein,N-methyl-D-aspartic acid receptor-Ca2+-Activin A,Hippo-Yes-associated protein,toll-like receptor 4/toll-interleukine-1 receptor domain-containing adapter-inducing interferon-β,and hepatocyte growth factor/mesenchymal-epithelial transition factor.In particular,we delve into their respective contributions to key pathological processes,including apoptosis,the inflammatory response,oxidative stress,extracellular matrix remodeling,angiogenesis,cell hypertrophy,fibrosis,ferroptosis,neurogenesis,and blood-brain barrier damage during I/R injury.Our comprehensive analysis of the mechanisms involved in Wnt signaling during I/R reveals that activation of the canonical Wnt pathway promotes organ recovery,while activation of the non-canonical Wnt pathways exacerbates injury.Moreover,we explore novel therapeutic approaches based on these mechanistic findings,incorporating evidence from animal experiments,current standards,and clinical trials.The objective of this review is to provide deeper insights into the roles of Wnt and its crosstalk signaling pathways in I/R-mediated processes and organ dysfunction,to facilitate the development of innovative therapeutic agents for I/R injury.

Major depressive disorder:hypothesis,mechanism,prevention and treatment

Worldwide,the incidence of major depressive disorder(MDD)is increasing annually,resulting in greater economic and social burdens.Moreover,the pathological mechanisms of MDD and the mechanisms underlying the effects of pharmacological treatments for MDD are complex and unclear,and additional diagnostic and therapeutic strategies for MDD still are needed.The currently widely accepted theories of MDD pathogenesis include the neurotransmitter and receptor hypothesis,hypothalamicpituitary-adrenal(HPA)axis hypothesis,cytokine hypothesis,neuroplasticity hypothesis and systemic influence hypothesis,but these hypothesis cannot completely explain the pathological mechanism of MDD.Even it is still hard to adopt only one hypothesis to completely reveal the pathogenesis of MDD,thus in recent years,great progress has been made in elucidating the roles of multiple organ interactions in the pathogenesis MDD and identifying novel therapeutic approaches and multitarget modulatory strategies,further revealing the disease features of MDD.Furthermore,some newly discovered potential pharmacological targets and newly studied antidepressants have attracted widespread attention,some reagents have even been approved for clinical treatment and some novel therapeutic methods such as phototherapy and acupuncture have been discovered to have effective improvement for the depressive symptoms.In this work,we comprehensively summarize the latest research on the pathogenesis and diagnosis of MDD,preventive approaches and therapeutic medicines,as well as the related clinical trials.

Ferroptosis in cancer: From molecular mechanisms to therapeutic strategies

Ferroptosis is a non-apoptotic form of regulated cell death characterized by the lethal accumulation of iron-dependent membranelocalized lipid peroxides.It acts as an innate tumor suppressor mechanism and participates in the biological processes of tumors.Intriguingly,mesenchymal and dedifferentiated cancer cells,which are usually resistant to apoptosis and traditional therapies,are exquisitely vulnerable to ferroptosis,further underscoring its potential as a treatment approach for cancers,especially for refractory cancers.However,the impact of ferroptosis on cancer extends beyond its direct cytotoxic effect on tumor cells.Ferroptosis induction not only inhibits cancer but also promotes cancer development due to its potential negative impact on anticancer immunity.Thus,a comprehensive understanding of the role of ferroptosis in cancer is crucial for the successful translation of ferroptosis therapy from the laboratory to clinical applications.In this review,we provide an overview of the recent advancements in understanding ferroptosis in cancer,covering molecular mechanisms,biological functions,regulatory pathways,and interactions with the tumor microenvironment.We also summarize the potential applications of ferroptosis induction in immunotherapy,radiotherapy,and systemic therapy,as well as ferroptosis inhibition for cancer treatment in various conditions.We finally discuss ferroptosis markers,the current challenges and future directions of ferroptosis in the treatment of cancer.

