Cancer Science最新文献

{"title":"Super-Enhancer Formation in Scirrhous Gastric CAFs, and the Presence of a Stromal Field in Non-Cancerous Tissues","authors":"Yoshimi Yasukawa,&nbsp;Naoko Hattori,&nbsp;Yu-Yu Liu,&nbsp;Masayuki Tobo,&nbsp;Genki Yamagishi,&nbsp;Takahiro Irie,&nbsp;Shigeki Sekine,&nbsp;Tohru Kiyono,&nbsp;Satoshi Yamashita,&nbsp;Yukinori Yamagata,&nbsp;Takaki Yoshikawa,&nbsp;Yasuyuki Seto,&nbsp;Toshikazu Ushijima","doi":"10.1111/cas.70408","DOIUrl":"10.1111/cas.70408","url":null,"abstract":"<p>Scirrhous gastric cancer has aggressive clinical courses and is characterized by dominating cancer-associated fibroblasts (CAFs). However, the origin of scirrhous CAFs remains unclear, and we here aimed to explore the epigenetic basis for scirrhous CAFs and their origin. Conditioned medium (CM) from scirrhous CAFs was shown to have a marked effect (2–4 folds) on the migration of gastric cancer cells compared to that from non-scirrhous CAFs. The aggressive phenotype of scirrhous CAFs was associated with activation of TGFβ1 and NF-κB, along with increased expression of their downstream genes. Scirrhous CAFs had heavily acetylated super-enhancers, and therapeutic targeting of super-enhancers by a BET bromodomain inhibitor, mivebresib and JQ-1, markedly decreased their migration-promoting activity. Notably, in scirrhous gastric cancer patients, normal fibroblasts in non-cancerous tissues also had a strong migration-promoting effect. It was suggested that fibroblasts in the non-cancerous tissue of scirrhous gastric patients have already acquired tumor-promoting capacity, forming a stromal field for scirrhous gastric cancer although its spatial extent remains to be solved.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 7","pages":"1894-1906"},"PeriodicalIF":4.9,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70408","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147822429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Atezolizumab + Chemotherapy in Older Patients With Lung Cancer in Japan","authors":"Junichi Shimizu,&nbsp;Makoto Nishio,&nbsp;Kadoaki Ohashi,&nbsp;Atsushi Osoegawa,&nbsp;Eiki Kikuchi,&nbsp;Hideharu Kimura,&nbsp;Yasushi Goto,&nbsp;Eisaku Miyauchi,&nbsp;Hiroshige Yoshioka,&nbsp;Ichiro Yoshino,&nbsp;Toshihiro Misumi,&nbsp;Kozo Yoshimori,&nbsp;Kazuhiko Shibata,&nbsp;Takeshi Tsuda,&nbsp;Masahiro Seike,&nbsp;Takahiro Ota,&nbsp;Koichi Samata,&nbsp;Yuki Kobayashi,&nbsp;Misa Tanaka,&nbsp;Akihiko Gemma","doi":"10.1111/cas.70411","DOIUrl":"10.1111/cas.70411","url":null,"abstract":"<p>Pivotal phase 3 trials leading to the approvals of atezolizumab─chemotherapy combinations for non-small cell and extensive-stage small cell lung cancer (NSCLC and ES-SCLC) had strict eligibility criteria. J-TAIL-2 was a prospective, observational study in Japan that evaluated atezolizumab regimens for advanced NSCLC/ES-SCLC, including patients ineligible for global trials. The primary endpoint was 12-month overall survival (OS); safety and efficacy in subgroups defined by age, ECOG PS and/or G8 score, and creatinine clearance were key secondary endpoints. As of February 3, 2023, 1217 patients were treated in clinical practice based on Japanese labeling/treatment guidelines. Patients received atezolizumab with either carboplatin and nab-paclitaxel (atezo + CnP), carboplatin/cisplatin and pemetrexed (atezo + PP), or bevacizumab and carboplatin and paclitaxel (atezo + bev + CP) in the NSCLC cohort (<i>n</i> = 814) or with carboplatin and etoposide (atezo + CE) in the ES-SCLC cohort (<i>n</i> = 403). Overall, 53.5% were ≥ 70 years old, and 11.8% had ECOG PS ≥ 2; median G8 scores were 13 (NSCLC cohort) and 12 (ES-SCLC). Patients &lt; 70 and ≥ 70 years had similar median (m)OS and progression-free survival (mPFS) across treatment regimens. Patients with ECOG PS &lt; 2 and G8 score ≥ median had the highest mOS/PFS vs. patients with ECOG PS ≥ 2 and G8 score&lt;median. Patients ≥ 70 years had higher incidence of Grade ≥ 3 adverse events with atezo + CnP and atezo + PP than patients &lt; 70 years; incidences were similar between groups for other regimens. Older vs. younger patients also had higher incidence of interstitial lung disease. Overall, these results suggest that atezolizumab-containing regimens remain effective in older patients, with no new safety signals.