Cancer letters最新文献

{"title":"The epigenetic landscape of tumor-associated macrophages: orchestrating immune evasion in the tumor microenvironment","authors":"Xiaodie Liu ,&nbsp;Hongqi Li ,&nbsp;Ming Yuan ,&nbsp;Jipeng Wan ,&nbsp;Jianbin Guo ,&nbsp;Xiaoyu Dong ,&nbsp;Xueyang Jin ,&nbsp;Chunrun Yang ,&nbsp;Guoyun Wang","doi":"10.1016/j.canlet.2025.217972","DOIUrl":"10.1016/j.canlet.2025.217972","url":null,"abstract":"<div><div>Tumor-associated macrophages (TAMs), the predominant immune cell population within the tumor immune microenvironment (TIME), play a vital role in promoting immune evasion and driving tumor progression. Beyond their well-established roles in reprogramming oncogenic signaling and silencing tumor suppressors, emerging evidence highlights that epigenetic modifications also critically shape the immunogenic landscape of tumors by modulating the phenotype and function of infiltrating immune cells. The TIME imposes persistent metabolic and inflammatory stressors—such as hypoxia, nutrient deprivation, and lactate accumulation—that profoundly influence the epigenetic and transcriptional states of TAMs, promoting their phenotypic plasticity and skewing them toward immunosuppressive, pro-tumoral phenotypes. Notably, this dynamic and reversible reprogramming closely parallels the defining features of epigenetic regulation, which is inherently sensitive to environmental stimuli and governs cellular identity. In this review, we comprehensively examine how extracellular cues within the TME rewire the expression and activity of key epigenetic regulators in TAMs, activate downstream signaling pathways, and reshape their molecular functions to reinforce tumor-supportive programs. Deciphering these epigenetic circuits provides a framework for therapeutic strategies aimed at re-educating TAMs toward anti-tumor phenotypes and enhancing the efficacy of immunotherapies.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"632 ","pages":"Article 217972"},"PeriodicalIF":10.1,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144803586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of succinate dehydrogenase subunit B-deficient tumor models for preclinical immunotherapy testing.","authors":"Katerina Hadrava Vanova, Ondrej Uher, Michal Kraus, Sona Miklovicova, Katerina Honigova, Stanislaw Gwiezdzinski, Timothy J Garrett, Hans Ghayee, Michal Masarik, Herui Wang, Zhengping Zhuang, Jiri Neuzil, Chunzhang Yang, Karel Pacak","doi":"10.1016/j.canlet.2025.217969","DOIUrl":"10.1016/j.canlet.2025.217969","url":null,"abstract":"<p><p>Immunotherapy has advanced the treatment landscape for many challenging cancers by harnessing the immune system to eliminate tumor cells. However, its efficacy in rare tumors such as pheochromocytoma and paraganglioma (PCC/PGL), particularly those with succinate dehydrogenase B (SDHB) mutations, remains underexplored. These tumors often exhibit complex tumor microenvironments and immune evasion mechanisms, and their low incidence hinders clinical trials development. Together, these challenges underscore the need for robust preclinical models that closely mirror human disease and support therapeutic discovery. In this study, we developed and characterized murine models of SDHB-deficient tumors using CRISPR-mediated gene editing in pheochromocytoma (MPC and MTT) and renal carcinoma (RenCa) cell lines. These models recapitulate key metabolic and immunological features of human SDHB-mutated tumors, which exhibit loss of SDHB protein expression, providing a relevant platform for evaluating immunotherapeutic strategies. We subsequently tested intratumoral immunotherapy with Mannan-BAM, TLR ligands, and an Anti-CD40 antibody (MBTA), a combination designed to overcome tumor-induced immune suppression. Our results indicate that SDHB-deficient PCC tumors exhibit increased antigen presentation and strong immune activation, leading to rejection or delayed progression in immunocompetent mice. In contrast, Sdhb knock-out RenCa tumors consistently formed, allowing therapeutic testing. MBTA therapy effectively eradicated these tumors, prevented metastasis, and induced long-term immune memory. These findings highlight the value of genetically engineered, tissue-specific murine models in predicting immunotherapy outcomes in rare cancers. Moreover, they support the therapeutic potential of MBTA for treating SDHB-deficient renal cell carcinoma and provide a rationale for further translational studies.