Cancer Science最新文献

{"title":"Deletion of the Mis12C-Binding Domain of CENP-C Promotes Chromosomal Aneuploidy in Cutaneous Squamous Cell Carcinoma.","authors":"Megumi Saito, Kazuhiro Okumura, Yurika Tokunaga, Sora Tanaka, Keisuke Otoyama, Yoshinori Hasegawa, Masatoshi Hara, Masakazu Hashimoto, Toshihiko Fujimori, Tatsuo Fukagawa, Yuichi Wakabayashi","doi":"10.1111/cas.70216","DOIUrl":"https://doi.org/10.1111/cas.70216","url":null,"abstract":"<p><p>CENP-C, an essential component of the kinetochore, connects centromeric chromatin to the outer kinetochore, and thereby ensures accurate chromosome segregation. Although deletion of the Mis12-binding domain (M12BD) of CENP-C does not cause developmental disorders in mice, it promotes malignant tumor progression in the two-stage DMBA/TPA-induced skin carcinogenesis model. In this study, we have demonstrated that M12BD deletion of CENP-C enhances proliferation and then promotes abnormal differentiation in DMBA/TPA-induced carcinomas in mice. To elucidate the underlying molecular mechanisms, we performed RNA sequencing and found the dysregulated expression of keratinization-related genes. Intriguingly, elevated chromosomal aneuploidy was detectable in mice with the M12BD deletion of CENP-C. Among the aneuploidies, trisomies of chromosomes 6 and 10 took place at the highest frequency. These specific chromosomal gains were accompanied by upregulation of genes involved in immune and inflammatory responses. Together, our present findings strongly suggest that M12BD of CENP-C plays a critical role in the regulation of epithelial differentiation during tumor development in mice.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145226089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reprimo (RPRM): A Tumor Suppressor That Induces Extrinsic Apoptosis via YAP Signaling.","authors":"Masahiro Takikawa, Rieko Ohki","doi":"10.1111/cas.70215","DOIUrl":"https://doi.org/10.1111/cas.70215","url":null,"abstract":"<p><p>Reprimo (encoded by RPRM) was initially identified as a p53 target gene in 2000 and functions as a tumor suppressor. Promoter hypermethylation of RPRM is frequently observed in various cancers, suggesting that it is transcriptionally silenced during tumorigenesis. Previous studies have reported that overexpression of RPRM induces G2/M cell cycle arrest, inhibits cell proliferation, promotes apoptosis, and increases cellular sensitivity to DNA damage. However, the molecular function of Reprimo is not completely understood. In particular, our recent studies revealed that Reprimo has a novel extracellular function, being secreted outside the cells where it functions to induce apoptosis in its target cells. Furthermore, we found that this apoptosis pathway is novel, mediated by a signaling pathway composed of p53-Reprimo-protocadherin family-Hippo-YAP/TAZ-p73. Reprimo is the first example of an extracellular ligand that induces cell death by modulating YAP activity and is a unique upstream regulator of Hippo signaling. This review summarizes current knowledge of the tumor-suppressive mechanisms of Reprimo, with an emphasis on its unique extracellular function and discusses potential future research directions and clinical applications in cancer therapy.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145208145","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Near-Infrared Photoimmunotherapy Targeting Esophagogastric Junction Adenocarcinoma With Fully Human Anti-EpCAM Antibody.","authors":"Maasa Sasabe, Kenji Takashima, Shingo Sakashita, Yoshikatsu Koga, Takahiro Anzai, Shiqi Yang, Shinji Saijou, Akihiro Ishikawa, Toru Yamaguchi, Hideki Tanaka, Yusuke Yoda, Takeo Fujita, Shuichi Mitsunaga, Masahiro Yasunaga, Tomonori Yano","doi":"10.1111/cas.70186","DOIUrl":"https://doi.org/10.1111/cas.70186","url":null,"abstract":"<p><p>Near-infrared photoimmunotherapy (NIR-PIT) is a tumor-specific treatment using monoclonal antibody (mAb) photosensitizer conjugates, followed by near-infrared light irradiation. This