Therapeutic cancer vaccines:advancements,challenges,and prospects

With the development and regulatory approval of immune checkpoint inhibitors and adoptive cell therapies,cancer immunotherapy has undergone a profound transformation over the past decades.Recently,therapeutic cancer vaccines have shown promise by eliciting de novo T cell responses targeting tumor antigens,including tumor-associated antigens and tumor-specific antigens.The objective was to amplify and diversify the intrinsic repertoire of tumor-specific T cells.However,the complete realization of these capabilities remains an ongoing pursuit.Therefore,we provide an overview of the current landscape of cancer vaccines in this review.The range of antigen selection,antigen delivery systems development the strategic nuances underlying effective antigen presentation have pioneered cancer vaccine design.Furthermore,this review addresses the current status of clinical trials and discusses their strategies,focusing on tumor-specific immunogenicity and anti-tumor efficacy assessment.However,current clinical attempts toward developing cancer vaccines have not yielded breakthrough clinical outcomes due to significant challenges,including tumor immune microenvironment suppression,optimal candidate identification,immune response evaluation,and vaccine manufacturing acceleration.Therefore,the field is poised to overcome hurdles and improve patient outcomes in the future by acknowledging these clinical complexities and persistently striving to surmount inherent constraints.

Targeting epigenetic and posttranslational modifications regulating ferroptosis for the treatment of diseases

Ferroptosis,a unique modality of cell death with mechanistic and morphological differences from other cell death modes,plays a pivotal role in regulating tumorigenesis and offers a new opportunity for modulating anticancer drug resistance.Aberrant epigenetic modifications and posttranslational modifications(PTMs)promote anticancer drug resistance,cancer progression,and metastasis.Accumulating studies indicate that epigenetic modifications can transcriptionally and translationally determine cancer cell vulnerability to ferroptosis and that ferroptosis functions as a driver in nervous system diseases(NSDs),cardiovascular diseases(CVDs),liver diseases,lung diseases,and kidney diseases.In this review,we first summarize the core molecular mechanisms of ferroptosis.Then,the roles of epigenetic processes,including histone PTMs,DNA methylation,and noncoding RNA regulation and PTMs,such as phosphorylation,ubiquitination,SUMOylation,acetylation,methylation,and ADP-ribosylation,are concisely discussed.The roles of epigenetic modifications and PTMs in ferroptosis regulation in the genesis of diseases,including cancers,NSD,CVDs,liver diseases,lung diseases,and kidney diseases,as well as the application of epigenetic and PTM modulators in the therapy of these diseases,are then discussed in detail.Elucidating the mechanisms of ferroptosis regulation mediated by epigenetic modifications and PTMs in cancer and other diseases will facilitate the development of promising combination therapeutic regimens containing epigenetic or PTM-targeting agents and ferroptosis inducers that can be used to overcome chemotherapeutic resistance in cancer and could be used to prevent other diseases.In addition,these mechanisms highlight potential therapeutic approaches to overcome chemoresistance in cancer or halt the genesis of other diseases.

Clinical applications of stem cell-derived exosomes

Although stem cell-based therapy has demonstrated considerable potential to manage certain diseases more successfully than conventional surgery,it nevertheless comes with inescapable drawbacks that might limit its clinical translation.Compared to stem cells,stem cell-derived exosomes possess numerous advantages,such as non-immunogenicity,non-infusion toxicity,easy access,effortless preservation,and freedom from tumorigenic potential and ethical issues.Exosomes can inherit similar therapeutic effects from their parental cells such as embryonic stem cells and adult stem cells through vertical delivery of their pluripotency or multipotency.After a thorough search and meticulous dissection of relevant literature from the last five years,we present this comprehensive,up-to-date,specialty-specific and disease-oriented review to highlight the surgical application and potential of stem cell-derived exosomes.Exosomes derived from stem cells(e.g.,embryonic,induced pluripotent,hematopoietic,mesenchymal,neural,and endothelial stem cells)are capable of treating numerous diseases encountered in orthopedic surgery,neurosurgery,plastic surgery,general surgery,cardiothoracic surgery,urology,head and neck surgery,ophthalmology,and obstetrics and gynecology.The diverse therapeutic effects of stem cells-derived exosomes are a hierarchical translation through tissue-specific responses,and cell-specific molecular signaling pathways.In this review,we highlight stem cell-derived exosomes as a viable and potent alternative to stem cell-based therapy in managing various surgical conditions.We recommend that future research combines wisdoms from surgeons,nanomedicine practitioners,and stem cell researchers in this relevant and intriguing research area.

