Taking early preventive interventions to manage the challenging issue of acquired resistance to third-generation EGFR inhibitors

Although the clinical efficacies of third-generation epidermal growth factor receptor(EGFR)-tyrosine kinase in-hibitors(TKIs)such as osimertinib in the treatment of non-small cell lung cancer(NSCLC)with EGFR-activating mutations are promising,drug-acquired resistance inevitably occurs whether they are used as first-line or second-line treatment.Therefore,managing the acquired resistance to third-generation EGFR-TKIs is crucial in the clinic for improving patient survival.Great efforts have been made to develop potentially effective strategies or regimens for the treatment of EGFR-mutant NSCLC patients after relapse following these TKIs therapies with the hope that patients will continue to benefit from treatment through overcoming acquired resistance.Although this approach,which aims to overcome drug-acquired resistance,is necessary and important,it is a passive practice.Taking pre-ventive action early before disease progression to manage the unavoidable development of acquired resistance offers an equally important and efficient approach.We strongly believe that early preventive interventions using effective and tolerable combination regimens that interfere with the process of developing acquired resistance may substantially improve the outcomes of EGFR-mutant NSCLC treatment with third-generation EGFR-TKIs.Thus,this review focuses on discussing the scientific rationale and mechanism-driven strategies for delaying and even preventing the emergence of acquired resistance to third-generation EGFR-TKIs,particularly osimertinib.

Suberoylanilide hydroxamic acid overcomes erlotinib-acquired resistance via phosphatase and tensin homolog deleted on chromosome 10-mediated apoptosis in non-small cell lung cancer

Background::Epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(TKIs),such as erlotinib and gefitinib,are widely used to treat non-small cell lung cancer(NSCLC).However,acquired resistance is unavoidable,impairing the anti-tumor effects of EGFR-TKIs.It is reported that histone deacetylase(HDAC)inhibitors could enhance the anti-tumor effects of other antineoplastic agents and radiotherapy.However,whether the HDAC inhibitor suberoylanilide hydroxamic acid(SAHA)can overcome erlotinib-acquired resistance is not fully clear.Methods::An erlotinib-resistant PC-9/ER cell line was established through cell maintenance in a series of erlotinib-containing cultures.NSCLC cells were co-cultured with SAHA,erlotinib,or their combination,and then the viability of cells was measured by the 3-(4,5-Dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and apoptosis was determined by flow cytometry and western blotting.Finally,the expression of phosphatase and tensin homolog deleted on chromosome 10(PTEN)was assessed by western blotting.Results::The half-maximal inhibitory concentration of parental PC-9 cells was significantly lower than the established erlotinib-acquired resistant PC-9/ER cell line.PC-9/ER cells demonstrated reduced expression of PTEN compared with PC-9 and H1975 cells,and the combination of SAHA and erlotinib significantly inhibited cell growth and increased apoptosis in both PC-9/ER and H1975 cells.Furthermore,treating PC-9/ER cells with SAHA or SAHA combined with erlotinib significantly upregulated the expression of PTEN mRNA and protein compared with erlotinib treatment alone.Conclusions::PTEN deletion is closely related to acquired resistance to EGFR-TKIs,and treatment with the combination of SAHA and erlotinib showed a greater inhibitory effect on NSCLC cells than single-drug therapy.SAHA enhances the suppressive effects of erlotinib in lung cancer cells,increasing cellular apoptosis and PTEN expression.SAHA can be a potential adjuvant to erlotinib treatment,and thus,can improve the efficacy of NSCLC therapy.