study aimed to identify the optimum target for treating esophagogastric junction (EGJ) adenocarcinoma and to evaluate the efficacy of NIR-PIT using mAbs in preclinical models. Tumor samples from 46 consecutive patients who had undergone surgery without any prior treatment for EGJ adenocarcinoma were assessed for expression and homogeneity of epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and epithelial cell adhesion molecule (EpCAM) through immunohistochemistry. Results showed positive rates of 22%, 13%, and 98% for EGFR, HER2, and EpCAM, respectively, with EpCAM also demonstrating the highest homogeneity (93%). Therefore, EpCAM was selected as the optimal target for NIR-PIT. The fully human monoclonal antibody targeting EpCAM, adecatumumab, was conjugated with the photosensitizer IR700 at different dye-antibody ratios (DAR2, DAR4, DAR7) and tested on OE19 cells and xenograft mouse models under near-infrared light irradiation. NIR-PIT with adecatumumab-IR700 significantly reduced tumor size and improved prognoses compared to controls, with DAR2 showing the best balance of efficacy and minimal side effects. Notable EpCAM expression and homogeneity underpin EpCAM as a promising target for NIR-PIT in EGJ adenocarcinoma. The fully human anti-EpCAM antibody may be suitable for NIR-PIT in EGJ adenocarcinoma.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145208139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FAM111B Suppression Enhances Sensitivity to Gemcitabine in Pancreatic Cancer Through Intracellular pH Regulation.","authors":"Motonobu Nishimura, Masaki Sunagawa, Toshio Kokuryo, Junpei Yamaguchi, Taisuke Baba, Takashi Mizuno, Shunsuke Onoe, Nobuyuki Watanabe, Shoji Kawakatsu, Tomoki Ebata","doi":"10.1111/cas.70212","DOIUrl":"https://doi.org/10.1111/cas.70212","url":null,"abstract":"<p><p>Pancreatic cancer remains a highly lethal disease, largely attributed to the rapid development of resistance against standard chemotherapy regimens. Although an acidic tumor microenvironment (TME) has been implicated in this resistance, the molecular mechanisms involved are not fully understood. In this study, we identified Family with Sequence Similarity 111 Member B (FAM111B) as significantly upregulated in pancreatic cancer cells under acidic conditions through RNA sequencing and validated. Functional analyses revealed that FAM111B regulates intracellular pH (pHi). Moreover, combining gemcitabine with α-cyano-4-hydroxycinnamic acid, a lactate transporter inhibitor known to decrease pHi, markedly suppressed pancreatic cancer cell viability compared to gemcitabine alone, thereby enhancing the sensitivity under acidic conditions in both in vitro and in mouse xenograft models. Clinically, elevated FAM111B expression correlated with significantly poorer overall survival in pancreatic cancer patients receiving gemcitabine-based chemotherapy (median OS: 2.05 vs. 3.66 years, p = 0.038). Multivariate analysis identified FAM111B expression as an independent predictor of poor prognosis (HR = 3.05, p = 0.032). These findings highlight the crucial role of FAM111B in maintaining pHi homeostasis under acidic TME conditions and contributing to gemcitabine resistance. Targeting FAM111B may represent a novel therapeutic strategy to overcome chemotherapy resistance and improve clinical outcomes in pancreatic cancer.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145201402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design and Evaluation of Eb₄Mab-7-mG_2a: A Dual-Action Anti-EphB4 Monoclonal Antibody for Targeted Breast Cancer Therapy.","authors":"Tomokazu Ohishi, Hiroyuki Suzuki, Mika K Kaneko, Tomohiro Tanaka, Akiko Harakawa, Junjiro Yoshida, Daisuke Tatsuda, Yukinari Kato, Manabu Kawada","doi":"10.1111/cas.70198","DOIUrl":"https://doi.org/10.1111/cas.70198","url":null,"abstract":"<p><p>Breast cancer remains a leading cause of cancer mortality worldwide, underscoring the urgent need for novel and effective therapeutic strategies. Eph receptor