Pub Date : 2026-01-16DOI: 10.1158/2159-8290.cd-nw2026-0001
Compared with atezolizumab monotherapy, a combination of chemotherapy, atezolizumab, and bevacizumab led to dramatically improved progression-free survival in patients with mismatch repair-deficient /microsatellite instability–high metastatic colorectal cancer. Because these patients often experience disease progression on immunotherapy, the results suggest that the combination approach could improve how they fare.
{"title":"Multiagent Combo Bests Immunotherapy Alone against Colorectal Cancer","authors":"","doi":"10.1158/2159-8290.cd-nw2026-0001","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-nw2026-0001","url":null,"abstract":"Compared with atezolizumab monotherapy, a combination of chemotherapy, atezolizumab, and bevacizumab led to dramatically improved progression-free survival in patients with mismatch repair-deficient /microsatellite instability–high metastatic colorectal cancer. Because these patients often experience disease progression on immunotherapy, the results suggest that the combination approach could improve how they fare.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"30 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986253","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 : 2026-01-16DOI: 10.1158/2159-8290.cd-nw2026-0002
In a large retrospective study, those taking a glucagon-like peptide 1 (GLP-1) receptor agonist drug were 36% less likely to develop colorectal cancer than those taking aspirin. Although the benefit seen for any one person was small, thousands could potentially see a benefit given the large number of people taking GLP-1s.d
{"title":"GLP-1s Spur Greater Reduction in Colorectal Cancer Risk than Aspirin","authors":"","doi":"10.1158/2159-8290.cd-nw2026-0002","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-nw2026-0002","url":null,"abstract":"In a large retrospective study, those taking a glucagon-like peptide 1 (GLP-1) receptor agonist drug were 36% less likely to develop colorectal cancer than those taking aspirin. Although the benefit seen for any one person was small, thousands could potentially see a benefit given the large number of people taking GLP-1s.d","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"268 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986254","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 : 2026-01-16DOI: 10.1158/2159-8290.cd-nw2026-0003
A large genetic analysis uncovered a variant that restrains clonal hematopoiesis by slowing the growth of mutated blood stem cells linked to myeloid malignancies. The mechanisms involved may offer targets for therapies aimed at preventing cancer progression.
{"title":"A Genetic Brake on Blood Cancer Risk","authors":"","doi":"10.1158/2159-8290.cd-nw2026-0003","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-nw2026-0003","url":null,"abstract":"A large genetic analysis uncovered a variant that restrains clonal hematopoiesis by slowing the growth of mutated blood stem cells linked to myeloid malignancies. The mechanisms involved may offer targets for therapies aimed at preventing cancer progression.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"68 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986318","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 : 2026-01-15DOI: 10.1158/2159-8290.cd-rw2026-008
{"title":"Melanosomes Act as Decoys to Evade Immunosurveillance of Melanoma.","authors":"","doi":"10.1158/2159-8290.cd-rw2026-008","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-rw2026-008","url":null,"abstract":"","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"263 1","pages":"OF1"},"PeriodicalIF":28.2,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986337","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 : 2026-01-14DOI: 10.1158/2159-8290.cd-25-1483
Avanish Mishra,Catherine B Meador,Kruthika Kikkeri,Quinn Cunneely,Maoxuan Lin,Thomas J Carmona-LaSalle,Shih-Bo Huang,Remy Bell,Victor Putaturo,Weikun Xia,Joyce H Liang,Jacy Fang,Sarah San Vicente,Caroline E Zielinski,Subba R Digumarthy,Yin P Hung,Beow Y Yeap,Jon F Edd,Michael S Lawrence,Moshe Sade-Feldman,Debattama R Sen,Mehmet Toner,Shyamala Maheswaran,Justin F Gainor,Daniel A Haber
The bispecific antibody tarlatamab recruits T cells to cancers expressing the neuroendocrine epitope DLL3. Tarlatamab is effective in small cell lung cancer (SCLC), but clinical outcomes vary, and no biomarkers enable patient selection. Single-cell RNA sequencing of SCLC biopsies identifies heterogeneity in DLL3 expression, and analysis of circulating tumor cells (CTCs) distinguishes individual patients as predominantly DLL3Pos or DLL3Low. In a prospective cohort of 20 patients, pretreatment DLL3 expression on CTCs predicts tarlatamab clinical benefit (85% sensitivity, 100% specificity). Necrotic CTC clusters in blood accompany treatment-induced tumor lysis. Acquired resistance to tarlatamab is associated in some cases with loss of DLL3 expression, but persistence of other targetable neuro-endocrine epitopes; in other patients, DLL3 is retained on CTCs, but accompanied by systemic markers of T cell dysfunction. Quantitation of DLL3-positive CTCs identifies patients likely to benefit from tarlatamab, and longitudinal monitoring may guide therapeutic decision-making at the time of acquired resistance.