Glycosylation of N-hydroxy-pipecolic acid equilibrates between systemic acquired resistance response and plant growth

N-hydroxy-pipecolic acid(NHP)activates plant systemic acquired resistance(SAR).Enhanced defense responses are typically accompanied by deficiency in plant development and reproduction.Despite of extensive studies on SAR induction,the effects of NHPmetabolismon plant growth remain largely unclear.In this study,we discovered that NHP glycosylation is a critical factor that fine-tunes the tradeoff between SAR defense and plant growth.We demonstrated that a UDP-glycosyltransferase(UGT76B1)forming NHP glycoside(NHPG)controls the NHP to NHPG ratio.Consistently,the ugt76b1 mutant exhibits enhanced SAR response and an inhibitory effect on plant growth,while UGT76B1 overexpression attenuates SAR response,promotes growth,and delays senescence,indicating that NHP levels are dependent on UGT76B1 function in the course of SAR.Furthermore,our results suggested that,upon pathogen attack,UGT76B1-mediated NHP glycosylation forms a‘‘hand brake’’on NHP accumulation by attenuating the positive regulation of NHP biosynthetic pathway genes,highlighting the complexity of SAR-associated networks.In addition,we showed that UGT76B1-mediated NHP glycosylation in the local site is important for fine-tuning SAR response.Our results implicate that engineering plant immunity through manipulating the NHP/NHPG ratio is a promising method to balance growth and defense response in crops.

Transport of chemical signals in systemic acquired resistance

Systemic acquired resistance(SAR) is a form of broad-spectrum resistance induced in response to local infections that protects uninfected parts against subsequent secondary infections by related or unrelated pathogens. SAR signaling requires two parallel branches,one regulated by salicylic acid(SA),and the other by azelaic acid(AzA) and glycerol-3-phosphate(G3P). Az A and G3P function downstream of the free radicals nitric oxide(NO) and reactive oxygen species(ROS). During SAR,SA,Az A and G3P accumulate in the infected leaves,but only a small portion of these is transported to distal uninfected leaves. SA is preferentially transported via the apoplast,whereas phloem loading of Az A and G3P occurs via the symplast. The symplastic transport of Az A and G3P is regulated by gating of the plasmodesmata(PD). The PD localizing proteins,PDLP1 and PDLP5,regulate SAR by regulating PD gating as well as the subcellular partitioning of a SAR-associated protein.

Targeting apoptosis to manage acquired resistance to third generation EGFR inhibitors

A significant clinical challenge in lung cancer treatment is management of the inevitable acquired resistance to third-generation epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(EGFR-TKIs),such as osimertinib,which have shown remarkable success in the treatment of advanced NSCLC with EGFR activating mutations,in order to achieve maximal response duration or treatment remission.Apoptosis is a major type of programmed cell death tightly associated with cancer development and treatment.Evasion of apoptosis is considered a key hallmark of cancer and acquisition of apoptosis resistance is accordingly a key mechanism of drug acquired resistance in cancer therapy.It has been clearly shown that effective induction of apoptosis is a key mechanism for third generation EGFR-TKIs,particularly osimertinib,to exert their therapeutic efficacies and the development of resistance to apoptosis is tightly associated with the emergence of acquired resistance.Hence,restoration of cell sensitivity to undergo apoptosis using various means promises an effective strategy for the management of acquired resistance to third generation EGFR-TKIs.

Antibiotic resistance in patients with liver cirrhosis:Prevalence and current approach to tackle

Regardless of etiology,complications with bacterial infection in patients with cirrhosis are reported in the range of 25%-46%according to the most recent data.Due to frequent episodes of bacterial infection and repetitive antibiotic treatment,most often with broad-spectrum gram negative coverage,patients with cirrhosis are at increased risk of encountering multidrug resistant bacteria,and this raises concern.In such patients,extended-spectrum beta-lactamase and AmpCproducing Enterobacterales,methicillin-or vancomycin-resistant Staphylococcus aureus,vancomycin-resistant Enterococci,carbapenem-resistant Pseudomonas aeruginosa,and Acinetobacter baumannii,all of which are difficult to treat,are the most common.That is why novel approaches to the prophylaxis and treatment of bacterial infections to avoid antibiotic resistance have recently been developed.At the same time,our knowledge of resistance mechanisms is constantly updated.This review summarizes the current situation regarding the burden of antibiotic resistance,including the prevalence and mechanisms of intrinsic and acquired resistance in bacterial species that most frequently cause complications in patients with liver cirrhosis and recent developments on how to deal with multidrug resistant bacteria.