TGF-βsignaling in health,disease,and therapeutics

ransforming growth factor(TGF)-βis a multifunctional cytokine expressed by almost every tissue and cell type.The signal transduction of TGF-βcan stimulate diverse cellular responses and is particularly critical to embryonic development,wound healing,tissue homeostasis,and immune homeostasis in health.The dysfunction of TGF-βcan play key roles in many diseases,and numerous targeted therapies have been developed to rectify its pathogenic activity.In the past decades,a large number of studies on TGF-βsignaling have been carried out,covering a broad spectrum of topics in health,disease,and therapeutics.Thus,a comprehensive overview of TGF-βsignaling is required for a general picture of the studies in this field.In this review,we retrace the research history of TGF-βand introduce the molecular mechanisms regarding its biosynthesis,activation,and signal transduction.We also provide deep insights into the functions of TGF-βsignaling in physiological conditions as well as in pathological processes.TGF-β-targeting therapies which have brought fresh hope to the treatment of relevant diseases are highlighted.Through the summary of previous knowledge and recent updates,this review aims to provide a systematic understanding of TGF-βsignaling and to attract more attention and interest to this research area.

Extracellular vesicles as tools and targets in therapy for diseases

Extracellular vesicles(EVs)are nano-sized,membranous structures secreted into the extracellular space.They exhibit diverse sizes,contents,and surface markers and are ubiquitously released from cells under normal and pathological conditions.Human serum is a rich source of these EVs,though their isolation from serum proteins and non-EV lipid particles poses challenges.These vesicles transport various cellular components such as proteins,mRNAs,miRNAs,DNA,and lipids across distances,influencing numerous physiological and pathological events,including those within the tumor microenvironment(TME).Their pivotal roles in cellular communication make EVs promising candidates for therapeutic agents,drug delivery systems,and disease biomarkers.Especially in cancer diagnostics,EV detection can pave the way for early identification and offers potential as diagnostic biomarkers.Moreover,various EV subtypes are emerging as targeted drug delivery tools,highlighting their potential clinical significance.The need for non-invasive biomarkers to monitor biological processes for diagnostic and therapeutic purposes remains unfulfilled.Tapping into the unique composition of EVs could unlock advanced diagnostic and therapeutic avenues in the future.In this review,we discuss in detail the roles of EVs across various conditions,including cancers(encompassing head and neck,lung,gastric,breast,and hepatocellular carcinoma),neurodegenerative disorders,diabetes,viral infections,autoimmune and renal diseases,emphasizing the potential advancements in molecular diagnostics and drug delivery.

Targeting proprotein convertase subtilisin/kexin type 9(PCSK9):from bench to bedside

Proprotein convertase subtilisin/kexin type 9(PCSK9)has evolved as a pivotal enzyme in lipid metabolism and a revolutionary therapeutic target for hypercholesterolemia and its related cardiovascular diseases(CVD).This comprehensive review delineates the intricate roles and wide-ranging implications of PCSK9,extending beyond CVD to emphasize its significance in diverse physiological and pathological states,including liver diseases,infectious diseases,autoimmune disorders,and notably,cancer.Our exploration offers insights into the interaction between PCSK9 and low-density lipoprotein receptors(LDLRs),elucidating its substantial impact on cholesterol homeostasis and cardiovascular health.It also details the evolution of PCSK9-targeted therapies,translating foundational bench discoveries into bedside applications for optimized patient care.The advent and clinical approval of innovative PCSK9 inhibitory therapies(PCSK9-iTs),including three monoclonal antibodies(Evolocumab,Alirocumab,and Tafolecimab)and one small interfering RNA(siRNA,Inclisiran),have marked a significant breakthrough in cardiovascular medicine.These therapies have demonstrated unparalleled efficacy in mitigating hypercholesterolemia,reducing cardiovascular risks,and have showcased profound value in clinical applications,offering novel therapeutic avenues and a promising future in personalized medicine for cardiovascular disorders.Furthermore,emerging research,inclusive of our findings,unveils PCSK9’s potential role as a pivotal indicator for cancer prognosis and its prospective application as a transformative target for cancer treatment.This review also highlights PCSK9’s aberrant expression in various cancer forms,its association with cancer prognosis,and its crucial roles in carcinogenesis and cancer immunity.In conclusion,this synthesized review integrates existing knowledge and novel insights on PCSK9,providing a holistic perspective on its transformative impact in reshaping therapeutic paradigms across various disorders.It emphasizes the clinical value and effect of PCSK9-iT,underscoring its potential in advancing the landscape of biomedical research and its capabilities in heralding new eras in personalized medicine.

