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":"2026-01-08","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 : 2026-01-07DOI: 10.1016/j.canlet.2025.218234
Courtney B. Cross , Joanne M. Bowen , Wayne R. Leifert , David J. Beale , Maxime Francois , Rohit Joshi , Beverley G. Fosh , Janet K. Coller , Jonathan Tuke , Monique Bareham , Denelle J. Cosier , Linh Hang To , Feargal J. Ryan , Hannah R. Wardill
{"title":"Pre-treatment gut microbiome and salivary metabolome signatures associate with chemotherapy-induced cognitive decline in women with breast cancer: A prospective pilot study","authors":"Courtney B. Cross , Joanne M. Bowen , Wayne R. Leifert , David J. Beale , Maxime Francois , Rohit Joshi , Beverley G. Fosh , Janet K. Coller , Jonathan Tuke , Monique Bareham , Denelle J. Cosier , Linh Hang To , Feargal J. Ryan , Hannah R. Wardill","doi":"10.1016/j.canlet.2025.218234","DOIUrl":"10.1016/j.canlet.2025.218234","url":null,"abstract":"","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"640 ","pages":"Article 218234"},"PeriodicalIF":10.1,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145942556","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 : 2026-01-07DOI: 10.1016/j.canlet.2026.218245
Chenggong Tu , Arne Van der Vreken , Sylvia Faict , Gamze Ates , Ann Massie , Kim De Veirman , Elke De Bruyne , Karin Vanderkerken , Eline Menu
Multiple myeloma (MM) is a hematological malignancy characterized by plasma cells residing in the bone marrow. Despite advancements in treatment, including proteasome inhibitors (PIs) such as bortezomib (Bz), drug resistance remains a major challenge. Metabolic reprogramming supports MM survival and drug resistance, with mitochondria emerging as promising therapeutic targets through their control of OXPHOS and mitochondrial reactive oxygen species (Mito-ROS). Using metabolic flux analyses, flow cytometry, and Western blot analysis, we identified pyruvate as a central metabolic intermediate, which not only enhances mitochondrial respiration and Mito-ROS production, but also the Integrated Stress Response (ISR) pathway. Conversely, metformin, an inhibitor of OXPHOS, was still able to activate the ISR pathway, but rather reduced Bz-induced cytotoxicity by decreasing both protein synthesis, and ROS production. Results were confirmed on primary murine and patient samples. Moreover, analysis of the CoMMpass study revealed that patients with prolonged progression-free survival under PI treatment showed enrichment in OXPHOS-related genes, highlighting the importance of mitochondrial metabolism in regulating MM responses to Bz. These data suggest that targeting pyruvate metabolism to increase ROS production could offer a strategy to enhance Bz activity in MM.
{"title":"The clinically available supplement pyruvate enhances the therapeutic effect of bortezomib in Multiple Myeloma by modulating mitochondrial metabolism","authors":"Chenggong Tu , Arne Van der Vreken , Sylvia Faict , Gamze Ates , Ann Massie , Kim De Veirman , Elke De Bruyne , Karin Vanderkerken , Eline Menu","doi":"10.1016/j.canlet.2026.218245","DOIUrl":"10.1016/j.canlet.2026.218245","url":null,"abstract":"<div><div>Multiple myeloma (MM) is a hematological malignancy characterized by plasma cells residing in the bone marrow. Despite advancements in treatment, including proteasome inhibitors (PIs) such as bortezomib (Bz), drug resistance remains a major challenge. Metabolic reprogramming supports MM survival and drug resistance, with mitochondria emerging as promising therapeutic targets through their control of OXPHOS and mitochondrial reactive oxygen species (Mito-ROS). Using metabolic flux analyses, flow cytometry, and Western blot analysis, we identified pyruvate as a central metabolic intermediate, which not only enhances mitochondrial respiration and Mito-ROS production, but also the Integrated Stress Response (ISR) pathway. Conversely, metformin, an inhibitor of OXPHOS, was still able to activate the ISR pathway, but rather reduced Bz-induced cytotoxicity by decreasing both protein synthesis, and ROS production. Results were confirmed on primary murine and patient samples. Moreover, analysis of the CoMMpass study revealed that patients with prolonged progression-free survival under PI treatment showed enrichment in OXPHOS-related genes, highlighting the importance of mitochondrial metabolism in regulating MM responses to Bz. These data suggest that targeting pyruvate metabolism to increase ROS production could offer a strategy to enhance Bz activity in MM.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"640 ","pages":"Article 218245"},"PeriodicalIF":10.1,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145942577","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}
