癌症耐药(英文)最新文献

{"title":"An epithelial-mesenchymal transition-related gene signature predicts prognosis, immune infiltration, and drug sensitivity in colorectal cancer.","authors":"Xiaonan Shen, Hao Zhong, Wenqing Jia, Zichao Guo, Haiqin Song, Zhenghao Cai, Xi Cheng, Jianwen Li, Bo Feng, Haoran Feng, Fei Yue","doi":"10.20517/cdr.2026.37","DOIUrl":"10.20517/cdr.2026.37","url":null,"abstract":"<p><p><b>Aim:</b> Colorectal cancer (CRC) ranks among the most prevalent malignancies across the globe, with treatment resistance often closely linked to the complexity of the tumor microenvironment (TME). This study aims to establish a gene signature associated with epithelial-mesenchymal transition (EMT) that integrates TME dynamics, prognosis prediction, and drug resistance assessment in CRC. <b>Methods:</b> We employed the Cancer Genome Atlas (TCGA) resource and bulk RNA-sequencing profiles linked to EMT to identify common differentially expressed genes (DEGs). An eight-gene signature was constructed using multivariable Cox regression analysis. The correlations of risk groups (scores) with overall survival, biological characteristics, and drug sensitivity were analyzed in CRC patients. <b>Results:</b> Patients in the high-risk group exhibited significantly worse clinical outcomes than those in the low-risk group. Moreover, a lower risk score was significantly correlated with increased responsiveness to both immune checkpoint inhibitors and 5-fluorouracil in CRC patients. Additionally, experiments <i>in vitro</i> and <i>in vivo</i> confirmed that FABP4 functions as an oncogene in CRC by facilitating cell growth, migration, and chemotherapy resistance. <b>Conclusion:</b> The EMT-associated gene signature holds significant value for predicting clinical prognosis, immunotherapy responsiveness, and chemotherapy sensitivity in CRC.</p>","PeriodicalId":70759,"journal":{"name":"癌症耐药(英文)","volume":"9 ","pages":"25"},"PeriodicalIF":4.6,"publicationDate":"2026-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13459117/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148714664","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lack of resolution of inflammation marks malignant pleural mesothelioma progression.","authors":"Veronica Gatti, Matti van Welzen, Alessandro Napoli, Marc Dubourdeau, Marta Tiberi, Andrea Marra, Giorgia Giorgi, Clémence Gély, Veronica Ceci, Olaf Wolkenhauer, Tommaso Mazza, Shailendra Gupta, Mario Cioce, Valerio Chiurchiù, Vito Michele Fazio","doi":"10.20517/cdr.2026.33","DOIUrl":"10.20517/cdr.2026.33","url":null,"abstract":"<p><p><b>Aim:</b> Malignant pleural mesothelioma (MPM) is a paradigmatic inflammation-associated cancer and a major therapeutic challenge due to its resistance to treatment. Inflammation is thought to promote both tumor progression and therapy resistance. Senescence-associated secretory phenotype (SASP)-mediated, chemotherapy-induced release of arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) contributes to pemetrexed resistance in MPM cells <i>in vitro</i>. <b>Methods:</b> Pro-inflammatory mediators (PIMs) and specialized pro-resolving mediators (SPMs) were quantified in pleural exudates using liquid chromatography-tandem mass spectrometry. Single-cell RNA-sequencing datasets were analyzed to assess the distribution of SPM-producing enzymes between mesothelial and mesothelioma cells in both tumor tissue and uninvolved pleura. Least Absolute Shrinkage and Selection Operator regression (LASSO) was used to derive a composite prognostic score (CPS) from SPM-related gene expression. <b>Results:</b> Chemotherapy-treated patients exhibited a reduction in SPMs - including resolvins, protectins, and maresins - alongside increased prostaglandin levels. Single-cell analysis revealed differential partitioning of SPM-producing enzymes, with lower expression in mesothelioma cells compared with mesothelial cells. A five-gene CPS derived from this lipid mediator landscape independently predicted overall survival beyond conventional clinical parameters. <b>Conclusion:</b> Chemotherapy alters the lipid mediator composition of pleural exudates in MPM by reducing SPMs, thereby disrupting resolution pathways. This effect is consistent with an intrinsic imbalance in expression between mesothelial and mesothelioma cells. Together, these findings suggest that impaired resolution of inflammation contributes to a pro-tumorigenic, pro-inflammatory, and chemoresistant microenvironment in MPM, with potential prognostic implications.