A case report of response to crizotinib in chemotherapy-refractory metastatic gallbladder cancer with met amplification and acquired resistance resulting from the loss of MET amplification

Gallbladder cancer(GBC)is a highly invasive disease and the most prevalent malignancy of the biliary system.Patients with GBC are commonly diagnosed at a late stage and have an unfavorable prognosis.Palliative chemotherapy has been the standard care for recurrent or metastatic disease in the past decades.Recently,several targeted therapies have been investigated in advanced biliary tract cancer(BTC)including inhibitors of genes or pathways such as FGFR2 fusions or rearrangements,IDH1 mutations,and NTRK gene fusions.Also,several clinical studies involving molecular stratification have been performed in defined patient groups,for example,BRAF V600E and HER2.Mesenchymal epithelial transition(MET)encodes a tyrosine kinase receptor and its ligand hepatocyte growth factor is a proto-oncogene.Targeting the MET signaling pathway is an effective strategy in numerous cancer types.However,the poor efficacy of MET inhibitors has been demonstrated in several phase II studies,but currently no reports have explained the potential mechanisms of resistance to MET inhibitors in BTC.In this article,we report a case of metastatic GBC with MET amplification that exhibited a rapid response to crizotinib after the failure of two lines of chemotherapy.After the patient had progressed and discontinued crizotinib,cabozantinib was introduced.Analysis of circulating tumor DNA(ctDNA)by nextgeneration sequencing(NGS)indicated a loss of MET amplification status.To our knowledge,this is the first case study demonstrating the use of NGS in ctDNA to monitor the development of acquired resistance during anti-MET treatment in GBC.

T790M mutation in stage IV EGFR-mutated NSCLC patient with acquired resistance reverted to original 19Del mutation after administration of a series of precision treatments:a case report

Existing studies have yet to elucidate clearly the mechanisms of secondary resistance to third generation epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(TKIs),neither is there any established standard therapy for patients resistant to third generation EGFR-TKIs.This case report demonstrates a rare mutation pattern in a male patient with a pathologic diagnosis of non-small cell lung cancer(NSCLC)harboring an EGFR exon 19 deletion(19Del)mutation,who then acquired an EGFR-T790M mutation after developing resistance to the first generation EGFR-TKI(gefitinib).The mutation reverted to the original EGFR-19Del mutation after the patient developed secondary resistance against the third generation TKI(osimertinib).This patient eventually achieved partial response(PR)with second generation TKI(afatinib)as a fourth-line treatment.

Mechanisms of acquired resistance to fibroblast growth factor receptor targeted therapy

Oncogenic activation of the fibroblast growth factor receptor(FGFR)through mutations and fusions of the FGFR gene occur in a variety of different malignancies such as urothelial carcinoma and cholangiocarcinoma.Inhibition of the kinase domain of the FGFR with targeted oral FGFR inhibitors has been shown in both preclinical and early phase clinical trials to lead to meaningful reductions in tumour size and larger confirmatory randomized trials are underway.Acquired resistance to FGFR inhibition using a variety of mechanisms that includes,activation of alternate signaling pathways and expansion of tumour clones with gatekeeper mutations in the FGFR gene.This review summarizes the acquired resistance mechanisms to FGFR therapy and therapeutic approaches to circumventing resistance.

Drug-adapted cancer cell lines as preclinical models of acquired resistance

Acquired resistance formation limits the efficacy of anti-cancer therapies.Acquired and intrinsic resistance differ conceptually.Acquired resistance is the consequence of directed evolution,whereas intrinsic resistance depends on the(stochastic)presence of pre-existing resistance mechanisms.Preclinical model systems are needed to study acquired drug resistance because they enable:(1)in depth functional studies;(2)the investigation of non-standard treatments for a certain disease condition(which is necessary to identify small groups of responders);and(3)the comparison of multiple therapies in the same system.Hence,they complement data derived from clinical trials and clinical specimens,including liquid biopsies.Many groups have successfully used drug-adapted cancer cell lines to identify and elucidate clinically relevant resistance mechanisms to targeted and cytotoxic anti-cancer drugs.Hence,we argue that drug-adapted cancer cell lines represent a preclinical model system in their own right that is complementary to other preclinical model systems and clinical data.