Cancer cachexia is a syndrome characterized by profound weight loss, muscle wasting, and metabolic disturbance in cancer patients. Cancer-associated cachexia represents significant biological and clinical challenges that profoundly affect human health. Approximately 20 % of cancer patients succumb directly to cachexia-related complications. Aging is characterized by a gradual decline in physiological functions and an increased vulnerability to chronic diseases. However, whether aging inherently increases vulnerability to cachexia or exacerbates its progression remains unclear, impeding the development of targeted strategies for this high-risk population. Ganoderma lucidum polysaccharides (GLP) have demonstrated diverse pharmacological activities; however, their potential role in attenuating of tumor cachexia remains inadequately explored and warrants further investigation. In this study, GLP was found to mitigate tumor cachexia in vitro and in vivo models, as evidenced by rescuing significant weight loss, muscle atrophy, and adipose tissue breakdown. Notably, its therapeutic potency is more profoundly marked in aged mice than in young ones. Mechanistically, GLP alleviated myofiber atrophy and dyslipolysis by inactivating NF-κB and AMPK pathways, while also activating Treg cells by regulating arginine metabolism. In conclusion, our findings indicate that GLP exhibits cachexia-attenuating activities, thereby positioning it as a potential therapeutic candidate for aging-related conditions.
{"title":"Ganoderma lucidum polysaccharide ameliorates cancer cachexia with enhanced efficacy in aged group by reprogramming arginine metabolism to modulate Treg formation.","authors":"Chunmiao Deng, Yunfang Chen, Jiaojiao Xu, Chanjin Liang, Cui Shao, Shiqi Mei, Yongkang Xu, Yin Li, Cancan Zheng, Yichang Luo, Xingyuan Shi","doi":"10.1016/j.canlet.2026.218247","DOIUrl":"10.1016/j.canlet.2026.218247","url":null,"abstract":"<p><p>Cancer cachexia is a syndrome characterized by profound weight loss, muscle wasting, and metabolic disturbance in cancer patients. Cancer-associated cachexia represents significant biological and clinical challenges that profoundly affect human health. Approximately 20 % of cancer patients succumb directly to cachexia-related complications. Aging is characterized by a gradual decline in physiological functions and an increased vulnerability to chronic diseases. However, whether aging inherently increases vulnerability to cachexia or exacerbates its progression remains unclear, impeding the development of targeted strategies for this high-risk population. Ganoderma lucidum polysaccharides (GLP) have demonstrated diverse pharmacological activities; however, their potential role in attenuating of tumor cachexia remains inadequately explored and warrants further investigation. In this study, GLP was found to mitigate tumor cachexia in vitro and in vivo models, as evidenced by rescuing significant weight loss, muscle atrophy, and adipose tissue breakdown. Notably, its therapeutic potency is more profoundly marked in aged mice than in young ones. Mechanistically, GLP alleviated myofiber atrophy and dyslipolysis by inactivating NF-κB and AMPK pathways, while also activating Treg cells by regulating arginine metabolism. In conclusion, our findings indicate that GLP exhibits cachexia-attenuating activities, thereby positioning it as a potential therapeutic candidate for aging-related conditions.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"218247"},"PeriodicalIF":10.1,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145942582","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 : 2026-01-06DOI: 10.1016/j.canlet.2026.218246
Fatemeh Mokhles, Mohammad Amin Moosavi, Alvaro Gutierrez-Uzquiza, Guillermo Velasco, Min Li, Marco Cordani
Cancer cells face a hostile microenvironment characterized by hypoxia, nutrient deprivation, endoplasmic reticulum (ER) stress, and oxidative imbalance. To cope with these challenges, they activate an interconnected network of adaptive pathways including autophagy, the unfolded protein response, metabolic reprogramming, and the integrated stress response., which promote cell survival, therapy resistance, immune evasion, and metastasis. CRISPR-based functional genomics has emerged as a powerful strategy to systematically dissect these stress-adaptive networks, enabling the identification of key regulators and vulnerabilities across diverse contexts. In this review, we first summarize tumor progression in major stress conditions and then highlight how CRISPR screening strategies ranging from genome-wide loss-of-function studies to single-cell and combinatorial platforms, are unraveling critical stress regulators. We further discuss emerging tools, model systems, and translational perspectives, underscoring how the integration of CRISPR technologies with multi-omics, artificial intelligence, and advanced preclinical models is reshaping our understanding of cancer stress biology and guiding the development of novel therapeutic strategies. Finally, we addressed how these novel dissection technologies influence translational opportunities, specifically in the context of combining stress-pathway modulators with immunotherapy and targeted therapy drugs.