Camouflaging attenuated Salmonella by cryo-shocked macrophages for tumor-targeted therapy

Live bacteria-mediated antitumor therapies mark a pivotal point in cancer immunotherapy.However,the difficulty in reconciling the safety and efficacy of bacterial therapies has limited their application.Improving bacterial tumor-targeted delivery while maintaining biosafety is a critical hurdle for the clinical translation of live microbial therapy for cancer.Here,we developed“dead”yet“functional”Salmonella-loaded macrophages using liquid nitrogen cold shock of an attenuated Salmonella typhimurium VNP20009-contained macrophage cell line.The obtained“dead”macrophages achieve an average loading of approximately 257 live bacteria per 100 cells.The engineered cells maintain an intact cellular structure but lose their original pathogenicity,while intracellular bacteria retain their original biological activity and are delay freed,followed by proliferation.This“Trojan horse”-like bacterial camouflage strategy avoids bacterial immunogenicity-induced neutrophil recruitment and activation in peripheral blood,reduces the clearance of bacteria by neutrophils and enhances bacterial tumor enrichment efficiently after systemic administration.Furthermore,this strategy also strongly activated the tumor microenvironment,including increasing antitumor effector cells(including M1-like macrophages and CD8+Teffs)and decreasing protumor effector cells(including M2-like macrophages and CD4+Tregs),and ultimately improved antitumor efficacy in a subcutaneous H22 tumor-bearing mouse model.The cryo-shocked macrophage-mediated bacterial delivery strategy holds promise for expanding the therapeutic applications of living bacteria for cancer.

New insights into the correlations between circulating tumor cells and target organ metastasis

Organ-specific metastasis is the primary cause of cancer patient death.The distant metastasis of tumor cells to specific organs depends on both the intrinsic characteristics of the tumor cells and extrinsic factors in their microenvironment.During an intermediate stage of metastasis,circulating tumor cells(CTCs)are released into the bloodstream from primary and metastatic tumors.CTCs harboring aggressive or metastatic features can extravasate to remote sites for continuous colonizing growth,leading to further lesions.In the past decade,numerous studies demonstrated that CTCs exhibited huge clinical value including predicting distant metastasis,assessing prognosis and monitoring treatment response et al.Furthermore,increasingly numerous experiments are dedicated to identifying the key molecules on or inside CTCs and exploring how they mediate CTC-related organ-specific metastasis.Based on the above molecules,more and more inhibitors are being developed to target CTCs and being utilized to completely clean CTCs,which should provide promising prospects to administer advanced tumor.Recently,the application of various nanomaterials and microfluidic technologies in CTCs enrichment technology has assisted to improve our deep insights into the phenotypic characteristics and biological functions of CTCs as a potential therapy target,which may pave the way for us to make practical clinical strategies.In the present review,we mainly focus on the role of CTCs being involved in targeted organ metastasis,especially the latest molecular mechanism research and clinical intervention strategies related to CTCs.

Neoadjuvant nivolumab with or without platinum-doublet chemotherapy based on PD-L1 expression in resectable NSCLC(CTONG1804):a multicenter open-label phase II study

This prospective multicenter phase II study evaluated the clinical efficacy of neoadjuvant nivolumab-exclusive(N)and nivolumab–chemotherapy(N/C)combinations based on PD-L1 expression.Eligible patients exhibited resectable clinical stage IIA–IIIB(AJCC 8th edition)NSCLC without EGFR/ALK alterations.Patients received either mono-nivolumab(N)or nivolumab+nabpaclitaxel+carboplatin(N/C)for three cycles based on PD-L1 expression.The primary endpoint was the major pathological response(MPR).Key secondary endpoints included the pathologic complete response(pCR),objective response rate(ORR),and event-free survival(EFS).Baseline PD-L1 expression and perioperative circulating tumor DNA(ctDNA)status were correlated with pCR and EFS.Fifty-two patients were enrolled,with 46 undergoing surgeries.The MPR was 50.0%(26/52),with 25.0%(13/52)achieving pCR,and 16.7%and 66.7%for patients with PD-L1≥50%in N and N/C groups,respectively.Thirteen(25.0%)patients experienced grade 3 or higher immune-related adverse events during neoadjuvant treatment.Patients with post-neoadjuvant ctDNA negativity was more likely to have pCR(39.1%)compared with those remained positive(6.7%,odds ratio=6.14,95%CI 0.84-Inf,p=0.077).With a median follow-up of 25.1 months,the 18-month EFS rate was 64.8%(95%CI 51.9–81.0%).For patients with ctDNA–vs.ctDNA+,the 18m-EFS rate was 93.8%vs 47.3%(HR,0.15;95%CI 0.04,0.94;p=0.005).Immunochemotherapy may serve as an optimal neoadjuvant treatment even for patients with PD-L1 expression≥50%.ctDNA negativity following neoadjuvant treatment and surgery could help identify superior pathological and survival benefits,which requires further confirmation in a prospective clinical trial(NCT04015778).

