Cancer letters最新文献

{"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}

{"title":"Corrigendum to “CXCR2/CXCL5 axis contributes to epithelial-mesenchymal transition of HCC cells through activating PI3K/Akt/GSK-3β/Snail signaling” [Cancer Lett. 358 2015 Pages 124–135]","authors":"Shao-Lai Zhou ,&nbsp;Zheng-Jun Zhou ,&nbsp;Zhi-Qiang Hu ,&nbsp;Xun Li ,&nbsp;Xiao-Wu Huang ,&nbsp;Zheng Wang ,&nbsp;Jia Fan ,&nbsp;Zhi Dai ,&nbsp;Jian Zhou","doi":"10.1016/j.canlet.2025.217927","DOIUrl":"10.1016/j.canlet.2025.217927","url":null,"abstract":"","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"630 ","pages":"Article 217927"},"PeriodicalIF":10.1,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144728112","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":"ECD co-operates with ERBB2 to promote tumorigenesis through upregulation of unfolded protein response and glycolysis.","authors":"Benjamin B Kennedy, Mohsin Raza, Sameer Mirza, Asher Rajkumar Rajan, Farshid Oruji, Matthew M Storck, Subodh M Lele, Timothy E Reznicek, Lusheng Li, M Jordan Rowley, Shibiao Wan, Bhopal C Mohapatra, Hamid Band, Vimla Band","doi":"10.1016/j.canlet.2025.217959","DOIUrl":"10.1016/j.canlet.2025.217959","url":null,"abstract":"<p><p>The ecdysoneless (ECD) mRNA and protein are overexpressed in breast cancer (BC), correlating with poor prognosis and shorter patient survival, particularly in ERBB2/HER2-positive BC. This study investigates the co-operative oncogenic mechanism of ECD and ERBB2 by deriving transgenic mice overexpressing ECD and/or ERBB2 (huHER2) in mammary epithelium under the MMTV promoter, as well as immortal human mammary epithelial cell lines (hMECs) overexpressing ECD and/or ERBB2. While the tumor latency and percentage of mice with tumors were similar between single and double-transgenic mice, we observed more and larger tumors in double transgenic mice in comparison to ECD or huHER2 single transgenic mice. Compared to huHER2Tg mice, which developed more homogenous solid nodular carcinomas, double transgenic mice (ECD;huHER2Tg) developed heterogenous and histologically aggressive mammary tumors with basal-like phenotype and epithelial mesenchymal transition (EMT) features, as seen in ECDTg mice and those reported in patients. ECD and ERBB2 overexpressing hMECs showed significant increase in oncogenic traits as compared to single gene expressing cells. Transcriptomic analysis revealed upregulation of two major oncogenic pathways, unfolded protein response (UPR) and glycolysis in ECD;huHER2Tg tumors as well as in ECD + ERBB2-overexpressing hMECs. ECD + ERBB2-overexpressing hMECs exhibited an increase in glucose uptake and enhanced glycolytic rate as compared to ECD or ERBB2-overexpressing hMECs. ECD as an RNA binding protein directly associated with mRNAs of three key glycolytic enzymes (LDHA, PKM2 and HK2) and mRNA of a major UPR regulated gene HSPA5, and increased mRNA stability. Knockdown of these genes resulted in decreased oncogenic traits of ECD + ERBB2 overexpressing hMECs. Taken together, our findings support a co-operative role of ECD and ERBB2 in oncogenesis by enhancing two major oncogenic pathways, UPR and glycolysis.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"217959"},"PeriodicalIF":10.1,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144752504","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":"O-GlcNAcylation of YBX1 drives a glycolysis-histone lactylation feedback loop in hepatocellular carcinoma","authors":"Yang Ji ,&nbsp;Zhenggang Xu ,&nbsp;Lei Tang ,&nbsp;Tianyu Huang ,&nbsp;Xiaoxin Mu ,&nbsp;Chuangye Ni ,&nbsp;Bai Tang ,&nbsp;Hao Lu ,&nbsp;Chuanyong Zhang ,&nbsp;Shikun Yang ,&nbsp;Xuehao Wang","doi":"10.1016/j.canlet.2025.217957","DOIUrl":"10.1016/j.canlet.2025.217957","url":null,"abstract":"<div><div>Metabolic reprogramming is a hallmark of tumorigenesis and