</p>","PeriodicalId":70759,"journal":{"name":"癌症耐药(英文)","volume":"9 ","pages":"24"},"PeriodicalIF":4.6,"publicationDate":"2026-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13459112/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148714579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LINC01607 promotes hepatocellular carcinoma progression and ferroptosis-associated therapy resistance with functional involvement of the p62-Keap1-Nrf2 pathway.","authors":"Yuxin Zhang, Weiqi Xu, Fangling Cheng, Jinghan Zhu, Yuanxiang Lu, Guangzhen Cai, Jiang Li, Yujie Zhang","doi":"10.20517/cdr.2026.02","DOIUrl":"10.20517/cdr.2026.02","url":null,"abstract":"<p><p><b>Aim:</b> Hepatocellular carcinoma (HCC) remains a formidable worldwide health challenge, characterized by inadequate treatment efficacy and unsatisfactory clinical prognosis. Our previous study implicated LINC01607 in lenvatinib resistance, but its role in HCC progression and ferroptosis-associated vulnerability remains unclear. <b>Methods:</b> LINC01607 expression was examined in HCC patient samples and The Cancer Genome Atlas datasets. Cellular, animal, and patient-derived organoid (PDO) models were used to evaluate its biological function. RNA sequencing, ferroptosis-related assays, rescue experiments, and drug-sensitivity analyses were performed to explore associated downstream pathways. <b>Results:</b> LINC01607 was upregulated in HCC tissues and associated with aggressive clinicopathological features and poor survival. Functional assays showed that LINC01607 promoted HCC cell proliferation, migration, invasion, tumor growth, and metastasis. LINC01607 depletion induced ferroptosis-associated changes, including increased lipid peroxidation, glutathione depletion, and Fe²⁺ accumulation under ferroptotic stress, which were partially reversed by ferroptosis inhibitors. LINC01607 knockdown also enhanced sensitivity to RSL3 and sorafenib, while ferrostatin-1 partially rescued the increased sorafenib sensitivity. RNA sequencing and rescue experiments suggested involvement of the p62-Keap1-Nrf2 pathway. LINC01607 depletion was associated with reduced SQSTM1/p62, Nrf2, and ferroptosis-resistance proteins, whereas p62 overexpression partially reversed these effects and Nrf2 knockdown abrogated the rescue. In xenograft and PDO models, LINC01607 depletion improved the response to sorafenib. <b>Conclusion:</b> LINC01607 contributes to HCC progression and ferroptosis-associated therapy resistance, at least in part through the p62-Keap1-Nrf2 pathway, supporting further investigation of LINC01607 as a potential therapeutic target.</p>","PeriodicalId":70759,"journal":{"name":"癌症耐药(英文)","volume":"9 ","pages":"23"},"PeriodicalIF":4.6,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13459114/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148714742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unveiling the role of UGT enzymes in chemoresistance: a path to enhanced cancer pharmacotherapy.","authors":"Gesine Kretzschmar, Youssif Budagaga, Lisa Groß, Jan-Heiner Küpper, Sarah Kammerer, Jakub Hofman","doi":"10.20517/cdr.2026.10","DOIUrl":"10.20517/cdr.2026.10","url":null,"abstract":"<p><p><b>Aim:</b> Chemotherapeutic resistance is a leading cause of cancer-related mortality worldwide. It has been suggested to be at least partly driven by the activity of uridine diphosphate glucuronosyltransferases (UGTs). However, this hypothesis is primarily supported by indirect evidence with potential confounding factors arising from the use of multienzymatic models among other things. Here we present new HepG2 models transduced with UGT1A1 or UGT2B7 that provide mechanistic insights into the potential role of UGTs in resistance to SN-38, etoposide, and epirubicin. <b>Methods:</b> The new cellular models were characterised by immunofluorescence, quantitative real-time PCR, and doubling-time assessment. Possible differences in chemotherapeutic efficacy were evaluated using comparative ATP viability assays and an inhibitor-based verification study. Drug combination assays were conducted to determine whether dual-activity modulation could combat enzyme-mediated resistance, using the quantitative Chou-Talalay method to detect synergistic effects. Finally, an advanced physiologically relevant model based on proliferating primary upcyte hepatocytes was characterised and used to verify the results obtained with the transduced models. <b>Results:</b> The comparative ATP viability assays and verification studies using the UGT inhibitors atazanavir and diclofenac confirmed that both UGT enzymes significantly reduced the tested drugs' pharmacodynamic activity. Drug combination experiments then showed that UGT1A1 activity can be synergistically targeted by nilotinib and regorafenib via a new dual-activity modulation approach. Finally, the role of UGT1A1 in resistance to SN-38 was confirmed in a complex model based on primary upcyte hepatocytes. <b>Conclusion:</b> After <i>in vivo</i> confirmation, our findings could potentially be translated into effective and safe combination regimens for oncology patients.