{"title":"Unraveling Stress-Adaptation Pathways in Cancer: Functional Dissection Through CRISPR-Based Genetic Screens.","authors":"Fatemeh Mokhles, Mohammad Amin Moosavi, Alvaro Gutierrez-Uzquiza, Guillermo Velasco, Min Li, Marco Cordani","doi":"10.1016/j.canlet.2026.218246","DOIUrl":"https://doi.org/10.1016/j.canlet.2026.218246","url":null,"abstract":"<p><p>Cancer cells face a hostile microenvironment characterized by hypoxia, nutrient deprivation, endoplasmic reticulum (ER) stress, and oxidative imbalance. To cope with these challenges, they activate an interconnected network of adaptive pathways including autophagy, the unfolded protein response, metabolic reprogramming, and the integrated stress response., which promote cell survival, therapy resistance, immune evasion, and metastasis. CRISPR-based functional genomics has emerged as a powerful strategy to systematically dissect these stress-adaptive networks, enabling the identification of key regulators and vulnerabilities across diverse contexts. In this review, we first summarize tumor progression in major stress conditions and then highlight how CRISPR screening strategies ranging from genome-wide loss-of-function studies to single-cell and combinatorial platforms, are unraveling critical stress regulators. We further discuss emerging tools, model systems, and translational perspectives, underscoring how the integration of CRISPR technologies with multi-omics, artificial intelligence, and advanced preclinical models is reshaping our understanding of cancer stress biology and guiding the development of novel therapeutic strategies. Finally, we addressed how these novel dissection technologies influence translational opportunities, specifically in the context of combining stress-pathway modulators with immunotherapy and targeted therapy drugs.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"218246"},"PeriodicalIF":10.1,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145931597","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 : 2026-01-06DOI: 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":"2026-01-06","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":"2026-01-04","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 : 2026-01-03DOI: 10.1016/j.canlet.2026.218241
Yifeng Li , Chao Li , Yueqi Wang , Jian Zhou , Boyu Zhou , Lan Mei , HuiYong Niu , Zhenhua Hu , Jie Tian , Changjian Li
Precise localization and complete resection are critical for preventing recurrence in non-small cell lung cancer (NSCLC), yet these goals remain clinically challenging. The second near-infrared window (1000–1700 nm, NIR-II) fluorescent molecular imaging offers a promising solution, and single-targeted probes have been developed for intraoperative guidance. However, tumor heterogeneity often limits the efficacy of single-target antibody probes, resulting in low detection sensitivity. Therefore, this study aimed to evaluate a dual-targeting strategy simultaneously engaging EGFR and cMET for NIR-II-guided lung cancer surgery. Based on the higher overexpression of EGFR and cMET in NSCLC, we implemented the bispecific probe Amivantamab-IRDye800CW to establish a dual-targeting imaging strategy. After validating its superior properties and NIR-II imaging advantages, we assessed its tumor-targeting capability and surgical navigation potential through in vivo imaging. Additionally, freshly resected NSCLC specimens were incubated with probes to confirm target specificity. Amivantamab-IRDye800CW exhibited NIR-II fluorescence emission (up to 1500 nm), with improved imaging performance over NIR-I. In subcutaneous xenograft models, the probe demonstrated precise tumor targeting (tumor-to-background ratio = 6.79 ± 0.49) and enabled complete resection of both subcutaneous tumors and orthotopic lung tumors. The probe also retained strong targeting ability in patient-derived xenograft (PDX) models, which better preserve tumor heterogeneity. Furthermore, Amivantamab-IRDye800CW accurately localized cancerous tissues in clinical NSCLC specimens. These findings demonstrate that implementing a dual-targeting strategy in NSCLC, effectively reduces the impact of tumor heterogeneity on NIR-II imaging. This approach improves tumor localization precision and provides reliable intraoperative guidance, highlighting its strong potential for clinical translation in NSCLC surgery.