Articulating beneficial rhizobacteria-mediated plant defenses through induced systemic resistance:A review

Induced systemic resistance(ISR)is a mechanism by which certain plant beneficial rhizobacteria and fungi produce immunity,which can stimulate crop growth and resilience against various phytopathogens,insects,and parasites.These beneficial rhizobacteria and fungi improve plant performance by regulating hormone signaling,including salicylic acid(SA),jasmonic acid(JA),prosystemin,pathogenesis-related gene 1,and ethylene(ET)pathways,which activate the gene expression of ISR,the synthesis of secondary metabolites,various enzymes,and volatile compounds that ultimately induce defense mechanisms in plant.To protect themselves from disease,plants have various advanced defense mechanisms in which local acquired resistance,systemic gene silencing,systemic wound response,systemic acquired resistance(SAR),and ISR are involved.Several rhizobacteria activate the SA-dependent SAR pathway by producing SA at the root’s surface.In contrast,other rhizobacteria can activate different signaling pathways independent of SA(SA-independent ISR pathways)such as those dependent on JA and ET signaling.The main objective of this review is to provide insight into the types of induced resistance utilized for plant defense.Further to this,the genetic approaches used to suppress disease-causing genes,i.e.,RNA interference and antisense RNA,which are still underutilized in sustainable agriculture,along with the current vision for virus-induced gene silencing are also discussed.

Predicting and overcoming resistance to CDK9 inhibitors for cancer therapy

Abnormally activated CDK9 participates in the super-enhancer mediated transcription of short-lived proteins required for cancer cell survival.Targeting CDK9 has shown potent anti-tumor activity in clinical trials among different cancers.However,the study and knowledge on drug resistance to CDK9 inhibitors are very limited.In this study,we established an AML cell line with acquired resistance to a highly selective CDK9 inhibitor BAY1251152.Through genomic sequencing,we identified in the kinase domain of CDK9 a mutation L156F,which is also a coding SNP in the CDK9 gene.By knocking in L156F into cancer cells using CRISPR/Cas9,we found that single CDK9 L156F could drive the resistance to CDK9 inhibitors,not only ATP competitive inhibitor but also PROTAC degrader.Mechanistically,CDK9 L156F disrupts the binding with inhibitors due to steric hindrance,further,the mutation affects the thermal stability and catalytic activity of CDK9 protein.To overcome the drug resistance mediated by the CDK9-L156F mutation,we discovered a compound,IHMT-CDK9-36 which showed potent inhibition activity both for CDK9 WT and L156F mutant.Together,we report a novel resistance mechanism for CDK9 inhibitors and provide a novel chemical scaffold for the future development of CDK9 inhibitors.

Mechanisms of tyrosine kinase inhibitor resistance in renal cell carcinoma

Renal cell carcinoma(RCC),the most prevalent type of kidney cancer,is a significant cause of cancer morbidity and mortality worldwide.Antiangiogenic tyrosine kinase inhibitors(TKls),in combination with immune checkpoint inhibitors(ICls),are among the first-line treatment options for patients with advanced RCC.These therapies target the vascular endothelial growth factor receptor(VEGFR)tyrosine kinase pathway and other kinases crucial to cancer proliferation,survival,and metastasis.TKls have yielded substantial improvements in progression-free survival(PFS)and overall survival(OS)for patients with advanced RCC.However,nearly all patients eventually progress on these drugs as resistance develops.This review provides an overview of TKl resistance in RCC and explores different mechanisms of resistance,including upregulation of alternative proangiogenic pathways,epithelial-mesenchymal transition(EMT),decreased intracellular drug concentrations due to efflux pumps and lysosomal sequestration,alterations in the tumor microenvironment including bone marrow-derived cells(BMDCs)and tumor-associated fibroblasts(TAFs),and genetic factors such as single nucleotide polymorphisms(SNPs).A comprehensive understanding of these mechanisms opens the door to the development of innovative therapeutic approaches that can effectively overcome TKl resistance,thereby improving outcomes for patients with advanced RCC.

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.