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"217969"},"PeriodicalIF":10.1,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144798236","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cancer stem cell enrichment in in vitro models: Techniques, insights, and applications","authors":"Fazeleh Ranjbar-Niavol ,&nbsp;Maryam Barisam ,&nbsp;Arezoo Khosravi ,&nbsp;Navid Kashaninejad ,&nbsp;Ali Zarrabi ,&nbsp;Massoud Vosough","doi":"10.1016/j.canlet.2025.217966","DOIUrl":"10.1016/j.canlet.2025.217966","url":null,"abstract":"<div><div>Due to the substantial role of cancer stem cells (CSCs) in therapeutic resistance and metastasis, the study of them is of great importance. However, their low abundance within the tumor cells makes it challenging to study their molecular pathophysiology. This limitation highlighted the critical need for reliable enrichment techniques to provide enough cells for in vitro tests. This review focuses on various methods that implemented for enrichment of cancer stem-like cells’ subpopulations from the heterogeneous population of cancer cells. In this regard, various key physicochemical parameters such as hypoxia, shear stress, high glucose concentration, autophagy, and chemotherapy-induced stress have been explored for their potential to enhance CSC enrichment. The results presented in the literature confirmed that modifying these parameters can improve the enrichment of CSCs by promoting stem-like cells phenotype. However, there is still a necessity for comprehensive studies that compare the impact of these parameters on CSC enrichment, which should be addressed in future works.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"632 ","pages":"Article 217966"},"PeriodicalIF":10.1,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144770584","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondria-centric lipid metabolism and inter-organelle crosstalk in pancreatic Cancer: Unveiling novel therapies","authors":"Runxian Wang ,&nbsp;Changhao Gao ,&nbsp;Zhiyao Fan ,&nbsp;Qingdi Qin,&nbsp;Hanxiang Zhan","doi":"10.1016/j.canlet.2025.217965","DOIUrl":"10.1016/j.canlet.2025.217965","url":null,"abstract":"<div><div>Pancreatic cancer is an aggressive malignancy with poor therapeutic responses to conventional treatments, partly due to its unique proliferation and drug resistance. This review focuses on the lipid metabolism in pancreatic cancer cells, emphasizing the crosstalk between mitochondria and other organelles. It highlights the importance of cellular membranes, endoplasmic reticulum, lipid droplets, and mitochondria in lipid transportation and metabolism, which are crucial for energy supplementation and cell structure to resist chemotherapy in pancreatic cancer. The review also discusses how these organelles interact to support the malignancy and suggests that lipid metabolism-regulating drugs targeting different organelles could overcome the resistance of treatments like gemcitabine. Moreover, it points out the role of mitochondrial and other organelles in the PD-L1 regulation of pancreatic cancer, indicating potential for novel therapeutic strategies.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"632 ","pages":"Article 217965"},"PeriodicalIF":10.1,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144768388","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel oncolytic poxvirus carrying CD47 nanomabs in the treatment of pancreatic cancer by reshaping the immune microenvironment.","authors":"Zheling Chen, Yu Cai, Keju Zhao, Anchen Qiu, Yanan Zhai, Shuting Jiang, Jingyi Pan, Peng Zhang, Hanchu Xiong, Qian Ye, Yunhua Liu, Liu Yang","doi":"10.1016/j.canlet.2025.217934","DOIUrl":"10.1016/j.canlet.2025.217934","url":null,"abstract":"<p><p>Pancreatic cancer remains a highly aggressive malignancy with limited treatment options. Recent advances have identified CD47 as a promising therapeutic target, though clinical translation faces challenges due to the complex immunosuppressive tumor microenvironment (TME). Here we developed an innovative oncolytic vaccinia virus platform expressing an anti-CD47 nanobody (OVV-aCD47nb), designed to simultaneously target tumor cells and modulate immune responses. Our in vitro studies demonstrated that OVV-aCD47nb effectively infected and replicated in pancreatic cancer cells while secreting functional aCD47nb that specifically bound to tumor cell surfaces. In vivo evaluation revealed remarkable therapeutic efficacy, with significant inhibition of primary tumor growth, suppression of contralateral and metastatic lesions, and substantial extension of survival in multiple pancreatic cancer models. Notably, the treatment induced robust and durable immune memory, providing protection against tumor rechallenge. At the mechanistic level, comprehensive analysis showed that OVV-aCD47nb induced profound remodeling of the TME, characterized by increased infiltration of cytotoxic CD8⁺ T cells, NK cells, and tumor-suppressive M1 macrophages. Through