Effects of dietary intervention on human diseases:molecular mechanisms and therapeutic potential

Diet,serving as a vital source of nutrients,exerts a profound influence on human health and disease progression.Recently,dietary interventions have emerged as promising adjunctive treatment strategies not only for cancer but also for neurodegenerative diseases,autoimmune diseases,cardiovascular diseases,and metabolic disorders.These interventions have demonstrated substantial potential in modulating metabolism,disease trajectory,and therapeutic responses.Metabolic reprogramming is a hallmark of malignant progression,and a deeper understanding of this phenomenon in tumors and its effects on immune regulation is a significant challenge that impedes cancer eradication.Dietary intake,as a key environmental factor,can influence tumor metabolism.Emerging evidence indicates that dietary interventions might affect the nutrient availability in tumors,thereby increasing the efficacy of cancer treatments.However,the intricate interplay between dietary interventions and the pathogenesis of cancer and other diseases is complex.Despite encouraging results,the mechanisms underlying diet-based therapeutic strategies remain largely unexplored,often resulting in underutilization in disease management.In this review,we aim to illuminate the potential effects of various dietary interventions,including calorie restriction,fasting-mimicking diet,ketogenic diet,protein restriction diet,high-salt diet,high-fat diet,and high-fiber diet,on cancer and the aforementioned diseases.We explore the multifaceted impacts of these dietary interventions,encompassing their immunomodulatory effects,other biological impacts,and underlying molecular mechanisms.This review offers valuable insights into the potential application of these dietary interventions as adjunctive therapies in disease management.

Targeting the RAS/RAF/MAPK pathway for cancer therapy: from mechanism to clinical studies

Metastatic dissemination of solid tumors,a leading cause of cancer-related mortality,underscores the urgent need for enhanced insights into the molecular and cellular mechanisms underlying metastasis,chemoresistance,and the mechanistic backgrounds of individuals whose cancers are prone to migration.The most prevalent signaling cascade governed by multi-kinase inhibitors is the mitogen-activated protein kinase(MAPK)pathway,encompassing the RAS–RAF–MAPK kinase(MEK)–extracellular signal-related kinase(ERK)pathway.RAF kinase is a primary mediator of the MAPK pathway,responsible for the sequential activation of downstream targets,such as MEK and the transcription factor ERK,which control numerous cellular and physiological processes,including organism development,cell cycle control,cell proliferation and differentiation,cell survival,and death.Defects in this signaling cascade are associated with diseases such as cancer.RAF inhibitors(RAFi)combined with MEK blockers represent an FDAapproved therapeutic strategy for numerous RAF-mutant cancers,including melanoma,non-small cell lung carcinoma,and thyroid cancer.However,the development of therapy resistance by cancer cells remains an important barrier.Autophagy,an intracellular lysosome-dependent catabolic recycling process,plays a critical role in the development of RAFi resistance in cancer.Thus,targeting RAF and autophagy could be novel treatment strategies for RAF-mutant cancers.In this review,we delve deeper into the mechanistic insights surrounding RAF kinase signaling in tumorigenesis and RAFi-resistance.Furthermore,we explore and discuss the ongoing development of next-generation RAF inhibitors with enhanced therapeutic profiles.Additionally,this review sheds light on the functional interplay between RAF-targeted therapies and autophagy in cancer.