progression, with alterations in glucose metabolism, often referred to as the Warburg effect, playing a central role. This shift allows tumor cells to rapidly acquire energy and generate essential metabolic intermediates, thereby supporting enhanced growth. Despite its significance, the mechanisms by which tumor cells upregulate glycolysis remain inadequately understood. In this study, we report that YBX1 is highly expressed in hepatocellular carcinoma (HCC) and is closely associated with glycolysis. We show that YBX1 is modified by O-linked N-acetylglucosamine (O-GlcNAc) at threonine 57 (T57), which stabilizes the protein and increases its expression. This modification also promotes the phosphorylation of YBX1 at serine 102, facilitating its nuclear translocation. Consequently, this process enhances the transcription of glycolysis-related genes and stimulates lactate production. Moreover, YBX1 activates the transcription of P300, which in turn drives the lactylation of histones, particularly H3K18la. Cleavage Under Targets and Tagmentation (CUT&amp;Tag) analysis reveals that H3K18 lactylation positively regulates YBX1 gene transcription. Our findings establish a positive feedback loop involving YBX1, glycolysis, and H3K18 lactylation that accelerates HCC progression. Disrupting this feedback loop may provide a novel therapeutic strategy for HCC.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"631 ","pages":"Article 217957"},"PeriodicalIF":10.1,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144720770","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":"OTUD3-mediated stabilization of SLC7A11 drives sunitinib resistance by suppressing ferroptosis in clear cell renal cell carcinoma","authors":"Tian Xu ,&nbsp;Huimin Liu ,&nbsp;Neng Ling ,&nbsp;Daiquan Chen ,&nbsp;Jing Dai ,&nbsp;Wenjing Chen ,&nbsp;Yuxuan Li ,&nbsp;Xirong Gao ,&nbsp;Wei Zhai ,&nbsp;Mao Ye ,&nbsp;Yang Sun ,&nbsp;Weihong Tan","doi":"10.1016/j.canlet.2025.217942","DOIUrl":"10.1016/j.canlet.2025.217942","url":null,"abstract":"<div><div>Clear cell renal cell carcinoma (ccRCC), as the main type of RCC was treated with tyrosine kinase inhibitor (TKI) at the late stage. While drug resistance is the main challenge for TKIs like sunitinib, and the underline mechanisms remain unclear. Here, we found that OTUD3 is over-expressed in ccRCC and promotes sunitinib resistance in tumor cells. OTUD3 deubiquitinates the cystine/glutamate transporter SLC7A11 and protect it from proteasome degradation, which promotes cystine transport into cells and reduces intracellular ROS levels, thereby inhibiting sunitinib-induced ferroptosis. Our findings suggest that targeting OTUD3 could be a potential strategy to enhance ferroptosis and improve the therapeutic efficacy of sunitinib in ccRCC.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"632 ","pages":"Article 217942"},"PeriodicalIF":10.1,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144724693","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":"Neoadjuvant immune checkpoint inhibition improves protection against hepatic melanoma metastasis","authors":"Sebastian A. Wohlfeil ,&nbsp;Céline Weller ,&nbsp;Bianca Dietsch ,&nbsp;Dennis Alexander Agardy ,&nbsp;Tamara Boschert ,&nbsp;Sheila A. Vormehr ,&nbsp;Christof Dormann ,&nbsp;Niklas Straub ,&nbsp;Verena Häfele ,&nbsp;Michael Platten ,&nbsp;Sergij Goerdt ,&nbsp;Cyrill Géraud","doi":"10.1016/j.canlet.2025.217950","DOIUrl":"10.1016/j.canlet.2025.217950","url":null,"abstract":"<div><h3>Background</h3><div>Liver metastasis of cutaneous melanoma (CM) correlates with a decreased response to immune checkpoint inhibition (ICI). Here, we investigated whether neoadjuvant ICI protects against liver metastasis to prevent the development of therapy resistances.