tyrosine kinases, particularly EphB4, exhibit diverse roles in cancer biology, acting as either tumor promoters or suppressors depending on the cellular environment and ligand engagement. EphB4 is frequently overexpressed in breast cancer and contributes to dysregulated signaling and tumor progression through the abnormal interaction with its ligand Ephrin-B2. We herein developed an improved anti-EphB4 monoclonal antibody, Eb₄Mab-7-mG_2a, which can be characterized as a subclass-switched IgG_2a variant designed to enhance immune effector function, specifically antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Our findings showed that Eb₄Mab-7-mG_2a effectively blocked Ephrin-B2-induced ERK phosphorylation and proliferation in EphB4-positive MCF-7 breast cancer cells but had no effect on EphB4-knockout (KO) MCF-7 cells. Flow cytometry confirmed high-affinity binding between Eb₄Mab-7-mG_2a and EphB4-expressing cells, whereas in vitro assays demonstrated potent and selective ADCC and CDC activities against EphB4-positive tumor cells. In vivo experiments showed that Eb₄Mab-7-mG_2a significantly suppressed xenograft growth in models bearing EphB4-overexpressing CHO-K1 and EphB4-positive MCF-7, but showed no therapeutic effect in EphB4-negative CHO-K1 and EphB4-KO MCF-7 xenografts. Immunohistochemical analysis revealed reduced Ki-67 proliferation indices in treated tumors, supporting the antiproliferative effects of the developed antibody. Overall, these findings demonstrate that Eb₄Mab-7-mG_2a exerts dual-action antitumor activity through ligand blockade and immune effector engagement. Further evaluations in other EphB4-overexpressing cancers and in combination with immune checkpoint inhibitors are warranted. Humanization and tumor-selective engineering may enhance its clinical potential for precision oncology.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145193583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activation of cGAS-STING Pathway by DAI-Triggered Ferroptosis in CRC Cells Reprograms TAMs Balance to Promote Anti-Tumor Immunity.","authors":"Pengrui Cheng, Que Yang, Xiao Zhang, Qiang Wang, Bingzheng Zhong","doi":"10.1111/cas.70196","DOIUrl":"https://doi.org/10.1111/cas.70196","url":null,"abstract":"<p><p>DNA-dependent activator of interferon-regulatory factors (DAI) has recently been identified to trigger ferroptosis in endothelial cells. However, it remains unclear whether it can also elicit ferroptosis in tumor cells and further remodel the tumor immune microenvironment (TIME). In this study, we found that activation of DAI could also trigger mouse colorectal cancer (CRC) cells ferroptosis. Further experiments showed that DAI-driven ferroptosis induced mitochondria oxidative stress and dysfunction, leading to the release of mitochondrial DNA (mtDNA) into the cytoplasm, which subsequently activated the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway and thereby reprogrammed the TIME by promoting tumor-associated macrophages (TAMs) M1 polarization while preventing TAMs from polarizing towards M2 type, exerting an effective anti-tumor effect, which significantly reduced tumor size and weight. In summary, our findings confirmed DAI-triggered ferroptosis-induced mtDNA-mediated cGAS-STING anti-tumor immunity pathway in mouse CRC cells, providing novel insights into the development of more effective tumor immunotherapeutic strategies that are based on DAI-mediated programmed cell death (PCD).