</p>","PeriodicalId":70759,"journal":{"name":"癌症耐药(英文)","volume":"9 ","pages":"22"},"PeriodicalIF":4.6,"publicationDate":"2026-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13352430/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148426938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A systematic review and network meta analysis of first-line immunotherapy for advanced urothelial carcinoma.","authors":"Yang Liu, Yuxuan Song, Jilin Wu, Jincong Li, Wenbo Yang, Yiqing Du, Caipeng Qin, Tao Xu","doi":"10.20517/cdr.2026.22","DOIUrl":"10.20517/cdr.2026.22","url":null,"abstract":"<p><p><b>Aim:</b> To compare the efficacy and safety of first-line systemic therapies for advanced urothelial carcinoma (UC) and identify the relative benefit-risk profiles of available regimens. <b>Methods:</b> We conducted a systematic review and Bayesian random-effects network meta-analysis of randomized controlled trials evaluating first-line systemic therapies for advanced UC (INPLASY2025100112). PubMed, Embase, and the Cochrane Library were searched from inception to November 30, 2025. Time-to-event outcomes were summarized as hazard ratios (HRs) with 95% credible intervals (CrIs) for overall survival (OS) and progression-free survival (PFS), and binary outcomes were summarized as odds ratios (ORs) with 95%CrIs for objective response rate (ORR) and grade ≥ 3 adverse events (AEs). <b>Results:</b> Thirteen trials comparing 10 regimens were included. Immune checkpoint inhibitor plus antibody-drug conjugate (ICI+ADC) was associated with the largest estimated improvements in OS, PFS, and ORR (OS: HR 0.47, 95%CrI 0.37-0.63; PFS: HR 0.45, 95%CrI 0.33-0.63; ORR: OR 2.70, 95%CrI 1.60-4.60) and showed consistent improvements across both cisplatin-eligible and cisplatin-ineligible patients. ICI plus chemotherapy (ICI+Chemo) also improved OS (HR 0.83, 95%CrI 0.70-0.96) and PFS (HR 0.78, 95% CrI 0.63-0.95). ICI monotherapy was associated with the lowest odds of grade ≥ 3 AEs (OR 0.11, 95%CrI 0.03-0.44) but ranked lowest for efficacy. <b>Conclusion:</b> ICI+ADC may represent a promising first-line option when available. ICI+Chemo remains an appropriate alternative, whereas ICI monotherapy may be reserved for patients unsuitable for combination therapy.</p>","PeriodicalId":70759,"journal":{"name":"癌症耐药(英文)","volume":"9 ","pages":"21"},"PeriodicalIF":4.6,"publicationDate":"2026-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13352428/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148426988","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fenretinide in cancer therapy and chemoprevention: past, present and future.","authors":"Paola Verachi, Federica Francescangeli, Rosanna Dattilo, Alessandro Vici, Rachele Rossi, Elena Landolfo, Maria Laura De Angelis, Ann Zeuner","doi":"10.20517/cdr.2025.210","DOIUrl":"10.20517/cdr.2025.210","url":null,"abstract":"<p><p>Fenretinide [N-(4-hydroxyphenyl) retinamide, 4-HPR] is a synthetic retinoid known for decades for its antitumor activity and favorable toxicological profile. <i>In vitro</i> and <i>in vivo</i> studies have demonstrated that fenretinide has broad-spectrum anticancer potential, eliciting multiple biological effects and acting as a multi-target compound that influences both tumor cells and the tumor microenvironment. However, the clinical application of fenretinide has been hampered by unfavorable physicochemical properties, such as poor solubility and low bioavailability, leading to highly variable outcomes in clinical studies. The development of novel fenretinide nanoformulations based on drug encapsulation in nanomicelles has helped overcome bioavailability limitations and improve anticancer efficacy in preclinical studies, thereby paving the way for new clinical opportunities. Moreover, recent studies have shown that fenretinide restrains the cancer stem cell compartment and promotes tumor cell dormancy, suggesting its potential use in dormancy-inducing strategies aimed at preventing and/or controlling metastatic disease. Here, we provide an overview of fenretinide's mechanisms of action in cancer cells, summarize the available clinical evidence and discuss advances achieved with novel formulations. Finally, we discuss the potential integration of fenretinide at different stages of clinical management, with particular emphasis on its prospective use as a chemopreventive strategy or as a therapeutic option for disease control.