</div></div><div><h3>Methods</h3><div>A stage II CM was modeled by intracutaneous injections of WT31 or B16F10 <em>luc2</em> melanoma cells. Combined ICI (anti-PD-1/anti-CTLA-4) was applied in murine models of hepatic melanoma metastasis comparing neoadjuvant or adjuvant regimens. Immune cell composition and responses in the liver and CMs were comparatively analyzed by scRNA-Seq, flow cytometry, immunofluorescence, <em>in situ</em> hybridization and multiplex cytokine assays.</div></div><div><h3>Results</h3><div>Neoadjuvant ICI resulted in improved protection against liver metastasis in comparison to adjuvant therapy. This superior response was associated with an expansion of T cells in CMs, the peripheral blood and the liver. An increased expression of T_H1-associated markers and a downregulation of T_H2-associated markers were detected in T cells from CMs and livers of mice by scRNA-Seq and immunofluorescence after neoadjuvant ICI. Analysis of hepatic cytokines also revealed lower levels of T_H2-associated IL-4 and of IL-15.</div></div><div><h3>Conclusion</h3><div>Our data demonstrate that neoadjuvant ICI provides superior protection against hepatic melanoma metastasis with a shift towards an anti-tumor T_H1 immune response. Therefore, neoadjuvant ICI is a promising therapeutic option for CM to prevent the development of organ-specific therapy resistance mechanisms.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"632 ","pages":"Article 217950"},"PeriodicalIF":10.1,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717615","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":"Radiotherapy in combination with PD-1 and TIGIT blockade mediate antitumor abscopal effects and immune memory via CD8+ T cells","authors":"Chunsheng Wang ,&nbsp;Linzhi Han ,&nbsp;Jianguo Zhang ,&nbsp;Qian Ji ,&nbsp;Xiuli Guo ,&nbsp;Yangyi Li ,&nbsp;Siqi Li ,&nbsp;Jingyi He ,&nbsp;Fajian He ,&nbsp;Weijing Dai ,&nbsp;Minghuan Li ,&nbsp;Jinming Yu ,&nbsp;Dawei Chen ,&nbsp;Yan Gong ,&nbsp;Conghua Xie","doi":"10.1016/j.canlet.2025.217935","DOIUrl":"10.1016/j.canlet.2025.217935","url":null,"abstract":"<div><div>This study investigated the synergistic antitumor effects of radiotherapy combined with <em>anti</em>-PD-1 and <em>anti</em>-TIGIT antibodies (aPD-1/aTIGIT), focusing on primary and abscopal tumor control, immune mechanisms, and long-term immune memory. Using bilateral subcutaneous tumor models (LLC, CMT-167, B16-F10, MC38) in C57/BL6 mice, we demonstrated that triple therapy (radiotherapy + aPD-1 + aTIGIT) significantly enhanced tumor regression and systemic antitumor responses. Flow cytometry, multicolor immunofluorescence, and single-cell transcriptomics revealed that triple therapy amplified CD8⁺ T cell activation, reversed exhaustion, and increased tumor infiltration. M1 macrophages exhibited robust immune activation and enhanced interactions with CD8⁺ T cells, driven by upregulated NF-κB, STAT1, and chemokine pathways. Longitudinal Luminex cytokine profiling identified sustained increases in TNF-α, CXCL10, and CCL5 post-treatment, supporting macrophage-T cell crosstalk. Rechallenge experiments and adoptive CD8⁺ T cell transfers confirmed that triple therapy generated durable central memory CD8⁺ T cells, which mediated antigen-specific immune memory and prevented tumor recurrence. These findings establish CD8⁺ T cells as central mediators of abscopal effects and long-term immunity, highlighting the critical role of M1 macrophage polarization in amplifying therapeutic synergy. By elucidating the mechanisms underlying resistance to PD-1 monotherapy, this study provides a translatable strategy to enhance clinical outcomes through radiotherapy-immunotherapy combinations.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"631 ","pages":"Article 217935"},"PeriodicalIF":9.1,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144711123","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}