Pub Date : 2026-03-01Epub Date: 2025-12-09DOI: 10.1016/j.canlet.2025.218215
Sheng Zhang , Yining Jin , Zhiliang Jia , Xueqing Xia , Yang Li , Qi Wang , Jing Wang , Jian Wang , Joya Chandra , Gregory K. Friedman , Shulin Li
The failure to prevent brain tumors, including both recurrent primary and metastatic brain tumors, is the primary cause of patients’ mortality. We developed a novel whole tumor-cell vaccine to rapidly induce long-duration brain-resident memory T (TRM) cells that prevent brain tumor progression. Ten Fgl2-KO primary and metastatic tumor cell lines, generated via CRISPR/Cas9, were used to vaccinate mice and for intracranial challenges with the WT tumor cells. Not only did vaccinated mice reject these tumor cell challenges, but also more than half of these mice became long-duration survivors. Transplanting brain immune cells from vaccinated mice into naïve mice enabled this rejection of intracranial challenges in the recipient mice, whereas depleting TRM cells impaired it. Mechanistic studies uncovered that Fgl2 KO impaired the immunosuppressive molecule CD47; reconstitution of CD47 expression in Fgl2-KO tumor cells reversed the protection. Likewise, vaccination with CD47-knockdown tumor cells produced similar effects. Proteomic analysis found that Fgl2-KO–mediated suppression of CD47 occurred through the Src and PKCα pathways; inhibition of either pathway reduced CD47 expression. This study is the first to show that disrupting the Fgl2-CD47 circuit in tumor cells impairs their tumorigenic properties and induces long-term brain TRM cells, thereby providing new strategies for improving the efficacy of currently used whole tumor-cell vaccines.
{"title":"Fgl2-knockout tumor cells serve as a vaccine inducing long-duration brain-resident memory T cells that reject subsequent intracranial tumor cell challenges","authors":"Sheng Zhang , Yining Jin , Zhiliang Jia , Xueqing Xia , Yang Li , Qi Wang , Jing Wang , Jian Wang , Joya Chandra , Gregory K. Friedman , Shulin Li","doi":"10.1016/j.canlet.2025.218215","DOIUrl":"10.1016/j.canlet.2025.218215","url":null,"abstract":"<div><div>The failure to prevent brain tumors, including both recurrent primary and metastatic brain tumors, is the primary cause of patients’ mortality. We developed a novel whole tumor-cell vaccine to rapidly induce long-duration brain-resident memory T (T<sub>RM</sub>) cells that prevent brain tumor progression. Ten Fgl2-KO primary and metastatic tumor cell lines, generated via CRISPR/Cas9, were used to vaccinate mice and for intracranial challenges with the WT tumor cells. Not only did vaccinated mice reject these tumor cell challenges, but also more than half of these mice became long-duration survivors. Transplanting brain immune cells from vaccinated mice into naïve mice enabled this rejection of intracranial challenges in the recipient mice, whereas depleting T<sub>RM</sub> cells impaired it. Mechanistic studies uncovered that Fgl2 KO impaired the immunosuppressive molecule CD47; reconstitution of CD47 expression in Fgl2-KO tumor cells reversed the protection. Likewise, vaccination with CD47-knockdown tumor cells produced similar effects. Proteomic analysis found that Fgl2-KO–mediated suppression of CD47 occurred through the Src and PKCα pathways; inhibition of either pathway reduced CD47 expression. This study is the first to show that disrupting the Fgl2-CD47 circuit in tumor cells impairs their tumorigenic properties and induces long-term brain T<sub>RM</sub> cells, thereby providing new strategies for improving the efficacy of currently used whole tumor-cell vaccines.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"640 ","pages":"Article 218215"},"PeriodicalIF":10.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145741179","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}