Anti-lymphangiogenesis for boosting drug accumulation in tumors

The inadequate tumor accumulation of anti-cancer agents is a major shortcoming of current therapeutic drugs and remains an even more significant concern in the clinical prospects for nanomedicines.Various strategies aiming at regulating the intratumoral permeability of therapeutic drugs have been explored in preclinical studies,with a primary focus on vascular regulation and stromal reduction.However,these methods may trigger or facilitate tumor metastasis as a tradeoff.Therefore,there is an urgent need for innovative strategies that boost intratumoral drug accumulation without compromising treatment outcomes.As another important factor affecting drug tumor accumulation besides vasculature and stroma,the impact of tumor-associated lymphatic vessels(LVs)has not been widely considered.In the current research,we verified that anlotinib,a tyrosine kinase inhibitor with anti-lymphangiogenesis activity,and SAR131675,a selective VEGFR-3 inhibitor,effectively decreased the density of tumor lymphatic vessels in mouse cancer models,further enhancing drug accumulation in tumor tissue.By combining anlotinib with therapeutic drugs,including doxorubicin(Dox),liposomal doxorubicin(Lip-Dox),and anti-PD-L1 antibody,we observed improved anti-tumor efficacy in comparison with monotherapy regimens.Meanwhile,this strategy significantly reduced tumor metastasis and elicited stronger anti-tumor immune responses.Our work describes a new,clinically transferrable approach to augmenting intratumoral drug accumulation,which shows great potential to address the current,unsatisfactory efficacies of therapeutic drugs without introducing metastatic risk.

Gut liver brain axis in diseases:the implications for therapeutic interventions

Gut-liver-brain axis is a three-way highway of information interaction system among the gastrointestinal tract,liver,and nervous systems.In the past few decades,breakthrough progress has been made in the gut liver brain axis,mainly through understanding its formation mechanism and increasing treatment strategies.In this review,we discuss various complex networks including barrier permeability,gut hormones,gut microbial metabolites,vagus nerve,neurotransmitters,immunity,brain toxic metabolites,β-amyloid(Aβ)metabolism,and epigenetic regulation in the gut-liver-brain axis.Some therapies containing antibiotics,probiotics,prebiotics,synbiotics,fecal microbiota transplantation(FMT),polyphenols,low FODMAP diet and nanotechnology application regulate the gut liver brain axis.Besides,some special treatments targeting gut-liver axis include farnesoid X receptor(FXR)agonists,takeda G protein-coupled receptor 5(TGR5)agonists,glucagon-like peptide-1(GLP-1)receptor antagonists and fibroblast growth factor 19(FGF19)analogs.Targeting gut-brain axis embraces cognitive behavioral therapy(CBT),antidepressants and tryptophan metabolism-related therapies.Targeting liver-brain axis contains epigenetic regulation and Aβmetabolism-related therapies.In the future,a better understanding of gut-liver-brain axis interactions will promote the development of novel preventative strategies and the discovery of precise therapeutic targets in multiple diseases.

Targeting carnitine palmitoyl transferase 1A(CPT1A)induces ferroptosis and synergizes with immunotherapy in lung cancer

Despite the successful application of immune checkpoint therapy,no response or recurrence is typical in lung cancer.Cancer stem cells(CSCs)have been identified as a crucial player in immunotherapy-related resistance.Ferroptosis,a form of cell death driven by iron-dependent lipid peroxidation,is highly regulated by cellular metabolism remolding and has been shown to have synergistic effects when combined with immunotherapy.Metabolic adaption of CsCs drives tumor resistance,yet the mechanisms of their ferroptosis defense in tumor immune evasion remain elusive.Here,through metabolomics,transcriptomics,a lung epithelialspecific Cptla-knockout mouse model,and clinical analysis,we demonstrate that CPT1A,a key rate-limiting enzyme of fatty acid oxidation,acts with L-carnitine,derived from tumor-associated macrophages to drive ferroptosis-resistance and CD8^(+)T cells inactivation in lung cancer.Mechanistically,CPT1A restrains ubiquitination and degradation of c-Myc,while c-Myc transcriptionally activates CPT1A expression.The CPT1A/c-Myc positive feedback loop further enhances the cellular antioxidant capacity by activating the NRF2/GPX4 system and reduces the amount of phospholipid polyunsaturated fatty acids through ACSL4 downregulating,thereby suppressing ferroptosis in CSCs.Significantly,targeting CPT1A enhances immune checkpoint blockadeinduced anti-tumor immunity and tumoral ferroptosis in tumor-bearing mice.The results illustrate the potential of a mechanismguided therapeutic strategy by targeting a metabolic vulnerability in the ferroptosis of CsCs to improve the efficacy of lung cancer immunotherapy.