Characterization of acquired nutlin-3 resistant non-small cell lung cancer cells

Aim:The purpose of this manuscript is to study the potential characteristics of acquired nutlin-3 resistant non-small cell lung cancer cells(NSCLC).Nutlin-3 is an inhibitor of the murine-double minute 2 protein,the main negative regulator of wild type p53,of which several derivatives are currently in clinical development.Methods:A549 NSCLC cells were exposed to increasing concentrations of nutlin-3 for a period of 18 weeks.Monoclonal derivates were cultured,and the most resistance subclone was selected for whole transcriptome analysis.Gene set enrichment analysis was performed on differentially expressed genes between A549 nutlin-3 resistant cancer cells and the parental A549 p53 wild type cancer cells.Relevant findings were validated at the gene,protein and/or functional level.Results:All nutlin-3 resistant subclones acquired mutations in the TP53 gene,resulting in overexpression of the mutant p53 protein.The most resistant subclone was enriched for genes related to epithelial to mesenchymal transition(EMT),resulting in increased migratory and invasive potential.Furthermore,these cells were enriched in genes related to inflammation,tissue remodelling,and angiogenesis.Importantly,expression of several immune checkpoints,including PD-L1 and PD-L2,was significantly upregulated,and cisplatin-induced cell death was reduced.Conclusion:Transcriptome analysis of a highly nutlin-3 resistant A549 subclone shows the relevance of studying(1)resistance to standard of care chemotherapy;(2)secretion of immunomodulating chemo-and cytokines;(3)immune checkpoint expression;and(4)EMT and invasion in nutlin-3 resistant cancer cells in addition to acquired mutations in the TP53 gene.

Approaches to identifying drug resistance mechanisms to clinically relevant treatments in childhood rhabdomyosarcoma

Aim:Despite aggressive multiagent protocols,patients with metastatic rhabdomyosarcoma(RMS)have poor prognosis.In a recent high-risk trial(ARST0431),25% of patients failed within the first year,while on therapy and 80% had tumor progression within 24 months.However,the mechanisms for tumor resistance are essentially unknown.Here we explore the use of preclinical models to develop resistance to complex chemotherapy regimens used in ARST0431.Methods:A Single Mouse Testing(SMT)protocol was used to evaluate the sensitivity of 34 RMS xenograft models to one cycle of vincristine,actinomycin D,cyclophosphamide(VAC)treatment.Tumor response was determined by caliper measurement,and tumor regression and event-free survival(EFS)were used as endpoints for evaluation.Treated tumors at regrowth were transplanted into recipient mice,and the treatment was repeated until tumors progressed during the treatment period(i.e.,became resistant).At transplant,tumor tissue was stored for biochemical and omics analysis.Results:The sensitivity to VAC of 34 RMS models was determined.EFS varied from 3 weeks to>20 weeks.Tumor models were classified as having intrinsic resistance,intermediate sensitivity,or high sensitivity to VAC therapy.Resistance to VAC was developed in multiple models after 2-5 cycles of therapy;however,there were examples where sensitivity remained unchanged after 3 cycles of treatment.Conclusion:The SMT approach allows for in vivo assessment of drug sensitivity and development of drug resistance in a large number of RMS models.As such,it provides a platform for assessing in vivo drug resistance mechanisms at a“population”level,simulating conditions in vivo that lead to clinical resistance.These VAC-resistant models represent“high-risk”tumors that mimic a preclinical phase 2 population and will be valuable for identifying novel agents active against VAC-resistant disease.

Does burning fat make tumor immune hot? Discovery of cD47 overexpression by radiation induced fatty acid oxidation

Although extensively studied,it is unknown what is the major cellular energy driving tumor metastasis after anti-cancer radiotherapy.Metabolic reprogramming is one of the fundamental hallmarks in carcinogenesis and tumor progression featured with the increased glycolysis in solid tumors.However,accumulating evidence indicates that in addition to the rudimentary glycolytic pathway,tumor cells are capable of reactivating mitochondrial OxPHOS under genotoxic stress condition to meet the increasing cellular fuel demand for repairing and surviving anti-cancer radiation.Such dynamic metabolic rewiring may play a key role in cancer therapy resistance and metastasis.Interestingly,data from our group and others have demonstrated that cancer cells can re-activate mitochondrial oxidative respiration to boost an annexing energy to meet the increasing cellular fuel demand for tumor cells surviving genotoxic anti-cancer therapy with metastatic potential.