Pub Date : 2026-03-01Epub Date: 2026-01-08DOI: 10.1016/j.canlet.2026.218249
Qing Shi , Muchen Zhang , Yang He , Ronggui Lin , Mingci Cai, Huijuan Zhong, Shu Cheng, Pengpeng Xu, Weili Zhao, Li Wang
{"title":"Baseline tumor-informed circulating tumor DNA concentration predicts early chemoimmunotherapy failure in diffuse large B-cell lymphoma","authors":"Qing Shi , Muchen Zhang , Yang He , Ronggui Lin , Mingci Cai, Huijuan Zhong, Shu Cheng, Pengpeng Xu, Weili Zhao, Li Wang","doi":"10.1016/j.canlet.2026.218249","DOIUrl":"10.1016/j.canlet.2026.218249","url":null,"abstract":"","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"640 ","pages":"Article 218249"},"PeriodicalIF":10.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145942624","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}
Radiation-induced oral mucositis (RIOM) is a common and debilitating toxicity of radiotherapy for head and neck squamous cell carcinoma (HNSCC), often compromising treatment adherence and profoundly impairing patient quality of life. Despite its significant clinical impact, there are currently no safe and well-tolerated FDA-approved therapies to prevent or treat RIOM. The underlying mechanisms remain poorly understood but are thought to involve inflammatory responses triggered by oxidative stress and DNA damage from ionizing radiation (IR). Here, we identify SIRT2, an NAD+ -dependent deacetylase, as a key modulator of RIOM susceptibility. We demonstrate that both genetic and pharmacologic activation of SIRT2 robustly protects mice from developing RIOM. Mechanistically, SIRT2 enhances homologous recombination (HR)-mediated repair of DNA double-strand breaks (DSBs), thereby preserving the epithelial stem cell population of the oral mucosa and reducing mucosal injury. Importantly, SIRT2 activation—achieved via NAD+ supplementation in vitro or nicotinamide riboside (NR) in vivo—does not compromise the tumoricidal efficacy of IR in HNSCC models. These findings uncover a previously unrecognized protective role for SIRT2 in mucosal radiation injury and establish its activation as a promising, non-oncogenic therapeutic strategy to mitigate RIOM in patients receiving radiotherapy for head and neck cancer.
{"title":"SIRT2 mitigates radiation-induced oral mucositis by promoting homologous recombination-mediated DNA double-strand break repair in epithelial stem cells","authors":"Mousumi Patra , Ratan Sadhukhan , Eva Allen, Faraz Kalantari, Heba Allam, Fen Xia","doi":"10.1016/j.canlet.2026.218239","DOIUrl":"10.1016/j.canlet.2026.218239","url":null,"abstract":"<div><div>Radiation-induced oral mucositis (RIOM) is a common and debilitating toxicity of radiotherapy for head and neck squamous cell carcinoma (HNSCC), often compromising treatment adherence and profoundly impairing patient quality of life. Despite its significant clinical impact, there are currently no safe and well-tolerated FDA-approved therapies to prevent or treat RIOM. The underlying mechanisms remain poorly understood but are thought to involve inflammatory responses triggered by oxidative stress and DNA damage from ionizing radiation (IR). Here, we identify SIRT2, an NAD<sup>+</sup> -dependent deacetylase, as a key modulator of RIOM susceptibility. We demonstrate that both genetic and pharmacologic activation of SIRT2 robustly protects mice from developing