{"title":"Circulating Tumor Cells Predict Response to the DLL3-targeting Bispecific Antibody Tarlatamab.","authors":"Avanish Mishra,Catherine B Meador,Kruthika Kikkeri,Quinn Cunneely,Maoxuan Lin,Thomas J Carmona-LaSalle,Shih-Bo Huang,Remy Bell,Victor Putaturo,Weikun Xia,Joyce H Liang,Jacy Fang,Sarah San Vicente,Caroline E Zielinski,Subba R Digumarthy,Yin P Hung,Beow Y Yeap,Jon F Edd,Michael S Lawrence,Moshe Sade-Feldman,Debattama R Sen,Mehmet Toner,Shyamala Maheswaran,Justin F Gainor,Daniel A Haber","doi":"10.1158/2159-8290.cd-25-1483","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-1483","url":null,"abstract":"The bispecific antibody tarlatamab recruits T cells to cancers expressing the neuroendocrine epitope DLL3. Tarlatamab is effective in small cell lung cancer (SCLC), but clinical outcomes vary, and no biomarkers enable patient selection. Single-cell RNA sequencing of SCLC biopsies identifies heterogeneity in DLL3 expression, and analysis of circulating tumor cells (CTCs) distinguishes individual patients as predominantly DLL3Pos or DLL3Low. In a prospective cohort of 20 patients, pretreatment DLL3 expression on CTCs predicts tarlatamab clinical benefit (85% sensitivity, 100% specificity). Necrotic CTC clusters in blood accompany treatment-induced tumor lysis. Acquired resistance to tarlatamab is associated in some cases with loss of DLL3 expression, but persistence of other targetable neuro-endocrine epitopes; in other patients, DLL3 is retained on CTCs, but accompanied by systemic markers of T cell dysfunction. Quantitation of DLL3-positive CTCs identifies patients likely to benefit from tarlatamab, and longitudinal monitoring may guide therapeutic decision-making at the time of acquired resistance.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"2 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145961277","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 : 2026-01-14DOI: 10.1158/2159-8290.cd-25-0778
Kie Kyon Huang,Takeshi Hagihara,Benedict Shi Xiang Lian,Zhi Xuan Ong,Shen Kiat Lim,Roxanne Hui Heng Chong,Supriya Srivastava,Jason Xing Kang,May Yin Lee,Angie Lay-Keng Tan,Minghui Lee,Shamaine Wei Ting Ho,Siti Aishah Binte Abdul Ghani,Clara Shi Ya Ng,Ruanyi Liang,Lin Liu,Su Ting Tay,Xuewen Ong,Feng Zhu,Hui Chen,Zhen Li,Tiing Leong Ang,Takuji Gotoda,Robert J Huang,Christopher J L Khor,Hyun-Soo Kim,Louis Ho Shing Lau,Yi-Chia Lee,Ayaka Takasu,Ming Teh,Mann Yie Thian,Wai Leong Tam,Xin Lu,Sunny H Wong,Jimmy B Y So,Hyunsoo Chung,Jonathan Lee,Khay Guan Yeoh,Patrick Tan
Intestinal metaplasia (IM) is a premalignant condition associated with increased risk of gastric cancer-a deadly malignancy with varying geographic incidence. High-depth targeted sequencing of more than 1,500 IM samples from six countries identified 47 significantly mutated genes, including driver genes associated with high-risk populations and worse prognosis (ARID1A), KRAS/MAPK signaling (KRAS, BRAF, MAP2K1, MAP3K1, and MAP2K4), and altered mucosal immunity (PIGR). IM whole-genome sequencing and DNA methylation analysis revealed SBS17 as a specific mutational signature separating IMs from normal gastric tissues, associated with late DNA replication, genomic hypomethylation, and tobacco exposure. Beyond epithelial-derived somatic mutations, we observed elevated clonal hematopoiesis (CH) in patients with IM associated with age, smoking, and enhanced risk of progressing to gastric cancer. Patients with CH expansions exhibited co-occurring IM PIGR truncating mutations and greater colonization of the IM microenvironment by orally derived bacteria, suggesting that CH may promote IM progression by modulating host-microbe mucosal immunity.SIGNIFICANCEThis international study identifies recurrent IM driver genes, IM-specific mutational signatures, and alterations in IM-associated immune landscapes and microbiomes. Our results highlight a role for nonepithelial somatic alterations (CH) in IM progression to gastric cancer, offering new translational opportunities for early cancer detection and interception.