</p><p><b>Trial Registration:</b> ClinicalTrials.gov: NCT04501497</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 7","pages":"1935-1947"},"PeriodicalIF":4.9,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70411","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147943288","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An Immune Dysfunction Signature Score Predicts Survival in MDS Patients: Insights From a Longitudinal, Multicenter Study","authors":"Yu-Hung Wang,&nbsp;Carmelo Gurnari,&nbsp;Valeria Visconte,&nbsp;Arda Durmaz,&nbsp;Luca Guarnera,&nbsp;Wan-Hsuan Lee,&nbsp;Chi-Yuan Yao,&nbsp;Andres Jerez,&nbsp;Kristian Gurashi,&nbsp;Kiran Batta,&nbsp;Hsin-An Hou,&nbsp;Wen-Chien Chou,&nbsp;Mrinal S. Patnaik,&nbsp;Jaroslaw Maciejewski,&nbsp;Daniel H. Wiseman,&nbsp;Chien-Chin Lin,&nbsp;Hwei-Fang Tien","doi":"10.1111/cas.70405","DOIUrl":"10.1111/cas.70405","url":null,"abstract":"<p>Myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) are clonal myeloid neoplasms shaped by genetic lesions and immune dysregulation, both of which contribute to disease progression and poor outcomes. Existing prognostic systems, such as IPSS-R and IPSS-M, do not incorporate immune alterations. We assessed the biological and clinical relevance of an immune dysfunction signature (IDS) across multi-center MDS and CMML cohorts. IDS scores, derived from bulk transcriptomic data, were significantly associated with inferior leukemia-free and overall survival. In multivariable analyses, IDS retained independent prognostic value alongside IPSS-R, IPSS-M, and bi-allelic TP53 inactivation. Incorporation of IDS into existing models improved prognostic discrimination and time-dependent predictive accuracy. Longitudinal analyses revealed that rising IDS scores paralleled disease progression and acute transformation, whereas declining scores were observed in remission. Biologically, IDS-high cases demonstrated reduced cytotoxic T-cell activity, expansion of regulatory T cells, enrichment of primitive progenitor signals, and increased expression of checkpoint pathway genes. These findings were validated across multiple independent MDS cohorts and consistently reproduced in CMML, where IDS also stratified risk and tracked disease evolution. Finally, integration with drug response signatures from the BeatAMLv2 cohort suggested potential therapeutic vulnerability of IDS-high cases to multikinase and NF-κB pathway inhibitors. These results establish IDS as a robust and dynamic biomarker in MDS and CMML, with applications in refined risk stratification, longitudinal disease monitoring, and guiding personalized therapeutic strategies targeting immune dysfunction.</p><p><b>Trial Registration:</b> #201709072RINC, #202109078RINB, #202207050RINB</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 7","pages":"1921-1934"},"PeriodicalIF":4.9,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70405","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147786347","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Losartan Enhances Radiosensitivity by Reversing Immunosuppressive Tumor Microenvironment Induced by Radiotherapy in TNBC","authors":"Xu Wang,&nbsp;Cuiwei Liu,&nbsp;Zihan Xia,&nbsp;Ting Hu,&nbsp;Yuting Li,&nbsp;Dan Han,&nbsp;Yunjie Song,&nbsp;Yuxi Ma,&nbsp;Yanxia Zhao","doi":"10.1111/cas.70407","DOIUrl":"10.1111/cas.70407","url":null,"abstract":"<p>Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, with limited therapeutic options. Radiotherapy (RT) is a cornerstone of TNBC treatment; however, preclinical studies suggest that RT may both stimulate and suppress immune responses within the tumor microenvironment (TME). While RT can enhance immune responses, it may also induce an immunosuppressive TME, contributing to radioresistance. The renin-angiotensin system (RAS) is also involved in the immunosuppressive TME and tumor radioresistance. Previous research showed blocker of angiotensin II receptor (AGTR1), losartan, as a RAS inhibitor, could alleviate hypoxia, thereby enhancing RT efficacy. Our study shows that high levels of AGTR1 may confer a poor prognosis and radioresistance in TNBC, and innovatively demonstrates losartan could enhance the radiosensitivity of TNBC in an immune dependent way. Furthermore, we found losartan could inhibit tumor-associated macrophages (TAMs) polarizing towards M2 phenotype, impedes the immunosuppressive function of myeloid-derived suppressive cells (MDSCs) induced by RT, and ultimately up-regulates the number and function of tumor-infiltrating CD8⁺ T lymphocytes. Besides, RNA-seq data reveals losartan impedes JAK2/STAT1 signaling activation upon irradiation, suppresses the interferon-related DNA damage resistant signature (IRDS) expression and diminishes the immune suppressive factors PD-L1 and IDO induced by irradiation in TNBC cells. Collectively, in our study, we investigate the role of losartan in radiosensitization and demonstrate losartan could reverse the immunosuppressive TME induced by RT in TNBC, which suggests that losartan combined with RT may represent a promising strategy for the treatment of TNBC.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 7","pages":"1795-1812"},"PeriodicalIF":4.9,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70407","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147845001","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Plasma Protein Analysis for Biomarker Discovery in Lung Cancer Treated With Atezolizumab Combination Therapy in J-TAIL-2","authors":"Yasushi Goto,&nbsp;Makoto Nishio,&nbsp;Kadoaki Ohashi,&nbsp;Atsushi Osoegawa,&nbsp;Eiki Kikuchi,&nbsp;Hideharu Kimura,&nbsp;Junichi Shimizu,&nbsp;Eisaku Miyauchi,&nbsp;Hiroshige Yoshioka,&nbsp;Ichiro Yoshino,&nbsp;Toshihiro Misumi,&nbsp;Yasutaka Watanabe,&nbsp;Nobuyuki Katakami,&nbsp;Akira Kisohara,&nbsp;Masafumi Yamaguchi,&nbsp;Hirotaka Kuroki,&nbsp;Masamichi Sugimoto,&nbsp;Hisao Ashimura,&nbsp;Misa Tanaka,&nbsp;Akihiko Gemma","doi":"10.1111/cas.70375","DOIUrl":"10.1111/cas.70375","url":null,"abstract":"<p>J-TAIL-2 evaluated the efficacy and safety of atezolizumab, an anti–programmed death-ligand 1 (PD-L1), plus chemotherapy in patients with non-small cell lung cancer (NSCLC) and extensive-stage small cell lung cancer (ES-SCLC) in Japanese clinical practice, demonstrating comparable outcomes to those in the corresponding Phase 3 trials. Although PD-L1 expression is predictive of atezolizumab efficacy in some settings, additional minimally invasive, blood-based biomarkers are needed. This exploratory biomarker study included 359 J-TAIL-2 patients. The NSCLC cohort received atezolizumab combined with carboplatin and nab-paclitaxel (CnP, <i>n</i> = 42), cisplatin/carboplatin and pemetrexed (<i>n</i> = 72), or bevacizumab plus carboplatin and paclitaxel (bev + CP, <i>n</i> = 135). The ES-SCLC cohort received atezolizumab plus carboplatin and etoposide (<i>n</i> = 100). Approximately 560 cancer- or immune-related proteins were evaluated using the Proximity Extension Assay from blood plasma collected at three timepoints: baseline, before the second atezolizumab dose, and at the onset of immune-related adverse events (irAEs). Protein-wise comparisons were made to evaluate significant changes (<i>P</i> &lt; 0.05 and &gt; 0.5 log2 fold change) and linked to clinical outcomes reported in J-TAIL-2. IL-6, MUC-16, and KRT-19 were associated with