RIOM. Mechanistically, SIRT2 enhances homologous recombination (HR)-mediated repair of DNA double-strand breaks (DSBs), thereby preserving the epithelial stem cell population of the oral mucosa and reducing mucosal injury. Importantly, SIRT2 activation—achieved via NAD<sup>+</sup> supplementation in vitro or nicotinamide riboside (NR) in vivo—does not compromise the tumoricidal efficacy of IR in HNSCC models. These findings uncover a previously unrecognized protective role for SIRT2 in mucosal radiation injury and establish its activation as a promising, non-oncogenic therapeutic strategy to mitigate RIOM in patients receiving radiotherapy for head and neck cancer.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"640 ","pages":"Article 218239"},"PeriodicalIF":10.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145948587","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}
Pub Date : 2026-03-01Epub Date: 2026-01-13DOI: 10.1016/j.canlet.2026.218254
Isabella Prantl , Reinhard Grausenburger , Julia Müller , Oliver Baumfried , Iris Elisabeth Ertl , Christoph Nössing , Paula Herek , Christine Pirker , Daniel Valcanover , Yuri Bastos-Moreira , Eszter Borsos , Lena Marie Hauser , Luis Rupp , Ursula Lemberger , Lisa Gabler-Pamer , Ekaterina Laukhtina , Agata Suleja , André Oszwald , Gabriel Wasinger , Eva Compérat , Bernhard Englinger
Pub Date : 2026-03-01Epub Date: 2026-01-06DOI: 10.1016/j.canlet.2025.218229
Yilong Huang , Zhitao Wei , Guanchao Ye , Yanfen Cui , Chuanpu Li , Guangyao Wu , Wei Yang , Bingqian Zhang , Zhenguang Zhang , Yuanming Jiang , Lizza E.L. Hendriks , Leonard Wee , Dirk De Ruysscher , Andre Dekker , Lei Shi , Zaiyi Liu , Bo He , Zhenwei Shi
Tumor-intrinsic biomarkers alone insufficiently predict pathological complete response (pCR) to neoadjuvant immunochemotherapy (NICT) in non-small cell lung cancer (NSCLC). Artificial intelligence (AI)-based three-dimensional CT-derived body composition may provide complementary predictive value. We evaluated its association with pCR following NICT in NSCLC. This multicenter retrospective study of NSCLC patients treated with NICT in China between July 2019 and July 2024. Pre- and post-treatment CT scans were used for automated T1–T12 localization and volumetric body composition segmentation. Metrics included skeletal muscle, intermuscular, visceral, and subcutaneous adipose volume index (SAVI), and their percentage changes between scans. Among 657 patients (mean age, 61.3 years; 87.4 % men), pCR rates were 39.7 % (training), 38.4 % (internal validation), and 34.9 % (external validation). In multivariable analysis, high baseline skeletal muscle volume index (SMVI) was independently associated with pCR (OR = 2.22). During NICT, each 1 % relative increase in SMVI was associated with a 16 % higher likelihood of pCR (OR = 1.16), whereas every 10 % relative increase in SAVI improved pCR probability (OR = 1.56). A machine learning model integrating clinical variables, baseline SMVI, %ΔSMVI, and %ΔSAVI demonstrated significantly better discrimination than models using clinical variables alone (p < 0.05) in all cohorts. The performance was observed in the internal and external validation cohorts, with sensitivities of 62.1 % and 52.8 %, and specificities of 66.7 % and 74.7 %, respectively. AI-based CT–derived body composition quantification, particularly baseline SMVI and dynamic changes in SMVI and SAVI during NICT, are independently associated with pCR in NSCLC. Incorporating these modifiable biomarkers into predictive models improves performance beyond clinical variables alone.