{"title":"Mitigating tumor heterogeneity in lung Cancer: A dual-targeted NIR-II imaging strategy for accurate tumor localization and intraoperative navigation","authors":"Yifeng Li , Chao Li , Yueqi Wang , Jian Zhou , Boyu Zhou , Lan Mei , HuiYong Niu , Zhenhua Hu , Jie Tian , Changjian Li","doi":"10.1016/j.canlet.2026.218241","DOIUrl":"10.1016/j.canlet.2026.218241","url":null,"abstract":"<div><div>Precise localization and complete resection are critical for preventing recurrence in non-small cell lung cancer (NSCLC), yet these goals remain clinically challenging. The second near-infrared window (1000–1700 nm, NIR-II) fluorescent molecular imaging offers a promising solution, and single-targeted probes have been developed for intraoperative guidance. However, tumor heterogeneity often limits the efficacy of single-target antibody probes, resulting in low detection sensitivity. Therefore, this study aimed to evaluate a dual-targeting strategy simultaneously engaging EGFR and cMET for NIR-II-guided lung cancer surgery. Based on the higher overexpression of EGFR and cMET in NSCLC, we implemented the bispecific probe Amivantamab-IRDye800CW to establish a dual-targeting imaging strategy. After validating its superior properties and NIR-II imaging advantages, we assessed its tumor-targeting capability and surgical navigation potential through in vivo imaging. Additionally, freshly resected NSCLC specimens were incubated with probes to confirm target specificity. Amivantamab-IRDye800CW exhibited NIR-II fluorescence emission (up to 1500 nm), with improved imaging performance over NIR-I. In subcutaneous xenograft models, the probe demonstrated precise tumor targeting (tumor-to-background ratio = 6.79 ± 0.49) and enabled complete resection of both subcutaneous tumors and orthotopic lung tumors. The probe also retained strong targeting ability in patient-derived xenograft (PDX) models, which better preserve tumor heterogeneity. Furthermore, Amivantamab-IRDye800CW accurately localized cancerous tissues in clinical NSCLC specimens. These findings demonstrate that implementing a dual-targeting strategy in NSCLC, effectively reduces the impact of tumor heterogeneity on NIR-II imaging. This approach improves tumor localization precision and provides reliable intraoperative guidance, highlighting its strong potential for clinical translation in NSCLC surgery.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"640 ","pages":"Article 218241"},"PeriodicalIF":10.1,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145898001","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 : 2026-01-03DOI: 10.1016/j.canlet.2026.218242
Boyuan Liu , Zhitao Cai , Haihan Sun , Zixu Liu , Ping Wang , Ning Dong , Han Zeng , Chunwen Zeng , Jingxin Gou , Yu Zhang , Tian Yin , Xing Tang , Haibing He
Currently, intraperitoneal (IP) chemoimmunotherapy offers synergistic effect, pharmacokinetic advantages and reduced systemic toxicity, achieving significant progress in peritoneal metastatic ovarian cancer (OC). However, its efficacy is limited by poor drug retention, lack of targeting, inadequate tumor penetration, drug resistance, and immunosuppression tumor microenvironment (TME). To address these challenges, a "three-in-one" thermosensitive gel system (PM/LOS@FLP/P1@G) was developed. Here, platinum prodrug (Pt-2CLB), TME modulator losartan (LOS), and immune checkpoint inhibitor (ICI) anti-PD-1 (P1) are integrated into a hierarchical micelle-liposome-thermosensitive gel structure, resulting in enhanced chemo-immunotherapy. Specifically, the enhancement of antitumor efficacy primarily involves five mechanisms: (i) prolonged IP retention and tumor tissue contact-dependent active targeting mediated by thermosensitive gel and folate-targeting; (ii) matrix metalloproteinase (MMP) and reduced glutathione (GSH)-triggered spatiotemporally sequential delivery of LOS to cancer-associated fibroblasts (CAFs), Pt-2CLB to tumor cells, and P1 to the PD-1/PD-L1 axis; (iii) the DNA damage, GSH depletion, and ROS accumulation induced by Pt-2CLB not only amplify chemotherapeutic efficacy while suppressing drug resistance but also activate the cGAS-STING signaling pathway, thereby enhancing immune responses; (iv) the blockade of transforming growth factor-β (TGF-β)/Smad signaling pathway by LOS inhibits CAFs activation and tumor extracellular matrix (ECM) production, thereby promoting the penetration of drugs and immune cells, boosting chemoimmunotherapy; (v) chemoimmunotherapy synergy exerts potent antitumor effects. In summary, PM/LOS@FLP/P1@G exhibited excellent antitumor efficacy and safety, demonstrating a significant tumor inhibition rate (93.28 %) and survival extension, while fostering immune memory to prevent recurrence, representing a promising IP chemoimmunotherapy strategy for peritoneal metastatic OC.