shorter progression-free survival across multiple regimens. Granzyme A and B, immune activation markers, were elevated in responders who received atezolizumab + CnP and atezolizumab + bev + CP. High levels of baseline immune stimulation proteins were associated with irAEs across regimens. Protein expression changes were varied and regimen-dependent in subgroup analyses including older patients and those with <i>EGFR</i>-mutant tumors. These data warrant further investigation across different cancer types and atezolizumab-containing regimens to determine their relevance to efficacy and irAE occurrence of atezolizumab combination therapy.</p><p><b>Trial Registration:</b> ClinicalTrials.gov ID, NCT04501497 (J-TAIL-2) and NCT04818983 (biomarker study)</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 7","pages":"1948-1960"},"PeriodicalIF":4.9,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70375","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147786489","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Decreased Expression of FAT4 Promotes Multiple Myeloma Proliferation and Migration by Targeting the Hippo/YAP Pathway","authors":"Lina Zhang,&nbsp;Na Shen,&nbsp;Xin Cheng,&nbsp;Qinglin Shi,&nbsp;Lijuan Chen,&nbsp;Xuxing Shen","doi":"10.1111/cas.70404","DOIUrl":"10.1111/cas.70404","url":null,"abstract":"<p>FAT4 is a member of the protocadherin family and plays an important role in various types of tumors. Multiple myeloma (MM) is a common hematological malignancy. Whole-exome sequencing revealed that FAT4 is a frequently mutated driver gene of MM, but its biological function in MM remains elusive. We performed targeted gene sequencing on MM cells isolated from 161 patients and retrospectively analyzed the clinical data of these patients. The mutation frequency of <i>FAT4</i> in newly diagnosed MM patients was 15.5%, ranking as the sixth most frequently mutated gene. <i>FAT4</i> mutations were associated with poor prognosis of MM and decreased expression of FAT4. In vitro experiments demonstrated that FAT4 knockdown promoted the proliferation and migration in MM cells. We then confirmed these findings in vivo using zebrafish and mouse models. We further revealed that FAT4 exerted tumor suppressor effects by targeting the Hippo/YAP pathway in MM. Knockdown of FAT4 promoted the nuclear translocation of YAP. Interestingly, FAT4 did not regulate YAP nuclear entry through the canonical phosphorylation cascade. Instead, coimmunoprecipitation assays revealed the interaction between FAT4 and YAP. This interaction retained YAP in the cytoplasm, thereby blocking its nuclear translocation. Our findings highlight the tumor-suppressive role of FAT4 in MM and uncover a novel mechanism by which FAT4 regulates the Hippo/YAP pathway.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 7","pages":"1883-1893"},"PeriodicalIF":4.9,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70404","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147786439","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aspartate Transporter SLC1A3 Promotes Colorectal Cancer via MDM2-p53 Pathway and M2 Macrophage Polarization","authors":"Chao Deng,&nbsp;You Zhou,&nbsp;Sijie Song,&nbsp;Hongtao Liu,&nbsp;Siqi Liao,&nbsp;Li Zhou,&nbsp;Siyuan Chen,&nbsp;Zhihang Zhou,&nbsp;Song He,&nbsp;Bingrong Liu","doi":"10.1111/cas.70396","DOIUrl":"10.1111/cas.70396","url":null,"abstract":"<p>Colorectal cancer (CRC) remains the most prevalent malignancy of the digestive system globally and ranks second in cancer-related deaths worldwide. Metabolic reprogramming is one of the hallmarks of cancer. Aspartate is a proteinogenic non-essential amino acid with several essential functions in cancer cells. SLC1A3 is the main aspartate transporter, but its role in CRC needs to be elucidated. We found that SLC1A3 is significantly overexpressed in CRC tissues compared to adjacent normal tissues, and elevated SLC1A3 expression is associated with poor prognosis. Further, SLC1A3 could enhance the proliferation, invasion, migration of CRC cells and organoids by activating the DAG/PKC/MDM2 signaling axis. In addition, we revealed that SLC1A3 in CRC cells could induce the immunosuppressive M2 phenotype of macrophages via upregulating IL17c and CSF2. In sum, these findings suggest that SLC1A3 plays a dual role in CRC progression and may represent a promising target for therapeutic intervention.