{"title":"Mutational Signatures and Clonal Hematopoiesis in Intestinal Metaplasia across Countries with Varying Stomach Cancer Incidence.","authors":"Kie Kyon Huang,Takeshi Hagihara,Benedict Shi Xiang Lian,Zhi Xuan Ong,Shen Kiat Lim,Roxanne Hui Heng Chong,Supriya Srivastava,Jason Xing Kang,May Yin Lee,Angie Lay-Keng Tan,Minghui Lee,Shamaine Wei Ting Ho,Siti Aishah Binte Abdul Ghani,Clara Shi Ya Ng,Ruanyi Liang,Lin Liu,Su Ting Tay,Xuewen Ong,Feng Zhu,Hui Chen,Zhen Li,Tiing Leong Ang,Takuji Gotoda,Robert J Huang,Christopher J L Khor,Hyun-Soo Kim,Louis Ho Shing Lau,Yi-Chia Lee,Ayaka Takasu,Ming Teh,Mann Yie Thian,Wai Leong Tam,Xin Lu,Sunny H Wong,Jimmy B Y So,Hyunsoo Chung,Jonathan Lee,Khay Guan Yeoh,Patrick Tan","doi":"10.1158/2159-8290.cd-25-0778","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-0778","url":null,"abstract":"Intestinal metaplasia (IM) is a premalignant condition associated with increased risk of gastric cancer-a deadly malignancy with varying geographic incidence. High-depth targeted sequencing of more than 1,500 IM samples from six countries identified 47 significantly mutated genes, including driver genes associated with high-risk populations and worse prognosis (ARID1A), KRAS/MAPK signaling (KRAS, BRAF, MAP2K1, MAP3K1, and MAP2K4), and altered mucosal immunity (PIGR). IM whole-genome sequencing and DNA methylation analysis revealed SBS17 as a specific mutational signature separating IMs from normal gastric tissues, associated with late DNA replication, genomic hypomethylation, and tobacco exposure. Beyond epithelial-derived somatic mutations, we observed elevated clonal hematopoiesis (CH) in patients with IM associated with age, smoking, and enhanced risk of progressing to gastric cancer. Patients with CH expansions exhibited co-occurring IM PIGR truncating mutations and greater colonization of the IM microenvironment by orally derived bacteria, suggesting that CH may promote IM progression by modulating host-microbe mucosal immunity.SIGNIFICANCEThis international study identifies recurrent IM driver genes, IM-specific mutational signatures, and alterations in IM-associated immune landscapes and microbiomes. Our results highlight a role for nonepithelial somatic alterations (CH) in IM progression to gastric cancer, offering new translational opportunities for early cancer detection and interception.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"82 1","pages":"OF1-OF24"},"PeriodicalIF":28.2,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145961278","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 : 2026-01-14DOI: 10.1158/2159-8290.cd-rw2025-006
{"title":"A Brainstem Organoid Model Enables the Study of Pediatric Glioma at Scale.","authors":"","doi":"10.1158/2159-8290.cd-rw2025-006","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-rw2025-006","url":null,"abstract":"","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"5 1","pages":"OF1"},"PeriodicalIF":28.2,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986340","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 : 2026-01-12DOI: 10.1158/2159-8290.cd-25-0779
Marco De Dominici,James DeGregori
The risks and health consequences of cancers increase dramatically at older ages. To develop interventions to limit the impact of cancers, from preventative to therapeutic, we must seek both evolutionary and proximate explanations for this age-dependence. Here, we discuss how natural selection has erected barriers to delay malignancy and maximize reproductive fitness. Each barrier need not be perfect, as long as malignant progression is delayed till older ages. With aging, mechanisms ranging from epigenetic deregulation to inflammation to senescence to mutation-driven clonal expansions contribute to increased cancer pathogenesis through mutually enhancing mechanisms, creating tissue contexts more favorable for malignant evolution.SIGNIFICANCEBetter understanding of the multiple barriers that we have evolved to limit cancer development and how they can fail at older ages could enable the development of preventative and therapeutic interventions that boost these tumor-suppressive mechanisms.