</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145193608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Variation of Gene Expression and Methylation Profiling in Gingival and Tongue Cancers.","authors":"Takafumi Kashiwagi, So Takata, Hidenori Tanaka, Shoko Ikuta, Yasushi Totoki, Yoichiro Nakatani, Hidenori Inohara, Narikazu Uzawa, Shinichi Yachida","doi":"10.1111/cas.70205","DOIUrl":"https://doi.org/10.1111/cas.70205","url":null,"abstract":"<p><p>While the development of innovative drugs has improved the outcomes of various cancers in recent years, the number of patients with oral squamous cell carcinoma (OSCC) and mortality rates has not yet decreased significantly. This could be attributed to the prognostic and molecular differences occurring at different locations of cancer development. In this study, we conducted gene expression, DNA methylation, and tumor immunological analyses of gingival squamous cell carcinoma (GSCC) and tongue squamous cell carcinoma (TSCC) to elucidate the characteristic gene expression changes, their mechanisms, and tumor immune profiles. Gene expression analysis suggested that pathways related to the cell cycle and antibacterial humoral immunity were upregulated in GSCC, whereas immune response pathways were upregulated in TSCC. Additionally, high HOXC13 expression may be associated with GSCC prognosis. DNA methylation analysis revealed hypermethylation of the 3' UTR of the HOXD11 gene, leading to increased expression in both GSCC and TSCC. In the tumor immune profile analysis, when comparing tumor and normal tissues in GSCC, the number of immune cells did not change significantly; however, the proportion of inflammatory cells, such as CD8+ T cells, changed. In TSCC, the number and percentage of inflammatory cells, such as T lymphocytes, increased in the tumor compared to those of normal tissues. These findings underscore the importance of understanding the characteristics of site-specific OSCC. Therefore, it is essential to establish standardized treatment protocols and develop novel therapeutic strategies tailored to each anatomical site of the tumor.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145187063","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"N6-Methyladenosine-Modified circNEK11 Promotes Hepatocellular Carcinoma Progression via the miR-1236-3p/GPX2 Axis.","authors":"Qian Li, Xu Huang, Yan Tong, Caiyu Yong, Minghui Song, Cunjie Chang, Heng Dong, Fangtian Bu, Shuanghong Yan, Jie Ying, Jianxiang Chen","doi":"10.1111/cas.70203","DOIUrl":"https://doi.org/10.1111/cas.70203","url":null,"abstract":"<p><p>circRNAs are endogenous covalently closed circular RNAs, and previous studies have validated their key regulatory roles in malignant tumors; however, the specific role and regulatory mechanism of circNEK11 in hepatocellular carcinoma (HCC) remain unclear. Here, we discovered that circNEK11 back-spliced from exons 12, 13, 14, and 15 of the NEK11 gene is significantly upregulated in HCC tissues, especially recurrent HCC tissues. YTHDC1 functions as a reader of m6A-modified circNEK11 and facilitates its cytoplasmic export. circNEK11 promotes HCC cell oncogenic functions in vitro and HCC growth in vivo. Mechanistically, circNEK11 directly binds to miR-1236-3p to regulate GPX2 expression, thus promoting HCC progression and recurrence. Collectively, our findings suggest that circNEK11 is a potential biomarker and target for HCC diagnosis and treatment.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145132433","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GWAS Identifies SNPs Associated With Severe Adverse Events and Efficacy in Advanced Renal Cell Carcinoma Treated With Nivolumab.","authors":"Tokiyoshi Tanegashima, Masaki Shiota, Shusuke Akamatsu, Hideaki Miyake, Masayuki Takahashi, Mototsugu Oya, Norihiko Tsuchiya, Naoya Masumori, Hideyasu Matsuyama, Wataru Obara, Nobuo Shinohara, Kiyohide Fujimoto, Masahiro Nozawa, Kojiro Ohba, Chikara Ohyama, Katsuyoshi Hashine, Tomomi Kamba, Koji Mita, Momokazu Gotoh, Shuichi Tatarano, Masato Fujisawa, Yoshihiko Tomita, Shoichiro Mukai, Keiichi Ito, Shoji Tokunaga, Masatoshi Eto","doi":"10.1111/cas.70204","DOIUrl":"https://doi.org/10.1111/cas.70204","url":null,"abstract":"<p><p>Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced renal cell carcinoma (RCC). However, ICIs often induce immune-related adverse events (irAEs), which vary greatly among individuals and may influence treatment outcomes. This study aimed to identify genetic markers associated with the risk