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 7","pages":"1813-1827"},"PeriodicalIF":4.9,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70396","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147786364","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"T Cell Heterogeneity Shaped by Alternative Splicing Predicts Prognosis in Hepatocellular Carcinoma","authors":"Xiaohui Peng,&nbsp;Zhenli Li,&nbsp;Xiuqing Dong,&nbsp;Zhixiong Cai,&nbsp;Chenfan Lu,&nbsp;Junjie Gao,&nbsp;Shuyue You,&nbsp;Yuwen Wang,&nbsp;Jianming Mao,&nbsp;Xiaolong Liu,&nbsp;Geng Chen,&nbsp;Yingchao Wang","doi":"10.1111/cas.70394","DOIUrl":"10.1111/cas.70394","url":null,"abstract":"<p>Alternative splicing (AS) plays a key role in the regulation of immune function and cellular heterogeneity. However, its impact on T-cell behavior and clinical outcomes in hepatocellular carcinoma (HCC) remains poorly understood. Single-cell full-length transcriptome data were used to obtain comprehensive splicing site information. Variable AS events were identified in each cell using the SCASL algorithm, and AS-based profiles were constructed. Based on this, differential expression, functional enrichment, cell interaction, and RNA velocity analyses were used to reveal functional differences among distinct cell populations based on AS profiles. Finally, based on the functional differences among distinct T-cell subpopulations, an AS event-based survival prognosis model was constructed to assess patient outcomes. Using the SCASL algorithm, major cell subpopulations were identified and T cells were further divided into two AS-based subtypes distinct from gene expression clustering. Functional analysis revealed that these subtypes were enriched in NOD-like receptors, C-type lectin receptors, T-cell receptor signaling, antigen processing and presentation, and other immune-related pathways. Based on the definition of AS events, we constructed a prognostic model capable of distinguishing between patients with different risk levels, which was further validated using public datasets. Collectively, our findings highlight the crucial role of AS in shaping T-cell functional heterogeneity, and the AS-based prognostic model we established further underscores its clinical relevance, providing novel insights into tumor–immune interactions and uncovering potential splicing-derived biomarkers for immunotherapy.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 7","pages":"1907-1920"},"PeriodicalIF":4.9,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70394","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147786454","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic Predictors of Progression and Skin Rash in Japanese mCSPC Patients Treated With Apalutamide: CUARTET Study","authors":"Masaki Shiota,&nbsp;Taku Naiki,&nbsp;Koji Hatano,&nbsp;Akira Yokomizo,&nbsp;Hiroaki Tsuchiya,&nbsp;Yoko Takahashi,&nbsp;Taku Nakayama,&nbsp;Masaki Yoshida,&nbsp;Hirotsugu Uemura","doi":"10.1111/cas.70401","DOIUrl":"10.1111/cas.70401","url":null,"abstract":"<p>Despite promising evidence of the efficacy of the androgen deprivation therapy (ADT) plus apalutamide in metastatic castration-sensitive prostate cancer (mCSPC), it remains unknown how its effectiveness and safety are shaped by genetic factors, particularly among Asian populations. We evaluated whether baseline circulating tumor deoxyribonucleic