{"title":"Automated CT-derived body composition predicts pathologic response to neoadjuvant immunotherapy in non–small cell lung cancer","authors":"Yilong Huang , Zhitao Wei , Guanchao Ye , Yanfen Cui , Chuanpu Li , Guangyao Wu , Wei Yang , Bingqian Zhang , Zhenguang Zhang , Yuanming Jiang , Lizza E.L. Hendriks , Leonard Wee , Dirk De Ruysscher , Andre Dekker , Lei Shi , Zaiyi Liu , Bo He , Zhenwei Shi","doi":"10.1016/j.canlet.2025.218229","DOIUrl":"10.1016/j.canlet.2025.218229","url":null,"abstract":"<div><div>Tumor-intrinsic biomarkers alone insufficiently predict pathological complete response (pCR) to neoadjuvant immunochemotherapy (NICT) in non-small cell lung cancer (NSCLC). Artificial intelligence (AI)-based three-dimensional CT-derived body composition may provide complementary predictive value. We evaluated its association with pCR following NICT in NSCLC. This multicenter retrospective study of NSCLC patients treated with NICT in China between July 2019 and July 2024. Pre- and post-treatment CT scans were used for automated T1–T12 localization and volumetric body composition segmentation. Metrics included skeletal muscle, intermuscular, visceral, and subcutaneous adipose volume index (SAVI), and their percentage changes between scans. Among 657 patients (mean age, 61.3 years; 87.4 % men), pCR rates were 39.7 % (training), 38.4 % (internal validation), and 34.9 % (external validation). In multivariable analysis, high baseline skeletal muscle volume index (SMVI) was independently associated with pCR (OR = 2.22). During NICT, each 1 % relative increase in SMVI was associated with a 16 % higher likelihood of pCR (OR = 1.16), whereas every 10 % relative increase in SAVI improved pCR probability (OR = 1.56). A machine learning model integrating clinical variables, baseline SMVI, %ΔSMVI, and %ΔSAVI demonstrated significantly better discrimination than models using clinical variables alone (<em>p</em> < 0.05) in all cohorts. The performance was observed in the internal and external validation cohorts, with sensitivities of 62.1 % and 52.8 %, and specificities of 66.7 % and 74.7 %, respectively. AI-based CT–derived body composition quantification, particularly baseline SMVI and dynamic changes in SMVI and SAVI during NICT, are independently associated with pCR in NSCLC. Incorporating these modifiable biomarkers into predictive models improves performance beyond clinical variables alone.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"640 ","pages":"Article 218229"},"PeriodicalIF":10.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145931644","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}
Kidney cancer is a major global health burden, with clear cell renal cell carcinoma (ccRCC) as the most common and aggressive subtype. Beyond the typical alterations of high glucose uptake and lipid accumulation, amino acid metabolism dysregulation in ccRCC is also gradually being uncovered. Pathways involving glutamine, cystine, serine, glycine, branched-chain amino acids, methionine, aspartate, arginine, proline and tryptophan are extensively rewired. These alterations enable cancer cells to sustain proliferation and biosynthesis, maintain redox balance, remodel the immune microenvironment, and develop resistance to therapy. At the same time, such reprogramming creates metabolic dependencies and vulnerabilities, including glutamine and cystine addiction as well as arginine auxotrophy. Dysregulation of key enzymes such as GLS1, ASS1 and IDO1 further highlights potential therapeutic targets. Exploiting these vulnerabilities through metabolic inhibitors or rational combinations with targeted and immunotherapy holds promise for overcoming resistance and improving outcomes in ccRCC.