of severe treatment-related adverse events (trAEs) and assess their impact on patient prognosis. From August 19, 2019, to September 30, 2020, patient recruitment for nivolumab treatment in advanced clear cell RCC (ccRCC) was conducted across 23 institutions in Japan, with follow-up concluding on March 31, 2021 (protocol ID: UMIN000037739). A genome-wide association study (GWAS) was conducted in a development cohort to identify single nucleotide polymorphisms (SNPs) associated with severe trAEs following nivolumab. Sixteen SNPs were identified, and thirteen were genotyped in a validation cohort. Eight SNPs showed consistent trends with the development cohort, but they have not reached statistical significance in the validation cohort. Among them, rs2545737, corresponding to CHD1, was significantly linked to prolonged progression-free survival (PFS), highlighting its potential as a biomarker for both safety and efficacy. Further analysis indicated that high CHD1 expression in tumors correlated with improved overall survival in nivolumab-treated patients but not in those receiving everolimus. Given the failure to replicate the development set findings in our validation cohort, further re-validation within the RCC population is warranted. However, these results enhance our understanding of the genetic predisposition to trAEs and provide a significant step toward safer and more effective cancer treatment strategies. This study was registered on the University Hospital Medical Information Network (UMIN) in Japan on August 20, 2019 (protocol ID: UMIN000037739).</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145139142","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Liposomal ¹⁸⁸Rhenium Plus Macrophage Depletion Enhances Anti-PD-L1 Efficacy and B Cell Infiltration Against Lung Metastatic Cancer.","authors":"Shin-Yi Liu, Liang-Ting Lin, Chih-Hsien Chang, Yu-Jen Chen","doi":"10.1111/cas.70206","DOIUrl":"https://doi.org/10.1111/cas.70206","url":null,"abstract":"<p><p>Radionuclides such as Rhenium-188 (Re188) hold promise for treating metastatic cancers due to their cytotoxic effects and potential to stimulate systemic anti-tumor immunity. However, mononuclear phagocyte system-mediated clearance of liposome encapsulated Re188 (Lipo-Re188) limits its tumor delivery. This study aimed to enhance the therapeutic effect of Lipo-Re188 against lung metastases through macrophage depletion and immune checkpoint blockade. A lung metastatic colon cancer model was established via intravenous injection of CT26-luciferase cells and then treated with Lipo-Re188 (11.1 MBq, 30% of MTD), liposomal clodronate (Lipo-clod) for macrophage depletion, and/or anti-PD-L1 antibody. Tumor progression was monitored by bioluminescence imaging, and radionuclide biodistribution was assessed at 1, 24, and 48 h post-injection. Flow cytometry was used to assess immune cell populations in the spleen and tumor microenvironment (TME). Cytokine levels were measured using a bead-based multiplex assay and analyzed by flow cytometry. Macrophage depletion significantly enhanced tumor accumulation of Lipo-Re188 while reducing hepatic uptake and prolonging survival. The combination of Lipo-clod and Lipo-Re188 promoted B cells, restored functional T cells, and suppressed MDSC in both spleen and TME. Notably, IL-1α and GM-CSF levels were significantly elevated in the combination group. Triple therapy with Lipo-clod, Lipo-Re188, and anti-PD-L1 provided the greatest survival benefit, highest intratumoral B cell accumulation, and lowest interstitial macrophage levels, with no significant biological toxicity. Our study reveals that triple therapy overcomes immunosuppressive feedback and promotes a tumor-suppressive microenvironment. These findings support a rational combination strategy integrating radiopharmaceutical therapy with immune modulation for metastatic cancer treatment.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145114985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}