</p>","PeriodicalId":70759,"journal":{"name":"癌症耐药(英文)","volume":"9 ","pages":"20"},"PeriodicalIF":4.6,"publicationDate":"2026-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13352429/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148426946","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deep spatial proteomics reveals a suppressive immune niche linked to immune evasion in renal cell carcinoma.","authors":"Yujia Zhang, Yicheng Zhu, Zichang Liu, Haonan Li, Bingxu Zhong, Xingang Cui, Yan Kong, Hui Lu","doi":"10.20517/cdr.2026.27","DOIUrl":"10.20517/cdr.2026.27","url":null,"abstract":"<p><p><b>Aim:</b> Clear cell renal cell carcinoma (ccRCC) presents an \"immune paradox\" where high CD8⁺ T cell infiltration correlates with poor survival and limited response to immune checkpoint blockade (ICB). Simple cell density metrics fail to capture the functional state of the immune microenvironment, suggesting an uncharacterized spatial mechanism underlying immune evasion and poor clinical outcomes. We aimed to develop an AI-driven spatial proteomics framework to decode this immunosuppressive phenotype. <b>Methods:</b> We developed PhenoSSP, a hierarchical deep learning framework based on a Vision Transformer backbone, designed for single-cell phenotyping from 7-channel multiplex immunofluorescence (mIF) images. It was applied to 1,633 tissue microarray (TMA) cores from 834 ccRCC patients. We defined a density-normalized Spatial Interaction Score was defined to quantify FOXP3⁺ regulatory T cell (Treg) enrichment within a 30 μm radius of CD8⁺ T cells. Survival analyses were performed using Kaplan-Meier curves with log-rank tests and multivariable Cox regression models. <b>Results:</b> PhenoSSP achieved a balanced accuracy of 71.0% and an F1-Macro of 70.7%, outperforming conventional methods. CD8⁺ T-cell density alone was not significantly associated with overall survival (OS, <i>P</i> = 0.057), whereas the Spatial Interaction Score was significantly associated with poor OS (log-rank test, <i>P</i> = 0.012) and was significantly higher in non-survivors (<i>P</i> = 0.032). <b>Conclusion:</b> This study reveals a spatial basis for immune evasion and poor prognosis in ccRCC: the pre-existing Treg enrichment near CD8⁺ T cells, rather than the abundance of effector cells, was associated with impaired antitumor immunity. The Spatial Interaction Score serves as a candidate prognostic biomarker and provides a rationale for Treg-targeting combination strategies in patients harboring spatially defined suppressive niches.</p>","PeriodicalId":70759,"journal":{"name":"癌症耐药(英文)","volume":"9 ","pages":"19"},"PeriodicalIF":4.6,"publicationDate":"2026-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13244267/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148213527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TRAP1 ablation improves mitochondrial cristae and oxidative phosphorylation in pancreatic cancer stem cells.","authors":"Giulia Ambrosini, Elisa Dalla Pozza, Ilaria Cristanini, Sara Vinco, Enrica Cappellozza, Barbara Cisterna, Claudio Laquatra, Andrea Rasola, Emanuela Bottani, Ilaria Dando","doi":"10.20517/cdr.2025.229","DOIUrl":"10.20517/cdr.2025.229","url":null,"abstract":"<p><p><b>Aim:</b> Cancer stem cells (CSCs) in pancreatic ductal adenocarcinoma (PDAC) display high metabolic plasticity, supporting tumor aggressiveness and therapeutic resistance. Here, we investigated the role of the mitochondrial chaperone TRAP1 in regulating mitochondrial architecture, metabolism, and adhesion in CSCs. <b>Methods:</b> We studied an <i>in vitro</i> model of CSCs using Panc1 cells and the corresponding stable TRAP1-knockout cells (TRAP1-KO). Molecular techniques used were quantitative polymerase chain reaction (qPCR), Western blot, transmission electron microscopy, and Seahorse technology. <b>Results:</b> CSCs showed increased TRAP1 expression after 2 weeks of culture, reflecting a preferential metabolic shift toward glycolysis. TRAP1 deletion impaired the ability of CSCs to form compact spheroids without altering canonical CSC traits, such as reduced proliferation, increased stem marker expression, and enhanced chemoresistance. We demonstrate that TRAP1 deletion increases <i>CDH1</i>, an effect that was reversed by succinate supplementation, indicating that the TRAP1-succinate-CDH1 axis controls adhesion-related properties. Ultrastructural analyses revealed profound mitochondrial remodeling in the absence of TRAP1: parental cells displayed enlarged, elongated mitochondria with wider cristae, whereas CSCs developed fragmented mitochondria with thinner cristae and tighter crista junctions. These alterations were closely associated with the differential regulation of mitochondrial fission factor (MFF). Functionally, loss of TRAP1 enhanced oxidative phosphorylation, leading to increased mitochondrial adenosine triphosphate (ATP) production, elevated maximal respiration, and reduced proton leak. <b>Conclusion:</b> Collectively, these findings identify TRAP1 as a critical regulator of mitochondrial organization, respiratory efficiency, and <i>CDH1</i>-mediated adhesion in PDAC CSCs, highlighting metabolic and structural vulnerabilities that may be exploited therapeutically to destabilize CSC homeostasis and enhance treatment response.