{"title":"Amino acid metabolic reprogramming in clear cell renal cell carcinoma: Pathogenic mechanisms and therapeutic targeting","authors":"Junzhe Xie, Fangjing Ni, Jialiang Shao, Dongliang Zhang, Tuanjie Guo, Xiang Wang","doi":"10.1016/j.canlet.2026.218244","DOIUrl":"10.1016/j.canlet.2026.218244","url":null,"abstract":"<div><div>Kidney cancer is a major global health burden, with clear cell renal cell carcinoma (ccRCC) as the most common and aggressive subtype. Beyond the typical alterations of high glucose uptake and lipid accumulation, amino acid metabolism dysregulation in ccRCC is also gradually being uncovered. Pathways involving glutamine, cystine, serine, glycine, branched-chain amino acids, methionine, aspartate, arginine, proline and tryptophan are extensively rewired. These alterations enable cancer cells to sustain proliferation and biosynthesis, maintain redox balance, remodel the immune microenvironment, and develop resistance to therapy. At the same time, such reprogramming creates metabolic dependencies and vulnerabilities, including glutamine and cystine addiction as well as arginine auxotrophy. Dysregulation of key enzymes such as GLS1, ASS1 and IDO1 further highlights potential therapeutic targets. Exploiting these vulnerabilities through metabolic inhibitors or rational combinations with targeted and immunotherapy holds promise for overcoming resistance and improving outcomes in ccRCC.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"640 ","pages":"Article 218244"},"PeriodicalIF":10.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145910580","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}
Pub Date : 2026-03-01Epub Date: 2026-01-16DOI: 10.1016/j.canlet.2026.218260
Kasey R. Cargill , Noah M. Feder , Tyler Wilhite , Walid F. Gellad , Heath D. Skinner , Yvonne M. Mowery , Christopher T. Wilke
{"title":"Price transparency compliance and variation for proton therapy in the United States","authors":"Kasey R. Cargill , Noah M. Feder , Tyler Wilhite , Walid F. Gellad , Heath D. Skinner , Yvonne M. Mowery , Christopher T. Wilke","doi":"10.1016/j.canlet.2026.218260","DOIUrl":"10.1016/j.canlet.2026.218260","url":null,"abstract":"","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"640 ","pages":"Article 218260"},"PeriodicalIF":10.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145997363","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}
Pub Date : 2026-03-01Epub Date: 2026-01-12DOI: 10.1016/j.canlet.2026.218255
Wen-Lung Wang , Chih-Chieh Yen , Chia-Sheng Yen , Yu-Hsuan Huang , Hsuan-Yi Huang , Ju-Fei Chen , Yen-Yu Liu , Sih-Ting Wang , Yu-Tzu Liu , Mien-Chie Hung , Chia-Jui Yen
PCSK9, besides its established role in cholesterol metabolism in the liver, has recently emerged as a tumor-promoting gene in various types of cancer including hepatocellular carcinoma (HCC). However, the regulatory pathways governing oncogenic PCSK9 in HCC remain poorly understood, particularly those involving epitranscriptomic modifications. Here, we identify PCSK9 as a novel mRNA target of METTL3 in HCC. Furthermore, METTL3 promotes tumor cell growth by upregulating PCSK9 mRNA through m6A methylation in the 3’ UTR. Additionally, IGF2BP3 exerts its m6A reading function to maintain PCSK9 mRNA stability in an m6A-dependent manner, thereby fostering the capacity of tumor growth. Moreover, ILF3 interacts with IGF2BP3 to collaboratively enhance PCSK9 mRNA stability and ultimately contributes to tumor growth. The METTL3-IGF2BP3-ILF3-PCSK9 signaling pathway is additionally confirmed in HCC patient cohorts. In summary, our findings highlight that PCSK9 is controlled by m6A-dependent METTL3-IGF2BP3-ILF3 epitranscriptomic programs and contributes to HCC progression. The study provides a rationale for repurposing PCSK9-depleting therapeutics into a potential antitumor treatment.