detailed T cell activation assays, we elucidated that virus-activated macrophages secreted key chemokines (CXCL9), creating a pro-inflammatory microenvironment that enhanced T cell recruitment and activation. Furthermore, the treatment upregulated PD-L1 expression in the TME, and combination therapy with PD-L1 blockade demonstrated synergistic anti-tumor effects, significantly improving survival outcomes. These findings establish OVV-aCD47nb as a multifaceted immunotherapeutic that reprograms the TME through coordinated immune activation. The macrophage-mediated T cell activation via chemokine signaling, combined with PD-L1 blockade, presents a transformative approach for pancreatic cancer with strong clinical potential.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"217934"},"PeriodicalIF":10.1,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144774731","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BCL-2/BCL-XL dual inhibition triggers Gasdermin D-mediated pyroptosis in mantle cell lymphoma","authors":"Yijing Li ,&nbsp;Joseph McIntosh ,&nbsp;Vivian Jiang ,&nbsp;Fangfang Yan ,&nbsp;Jovanny Vargas ,&nbsp;Yuxuan Che ,&nbsp;Wei Wang ,&nbsp;Ching-Fei Li ,&nbsp;Yue Fei ,&nbsp;Celeste Lee ,&nbsp;Lei Nie ,&nbsp;Yixin Yao ,&nbsp;Michael Wang ,&nbsp;Heng-Huan Lee ,&nbsp;Yang Liu","doi":"10.1016/j.canlet.2025.217961","DOIUrl":"10.1016/j.canlet.2025.217961","url":null,"abstract":"","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"632 ","pages":"Article 217961"},"PeriodicalIF":10.1,"publicationDate":"2025-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144763752","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The ALDH2-PKC delta-SHMT2 axis regulates cellular metabolic plasticity to promote leukemia stem cells self-renewal and evasion of chemotherapy in AML","authors":"Xiuying Hu ,&nbsp;Tianzhen Hu ,&nbsp;Shuyun Cao ,&nbsp;Lin Zheng ,&nbsp;Ming Ni ,&nbsp;Qin Shang ,&nbsp;Yanju Li ,&nbsp;Hong Luo ,&nbsp;Naiqin Zhao ,&nbsp;Li Wang ,&nbsp;Yaming Zhang ,&nbsp;Jiangyuan Zhao ,&nbsp;Bingqing Cheng ,&nbsp;Chengyun Pan ,&nbsp;Tianzhuo Zhang ,&nbsp;Li Jiang ,&nbsp;Qian Kang ,&nbsp;Qin Fang ,&nbsp;Jishi Wang","doi":"10.1016/j.canlet.2025.217963","DOIUrl":"10.1016/j.canlet.2025.217963","url":null,"abstract":"<div><div>Leukemia stem cells (LSCs) exhibit unique characteristics distinct from those of leukemia cells and are insensitive to conventional chemotherapeutics; thus, these cells ultimately contribute to treatment failure and relapse in acute myeloid leukemia (AML) patients. A critical challenge remains as strategies are needed to precisely target the diverse molecular drivers of leukemia stem cells (LSCs), particularly in the context of their protective microenvironment, to achieve optimal therapeutic outcomes. In this study, we investigated the role of aldehyde dehydrogenase 2 (ALDH2) in chemotherapy resistance in patients with relapsed/refractory AML and demonstrated that elevated ALDH2 expression in LSCs is closely associated with AML relapse and treatment resistance. Mechanistically, ALDH2 sustains mitochondrial homeostasis in LSCs by increasing the expression of protein kinase C delta (PKC delta) and serine hydroxymethyltransferase 2 (SHMT2), revealing a previously unidentified mechanism of metabolic reprogramming that facilitates LSC adaptation to chemotherapy-induced stress. The ALDH2‒PKC delta–SHMT2 axis plays a pivotal role in conferring resistance to chemotherapy in LSCs. Notably, rhoifolin, a compound designed to inhibit the specific binding site of ALDH2–PKC delta, significantly increased chemosensitivity. It could target LSCs within the bone marrow microenvironment, work synergistically with conventional chemotherapy drugs, and exhibit no toxicity toward normal cells. These findings underscore the therapeutic potential of targeting the ALDH2‒PKC delta axis as a novel and effective strategy for the treatment of AML and the eradication of minimal residual disease.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"632 ","pages":"Article 217963"},"PeriodicalIF":10.1,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144768389","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bacteria and tumor debris induced pancreatic cancer progression via the NF-κB signaling pathway.","authors":"Qi Chen, Yonghao Xu, Yisu Wang, Suya Zheng, Tao Yao, Junyu Qiu, Hao Qin, Tingbo Liang","doi":"10.1016/j.canlet.2025.217964","DOIUrl":"10.1016/j.canlet.2025.217964","url":null,"abstract":"<p><p>The tumor microenvironment (TME) of metastatic pancreatic ductal adenocarcinoma (PDAC) is characterized by significant cellular and spatial heterogeneity, and long-term hypoxia, leading to micronecrotic regions. PDAC clinical specimens were employed