Bidirectional crosstalk between therapeutic cancer vaccines and the tumor microenvironment:Beyond tumor antigens

Immunotherapy has rejuvenated cancer therapy,especially after anti-PD-(L)1 came onto the scene.Among the many therapeutic options,therapeutic cancer vaccines are one of the most essential players.Although great progress has been made in research on tumor antigen vaccines,few phase III trials have shown clinical benefits.One of the reasons lies in obstruction from the tumor microenvironment(TME).Meanwhile,the therapeutic cancer vaccine reshapes the TME in an ambivalent way,leading to immune stimulation or immune escape.In this review,we summarize recent progress on the interaction between therapeutic cancer vaccines and the TME.With respect to vaccine resistance,innate immunosuppressive TME components and acquired resistance caused by vaccination are both involved.Understanding the underlying mechanism of this crosstalk provides insight into the treatment of cancer by directly targeting the TME or synergizing with other therapeutics.

An Alternative Low-Cost Strategy for Simultaneous Sensitive Detection of Adjacent ESR1 Mutations in Single Circulating Tumor Cell

ESR1 mutation is of great clinical significance and being promoted as a marker of resistance to endocrine therapy in breast cancers.However,it is a challenging task to detect ESR1 mutations from traditional biopsies and cell-free DNA(cfDNA),especially for polyclonal mutations.This is mainly attributed to massive wild-type background and the low-abundance of the mutations.Here,using one-step single-cell amplification coupling with pyrosequencing,we developed and validated an original strategy for simultaneous sensitive detection of adjacent ESR1 mutations in single circulating tumor cell(CTC)from breast cancers.Unlike expensive single-cell sequencing used in previous studies,the strategy does not require complicated two-step amplification or high-cost single-cell amplification kits.Three pivotal parts involved in the strategy are collection of CTCs from whole blood of breast cancer patients,one-step single-cell amplification and pyrosequencing of single-cell amplicons.To achieve better e fficiency of one-step single-cell amplification for pyrosequencing,a set of experimental conditions were thoroughly trialed.The developed strategy enabled a highly specific detection of the ESR1 hotspot mutations from large wild-type background with the specificity as low as 1%and a high sensitivity of two copies of artificial samples or single-cell level and pretty good quantitative accuracy(R^(2)≥0.9888).Using this strategy,141 single CTCs from 11 cases of breast cancer patients were identified and collected,126 of which were successfully analyzed with a high rate of 89.4%.These results indicate that the cost-effective and reliable strategy could be used for clinical management,showing promising application in the treatment decision-making of breast cancer patients.

The cutting-edge progress of immune-checkpoint blockade in lung cancer

Great advances in immune checkpoint blockade have resulted in a paradigm shift in patients with lung cancer.Immune-checkpoint inhibitor(ICI)treatment,either as monotherapy or combination therapy,has been established as the standard of care for patients with locally advanced/metastatic non-small cell lung cancer without EGFR/ALK alterations or extensive-stage small cell lung cancer.An increasing number of clinical trials are also ongoing to further investigate the role of ICIs in patients with early-stage lung cancer as neoadjuvant or adjuvant therapy.Although PD-L1 expression and tumor mutational burden have been widely studied for patient selection,both of these biomarkers are imperfect.Due to the complex cancer-immune interactions among tumor cells,the tumor microenvironment and host immunity,collaborative efforts are needed to establish a multidimensional immunogram to integrate complementary predictive biomarkers for personalized immunotherapy.Furthermore,as a result of the wide use of ICIs,managing acquired resistance to ICI treatment remains an inevitable challenge.A deeper understanding of the underlying biological mechanisms of acquired resistance to ICIs is helpful to overcome these obstacles.In this review,we describe the cutting-edge progress made in patients with lung cancer,the optimal duration of ICI treatment,ICIs in some special populations,the unique response patterns during ICI treatment,the emerging predictive biomarkers,and our understanding of primary and acquired resistance mechanisms to ICI treatment.