{"title":"Dysregulation of PCSK9 via m6A-dependent epitranscriptomic programs fosters hepatocellular carcinoma progression","authors":"Wen-Lung Wang , Chih-Chieh Yen , Chia-Sheng Yen , Yu-Hsuan Huang , Hsuan-Yi Huang , Ju-Fei Chen , Yen-Yu Liu , Sih-Ting Wang , Yu-Tzu Liu , Mien-Chie Hung , Chia-Jui Yen","doi":"10.1016/j.canlet.2026.218255","DOIUrl":"10.1016/j.canlet.2026.218255","url":null,"abstract":"<div><div>PCSK9, besides its established role in cholesterol metabolism in the liver, has recently emerged as a tumor-promoting gene in various types of cancer including hepatocellular carcinoma (HCC). However, the regulatory pathways governing oncogenic PCSK9 in HCC remain poorly understood, particularly those involving epitranscriptomic modifications. Here, we identify PCSK9 as a novel mRNA target of METTL3 in HCC. Furthermore, METTL3 promotes tumor cell growth by upregulating PCSK9 mRNA through m<sup>6</sup>A methylation in the 3’ UTR. Additionally, IGF2BP3 exerts its m<sup>6</sup>A reading function to maintain PCSK9 mRNA stability in an m<sup>6</sup>A-dependent manner, thereby fostering the capacity of tumor growth. Moreover, ILF3 interacts with IGF2BP3 to collaboratively enhance PCSK9 mRNA stability and ultimately contributes to tumor growth. The METTL3-IGF2BP3-ILF3-PCSK9 signaling pathway is additionally confirmed in HCC patient cohorts. In summary, our findings highlight that PCSK9 is controlled by m<sup>6</sup>A-dependent METTL3-IGF2BP3-ILF3 epitranscriptomic programs and contributes to HCC progression. The study provides a rationale for repurposing PCSK9-depleting therapeutics into a potential antitumor treatment.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"640 ","pages":"Article 218255"},"PeriodicalIF":10.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145984454","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}
Pub Date : 2026-02-28Epub Date: 2025-11-29DOI: 10.1016/j.canlet.2025.218183
Ana Catarina Matos , Maria Lima , Vera Miranda-Gonçalves , Stefano Indraccolo , Carmen Jerónimo , Lucília Saraiva
Prostate cancer (PCa) remains one of the most prevalent malignancies among men, with radiotherapy (RT) serving as a cornerstone of treatment. However, radioresistance (RR) remains a major clinical challenge, contributing to treatment failure, disease recurrence, and poor prognosis. A major driver of RR is the enhanced DNA damage repair (DDR) ability of PCa cells, which allows them to evade RT-induced cell death. This review critically examines the molecular basis of RR in PCa, with particular focus on DDR pathways. We address the role of key genetic alterations, including mutations in BRCA2, ATM, and PARP1, on RT response, highlighting their potential as therapeutic targets to overcome RR. We further explore the interplay of DDR inhibition with androgen receptor (AR) signaling and its ability to potentiate antitumor immunity through activation of the cGAS-STING pathway, type I interferon production, and regulation of immune checkpoints. By leveraging insights into DDR mechanisms and therapeutic opportunities, this review provides a comprehensive perspective to enhance RT efficacy and improve clinical outcomes in PCa patients.
{"title":"Overcoming radioresistance in prostate cancer by targeting DNA damage repair","authors":"Ana Catarina Matos , Maria Lima , Vera Miranda-Gonçalves , Stefano Indraccolo , Carmen Jerónimo , Lucília Saraiva","doi":"10.1016/j.canlet.2025.218183","DOIUrl":"10.1016/j.canlet.2025.218183","url":null,"abstract":"<div><div>Prostate cancer (PCa) remains one of the most prevalent malignancies among men, with radiotherapy (RT) serving as a cornerstone of treatment. However, radioresistance (RR) remains a major clinical challenge, contributing to treatment failure, disease recurrence, and poor prognosis. A major driver of RR is the enhanced DNA damage repair (DDR) ability of PCa cells, which allows them to evade RT-induced cell death. This review critically examines the molecular basis of RR in PCa, with particular focus on DDR pathways. We address the role of key genetic alterations, including mutations in BRCA2, ATM, and PARP1, on RT response, highlighting their potential as therapeutic targets to overcome RR. We further explore the interplay of DDR inhibition with androgen receptor (AR) signaling and its ability to potentiate antitumor immunity through activation of the cGAS-STING pathway, type I interferon production, and regulation of immune checkpoints. By leveraging insights into DDR mechanisms and therapeutic opportunities, this review provides a comprehensive perspective to enhance RT efficacy and improve clinical outcomes in PCa patients.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"639 ","pages":"Article 218183"},"PeriodicalIF":10.1,"publicationDate":"2026-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145647369","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}
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