{"title":"Of Barriers and Loops-How Evolution Limits Most Cancer Risks to Older Ages.","authors":"Marco De Dominici,James DeGregori","doi":"10.1158/2159-8290.cd-25-0779","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-0779","url":null,"abstract":"The risks and health consequences of cancers increase dramatically at older ages. To develop interventions to limit the impact of cancers, from preventative to therapeutic, we must seek both evolutionary and proximate explanations for this age-dependence. Here, we discuss how natural selection has erected barriers to delay malignancy and maximize reproductive fitness. Each barrier need not be perfect, as long as malignant progression is delayed till older ages. With aging, mechanisms ranging from epigenetic deregulation to inflammation to senescence to mutation-driven clonal expansions contribute to increased cancer pathogenesis through mutually enhancing mechanisms, creating tissue contexts more favorable for malignant evolution.SIGNIFICANCEBetter understanding of the multiple barriers that we have evolved to limit cancer development and how they can fail at older ages could enable the development of preventative and therapeutic interventions that boost these tumor-suppressive mechanisms.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"6 1","pages":"16-34"},"PeriodicalIF":28.2,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145949628","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 : 2026-01-12DOI: 10.1158/2159-8290.cd-25-1593
Feiyu Zhao,William Hill
In this issue, Griffith and colleagues describe a novel mechanism by which exposure to the carcinogen 2,3,7,8-tetrachlorodibenzo-p-dioxin through cigarette smoking promotes pancreatic tumorigenesis via the orchestration of a tumor-permissive local T-cell compartment. By stimulating aryl hydrocarbon receptors in CD4+ T cells, 2,3,7,8-tetrachlorodibenzo-p-dioxin skews the pancreatic immune landscape toward tolerance by promoting the expansion of IL22-secreting Th22 cells and regulatory T cells while simultaneously depleting tumor-targeting CD8+ T cells, thereby accelerating pancreatic dysplasia and tumor progression. See related article by Griffith et al., p. 114.
{"title":"Cigarette Smoke Skews T Cells to Promote Pancreatic Cancer.","authors":"Feiyu Zhao,William Hill","doi":"10.1158/2159-8290.cd-25-1593","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-1593","url":null,"abstract":"In this issue, Griffith and colleagues describe a novel mechanism by which exposure to the carcinogen 2,3,7,8-tetrachlorodibenzo-p-dioxin through cigarette smoking promotes pancreatic tumorigenesis via the orchestration of a tumor-permissive local T-cell compartment. By stimulating aryl hydrocarbon receptors in CD4+ T cells, 2,3,7,8-tetrachlorodibenzo-p-dioxin skews the pancreatic immune landscape toward tolerance by promoting the expansion of IL22-secreting Th22 cells and regulatory T cells while simultaneously depleting tumor-targeting CD8+ T cells, thereby accelerating pancreatic dysplasia and tumor progression. See related article by Griffith et al., p. 114.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"34 1","pages":"13-15"},"PeriodicalIF":28.2,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145949626","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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