</p>","PeriodicalId":70759,"journal":{"name":"癌症耐药(英文)","volume":"9 ","pages":"17"},"PeriodicalIF":4.6,"publicationDate":"2026-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13244268/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148213515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Overcoming resistance to anti-PD-1/PD-L1 therapy in cancer.","authors":"Lijun Li, Yanbin Zhao, Xinhong Shi, Xiaotian Guo, Xiaoxin Zhang, Guangrui Li, Qingwei Meng, Minghui Zhang, Mingzhu Yin","doi":"10.20517/cdr.2026.12","DOIUrl":"10.20517/cdr.2026.12","url":null,"abstract":"<p><p>Recently, programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors have achieved major breakthroughs in oncology, with 32 drugs approved over the past decade. This advancement has established immunotherapy as the fifth major antitumor modality following surgery, chemotherapy, radiotherapy, and targeted therapy. However, PD-1/PD-L1 inhibitors induce sustained responses in only a limited number of patients, and primary and acquired resistance remain critical challenges in clinical practice. As understanding of the complex crosstalk among cancer cells, the tumor microenvironment, and the host immune system deepens, numerous strategies to overcome PD-1/PD-L1 inhibitor resistance have been proposed. In this review, we examine the current development of PD-1/PD-L1 inhibitors, analyze global approval trends, and evaluate their monotherapy efficacy across various tumor types. As multi-target combination therapy is an essential strategy for overcoming resistance, we analyze key combination targets - such as vascular endothelial growth factor (VEGF), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and lymphocyte activation gene 3 (LAG-3) - and highlight the clinical success of novel dual-target regimens such as ivonescimab (PD-1/VEGF). Furthermore, we discuss potential approaches to overcoming resistance from both microenvironmental (e.g., targeting cancer-associated fibroblasts or utilizing antibody-drug conjugates) and macroenvironmental (e.g., modulating the microbiota or sex hormones) perspectives. This review provides a forward-looking framework for designing precision- and mechanism-driven combination therapies aimed at converting non-responders into responders.</p>","PeriodicalId":70759,"journal":{"name":"癌症耐药(英文)","volume":"9 ","pages":"18"},"PeriodicalIF":4.6,"publicationDate":"2026-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13244269/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148213476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor heterogeneity as a driver of drug resistance and its implications for personalized therapy.","authors":"Erhan Da, Ronglan Zhu, Bin Xi, Liyang Zhang, Guodong Tang","doi":"10.20517/cdr.2025.216","DOIUrl":"10.20517/cdr.2025.216","url":null,"abstract":"<p><p>Tumors are highly dynamic diseases characterized by significant heterogeneity. They consist of multiple cellular populations with distinct properties that respond differently to therapeutic pressure. This heterogeneity may arise from spatial variation across tumor regions (spatial heterogeneity) as well as from temporal changes during tumor evolution and treatment (temporal heterogeneity). As a consequence, drug-resistant subclones often emerge under therapy and contribute to treatment failure. Advances in single-cell and spatial multi-omics technologies enable precise quantification of tumor heterogeneity, supporting detailed investigation of how heterogeneity contributes to chemoresistance and informing the development of personalized therapeutic strategies. In this review, we summarize the evolutionary dynamics underlying the emergence of tumor drug resistance and examine the molecular mechanisms responsible for failure of targeted therapies. We highlight how advances in single-cell and spatial multi-omics have significantly improved our ability to elucidate these processes. We further suggest that addressing tumor drug resistance may require a shift from static, single-target approaches toward dynamic, biology-informed personalized strategies. Integrating high-resolution multi-omics monitoring with functional validation could enable identification of subclonal vulnerabilities, support adaptive treatment adjustment, and contribute to more durable clinical responses.</p>","PeriodicalId":70759,"journal":{"name":"癌症耐药(英文)","volume":"9 ","pages":"16"},"PeriodicalIF":4.6,"publicationDate":"2026-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13244270/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148213464","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}