{"title":"A Pt (IV)/losartan/immunotherapy Co-delivery thermosensitive gel synergizes STING activation and cancer-associated fibroblast inhibition for ovarian cancer chemoimmunotherapy","authors":"Boyuan Liu , Zhitao Cai , Haihan Sun , Zixu Liu , Ping Wang , Ning Dong , Han Zeng , Chunwen Zeng , Jingxin Gou , Yu Zhang , Tian Yin , Xing Tang , Haibing He","doi":"10.1016/j.canlet.2026.218242","DOIUrl":"10.1016/j.canlet.2026.218242","url":null,"abstract":"<div><div>Currently, intraperitoneal (IP) chemoimmunotherapy offers synergistic effect, pharmacokinetic advantages and reduced systemic toxicity, achieving significant progress in peritoneal metastatic ovarian cancer (OC). However, its efficacy is limited by poor drug retention, lack of targeting, inadequate tumor penetration, drug resistance, and immunosuppression tumor microenvironment (TME). To address these challenges, a \"three-in-one\" thermosensitive gel system (PM/LOS@FLP/P1@G) was developed. Here, platinum prodrug (Pt-2CLB), TME modulator losartan (LOS), and immune checkpoint inhibitor (ICI) anti-PD-1 (P1) are integrated into a hierarchical micelle-liposome-thermosensitive gel structure, resulting in enhanced chemo-immunotherapy. Specifically, the enhancement of antitumor efficacy primarily involves five mechanisms: (i) prolonged IP retention and tumor tissue contact-dependent active targeting mediated by thermosensitive gel and folate-targeting; (ii) matrix metalloproteinase (MMP) and reduced glutathione (GSH)-triggered spatiotemporally sequential delivery of LOS to cancer-associated fibroblasts (CAFs), Pt-2CLB to tumor cells, and P1 to the PD-1/PD-L1 axis; (iii) the DNA damage, GSH depletion, and ROS accumulation induced by Pt-2CLB not only amplify chemotherapeutic efficacy while suppressing drug resistance but also activate the cGAS-STING signaling pathway, thereby enhancing immune responses; (iv) the blockade of transforming growth factor-β (TGF-β)/Smad signaling pathway by LOS inhibits CAFs activation and tumor extracellular matrix (ECM) production, thereby promoting the penetration of drugs and immune cells, boosting chemoimmunotherapy; (v) chemoimmunotherapy synergy exerts potent antitumor effects. In summary, PM/LOS@FLP/P1@G exhibited excellent antitumor efficacy and safety, demonstrating a significant tumor inhibition rate (93.28 %) and survival extension, while fostering immune memory to prevent recurrence, representing a promising IP chemoimmunotherapy strategy for peritoneal metastatic OC.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"639 ","pages":"Article 218242"},"PeriodicalIF":10.1,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145899065","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 : 2026-01-02DOI: 10.1016/j.canlet.2026.218238
Caiqi Liu , Jianhua Nie , Shun Li , Sainan Ma , Dan Su , Zhigang Ma , Jiebing Tang , Chunhui Zhang , Changjie Lou , Jinghong Su , Huijia Zhang , Ruihan Zhou , Xiaowei Sun , Guangyu Wang , Tongsen Zheng
Microsatellite-stable metastatic colorectal cancer (MSS-mCRC) is generally unresponsive to immune checkpoint inhibitors (ICIs). Combining vascular endothelial growth factor receptor tyrosine kinase inhibitors (TKIs) with ICIs improves outcomes but often causes severe toxicities. Our previous preclinical work demonstrated that electroacupuncture (EA) potentiates anti-PD-1 therapy in MSS-CRC models by reprogramming the immunosuppressive microenvironment. Based on this rationale, we conducted a phase II trial to evaluate whether integrating EA with fruquintinib (a potent, selective small molecule inhibitor of VEGFR 