acid (ctDNA) and germline variants predict outcomes and tolerability in the phase IV, open label, multicenter CUARTET trial in Japan. We enrolled 101 patients with mCSPC starting apalutamide with ADT; 99 contributed pretreatment plasma for ctDNA profiling across 73 prostate cancer driver genes and 86 provided genome-wide single nucleotide polymorphism (SNP) data. Primary endpoints were time to castration resistant prostate cancer (CRPC) and overall survival; skin rash incidence was assessed as a key adverse event. Cox models (adjusted for volume of disease) and exploratory machine-learning–assisted logistic regression were applied. ctDNA presence at baseline was associated with shorter time to CRPC (adjusted hazard ratio [HR] 3.18; 95% confidence interval [CI], 1.17–11.09) and overall survival (adjusted HR for all-cause mortality 3.95; 95% CI, 1.06–25.63). Among 55 paired samples, ctDNA presence increased from 61.8% pretreatment to 87.2% posttreatment, and alterations in androgen receptor and DNA repair pathways were enriched in patients who discontinued for progression. Any grade skin rash occurred in 59.4% and grade ≥ 3 in 5.9%. An exploratory genome-wide screen identified 12 SNPs associated with skin rash. This study demonstrated that baseline ctDNA predicts prognosis of Japanese patients with mCSPC receiving apalutamide with ADT and identified potential genetic predictors for treatment-related skin rash.</p><p><b>Trial Registration:</b> ClinicalTrials.gov identifier: jRCTs071200040</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 7","pages":"1985-1995"},"PeriodicalIF":4.9,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70401","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147786355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Autophagy Inhibition by Fangji Huangqi Decoction Enhances Tumor Immunogenicity and Potentiates PD-1 Blockade","authors":"Yuxiao Jiang,&nbsp;Shiji Zeng,&nbsp;Dingye Wang,&nbsp;Junbo Jiang,&nbsp;Zhenzhen Li,&nbsp;Jingbi Li,&nbsp;Dan Chen,&nbsp;Xu Zhao,&nbsp;Zheng Ying,&nbsp;Yuehua Deng,&nbsp;Qianwei Cai,&nbsp;Silin Mai,&nbsp;Jiayi Zheng,&nbsp;Qiaohong Yang,&nbsp;Fang Liu,&nbsp;Biaoyan Du,&nbsp;Jianyong Xiao,&nbsp;Xiaoyi Liu,&nbsp;Kun Wang","doi":"10.1111/cas.70399","DOIUrl":"10.1111/cas.70399","url":null,"abstract":"<p><i>Fangji Huangqi Decoction</i> (FJHQ), a traditional Chinese medicine formula derived from “Jin Gui Yao Lue,” has been reported to exhibit immunomodulatory and anti-inflammatory effects. This study investigates its potential anti-tumor mechanism via the enhancement of CD8⁺ T cell-mediated immunity. In murine B16 melanoma and Lewis lung carcinoma models, FJHQ significantly suppressed tumor growth and enhanced CD8⁺ T cell infiltration and cytotoxicity. CD8⁺ T cell depletion abrogated these effects, confirming their necessity. In vitro, FJHQ treatment augmented antigen presentation by tumor cells through upregulation of MHC-I expression, leading to improved CD8⁺ T cell recognition and killing. Mechanistically, FJHQ inhibited autophagic flux in tumor cells, as evidenced by mCherry-GFP-LC3 reporter assays and electron microscopy, resulting in impaired lysosomal function and elevated MHC-I levels. Furthermore, combining FJHQ with anti–PD-1 therapy synergistically promoted CD8⁺ T cell activity, increased granzyme B and IFN-γ expression, and induced substantial tumor regression. These findings demonstrate that FJHQ enhances antitumor immunity by suppressing autophagy and elevating MHC-I expression, thereby sensitizing tumors to PD-1 blockade. FJHQ represents a promising immunoadjuvant for cancer therapy.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"117 7","pages":"1778-1794"},"PeriodicalIF":4.9,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70399","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147786446","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}