to investigate micronecrosis and we identified that bacteria and lipopolysaccharide (LPS) co-existed in PDAC tissue. Tumor-associated macrophages (TAMs) polarized by these complex components exhibit a distinct pro-inflammatory effect and correlate with drug resistance in pancreatic cancer. Single-cell data from the GEO database were used to identify differentially enrichment pathways between normal and cancer tissues. We explored the molecular mechanism of PDAC progression via macrophage-induced inflammation and immune evacuation. The bacterial components, in conjunction with PDAC debris, induced epithelial-mesenchyme transition in pancreatic cancer cells by activating nuclear factor kappa B (NF-κB) signaling and increasing programmed cell death ligand 1 (PD-L1) expression in TAMs, thus facilitating tumor progression. We then identified that CBL0137 significantly decreased PD-L1 expression by inhibiting NF-κB signaling and therapeutic efficacy was evaluated through systematic in vivo and in vitro drug experiments, Additionally, CBL0137 could synergize with gemcitabine to enhance its anti-tumor effect. Our results demonstrated the impact of necrosis and inflammation on tumor progression via TAMs and potential therapy strategies, suggesting that CBL0137 may be represented as a promising therapeutic candidate for PDAC.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"217964"},"PeriodicalIF":10.1,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144768387","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting activation of intrinsic apoptotic pathway through Mcl-1 inhibition to delay emergence of acquired resistance of lung cancer to osimertinib","authors":"Guangzhi Ma ,&nbsp;Dongsheng Wang ,&nbsp;Yunfu Deng ,&nbsp;Weijia Huang ,&nbsp;Yifan Zhai ,&nbsp;Shi-Yong Sun","doi":"10.1016/j.canlet.2025.217962","DOIUrl":"10.1016/j.canlet.2025.217962","url":null,"abstract":"<div><div>Treatment of patients with EGFR-mutant non-small cell lung cancer (NSCLC) using mutation-selective third generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs) such as osimertinib has achieved remarkable success. However, the emergence of acquired resistance is an inevitable challenge that limits the long-term remission of patients. Thus, it is critical to manage acquired resistance to osimertinib to maximize its therapeutic efficacy for long-term therapeutic benefit. To this end, taking an early intervention to delay or even prevent the emergence of acquired resistance to osimertinib offers an effective strategy. The current study suggests an effective strategy to do so through directly targeting the intrinsic apoptotic pathway via Mcl-1 inhibition. Several EGFR-mutant NSCLC cell lines with primary resistance to osimertinib possessed elevated levels of Mcl-1, which were no longer reduced by osimertinib. The combination of osimertinib with an Mcl-1 inhibitor (e.g., S63845 or APG3526) synergistically decreased the survival of these resistant cell lines with enhanced induction of apoptosis including augmentation of mitochondrial cytochrome C and Smac release. This combination effectively eliminated senescence-like drug-tolerant persister cells, which had elevated Mcl-1 levels, and abrogated emergence of acquired resistance to osimertinib as demonstrated using both <em>in vitro</em> cell culture and <em>in vivo</em> animal models. Collectively, these results convincingly demonstrate a novel and effective strategy for delaying the emergence of acquired resistance to osimertinib by targeting activation of the intrinsic apoptotic pathway through Mcl-1 inhibition, warranting further clinical validation of this strategy.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"632 ","pages":"Article 217962"},"PeriodicalIF":10.1,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144757528","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparative safety of sodium-glucose co-transporter-2 inhibitors and dipeptidyl peptidase-4 inhibitors in patients receiving anti-neoplastic therapies for cancer: An inverse probability treatment weighting analysis","authors":"Jiaxuan Lyu ,&nbsp;Katherine Specht ,&nbsp;Jacqueline A. Seiglie ,&nbsp;Tianqi Ouyang ,&nbsp;Kavita Mistry ,&nbsp;Harish Seethapathy ,&nbsp;Leyre Zubiri ,&nbsp;Si Yuan Khor ,&nbsp;Paul E. Hanna ,&nbsp;Andrew Cao ,&nbsp;Daiana Moreno ,&nbsp;Sherley M. Mejia ,&nbsp;Shruti Gupta ,&nbsp;Meghan E. Sise","doi":"10.1016/j.canlet.2025.217958","DOIUrl":"10.1016/j.canlet.2025.217958","url":null,"abstract":"","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"632 ","pages":"Article 217958"},"PeriodicalIF":10.1,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144749405","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}