1, 2, and 3) and sintilimab (a monoclonal antibody against PD-1) could improve tolerability and efficacy in MSS-mCRC. In this single-arm, investigator-initiated study, patients with histologically confirmed MSS-mCRC who had progressed through at least two prior regimens received 21-day cycles of EA (day 1–7), intravenous sintilimab (200 mg, day 8), and oral fruquintinib (5 mg/day, day 8–21). The primary endpoint was investigator-assessed objective response rate (ORR). From May 2024 to May 2025, 31 patients were enrolled and 28 were efficacy-evaluable. ORR was 21.4% [95% confidence interval (CI), 10.2–39.5] and DCR was 92.9% (95% CI, 77.4–98.0). Median PFS was 6.1 months (95% CI, 4.8–9.9) and median OS was 12.4 months (95% CI, 11.0–NA). TRAEs occurred in 80.6% of patients, with grade ≥3 in 29.0%, lower than rates reported for historical TKI–ICI combinations. No EA-related toxicity was observed. Overall, EA plus fruquintinib and sintilimab was feasible and showed an acceptable safety profile while maintaining antitumor activity in MSS-mCRC, warranting further evaluation in larger randomized trials.
{"title":"Electroacupuncture combined with fruquintinib and sintilimab in microsatellite-stable metastatic colorectal cancer: A phase II study","authors":"Caiqi Liu , Jianhua Nie , Shun Li , Sainan Ma , Dan Su , Zhigang Ma , Jiebing Tang , Chunhui Zhang , Changjie Lou , Jinghong Su , Huijia Zhang , Ruihan Zhou , Xiaowei Sun , Guangyu Wang , Tongsen Zheng","doi":"10.1016/j.canlet.2026.218238","DOIUrl":"10.1016/j.canlet.2026.218238","url":null,"abstract":"<div><div>Microsatellite-stable metastatic colorectal cancer (MSS-mCRC) is generally unresponsive to immune checkpoint inhibitors (ICIs). Combining vascular endothelial growth factor receptor tyrosine kinase inhibitors (TKIs) with ICIs improves outcomes but often causes severe toxicities. Our previous preclinical work demonstrated that electroacupuncture (EA) potentiates anti-PD-1 therapy in MSS-CRC models by reprogramming the immunosuppressive microenvironment. Based on this rationale, we conducted a phase II trial to evaluate whether integrating EA with fruquintinib (a potent, selective small molecule inhibitor of VEGFR 1, 2, and 3) and sintilimab (a monoclonal antibody against PD-1) could improve tolerability and efficacy in MSS-mCRC. In this single-arm, investigator-initiated study, patients with histologically confirmed MSS-mCRC who had progressed through at least two prior regimens received 21-day cycles of EA (day 1–7), intravenous sintilimab (200 mg, day 8), and oral fruquintinib (5 mg/day, day 8–21). The primary endpoint was investigator-assessed objective response rate (ORR). From May 2024 to May 2025, 31 patients were enrolled and 28 were efficacy-evaluable. ORR was 21.4% [95% confidence interval (CI), 10.2–39.5] and DCR was 92.9% (95% CI, 77.4–98.0). Median PFS was 6.1 months (95% CI, 4.8–9.9) and median OS was 12.4 months (95% CI, 11.0–NA). TRAEs occurred in 80.6% of patients, with grade ≥3 in 29.0%, lower than rates reported for historical TKI–ICI combinations. No EA-related toxicity was observed. Overall, EA plus fruquintinib and sintilimab was feasible and showed an acceptable safety profile while maintaining antitumor activity in MSS-mCRC, warranting further evaluation in larger randomized trials.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"639 ","pages":"Article 218238"},"PeriodicalIF":10.1,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145880903","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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