Cancer Science最新文献

{"title":"Targeted Photo-Induced Elimination of Tumor-Associated Macrophages Suppresses Cancer Progression in a Murine Model.","authors":"Kohei Nakajima, Tomomi Uchiyama, Kazuki Funayama, Yuto Goto, Akari Mukaimine, Naoya Ieda, Mikako Ogawa","doi":"10.1111/cas.70489","DOIUrl":"10.1111/cas.70489","url":null,"abstract":"<p><p>Tumor-associated macrophages (TAMs) are key components of the immunosuppressive tumor microenvironment (TME) and represent attractive therapeutic targets to enhance antitumor immunity. However, systemic TAM-depletion strategies targeting colony-stimulating factor 1 receptor (CSF1R) are associated with the risk of off-target toxicity due to the depletion of macrophages in healthy tissues. Here, we investigated the potential of near-infrared photoimmunotherapy (NIR-PIT) as a strategy for selective, photo-induced elimination of TAMs. The Fab fragment of an anti-CSF1R antibody was conjugated with the photosensitizer IRDye 700DX (IR700), and the therapeutic effects of the conjugate were evaluated in a murine cancer model. Upon NIR light irradiation, Fab-IR700 significantly suppressed tumor growth and improved overall survival of the tumor-bearing mice. Notably, repeated NIR-PIT cycles enhanced therapeutic outcomes and induced durable anticancer effects, as indicated by the rejection of reimplanted cancer cells. Flow cytometry and histological analyses confirmed TAM depletion and significant alterations in the intra-tumoral immune cell populations posttreatment. Overall, CSF1R-targeted NIR-PIT can effectively eliminate TAMs without systemic toxicity, thus presenting a promising strategy to remodel the TME toward an antitumor state and synergize with other immunotherapies against refractory tumors.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13435534/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148671036","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":"tRNA-Derived Small RNAs in Digestive Cancers: From Translational Regulation to Immune and Extracellular Communication.","authors":"Wang Xitan, Li Han","doi":"10.1111/cas.70494","DOIUrl":"10.1111/cas.70494","url":null,"abstract":"<p><p>Transfer RNA-derived small RNAs (tsRNAs), comprising tRNA-derived fragments (tRFs) and stress-induced tRNA halves (tiRNAs), have increasingly been recognized as an important regulatory class in gastric cancer (GC), colorectal cancer (CRC), hepatocellular carcinoma (HCC), and pancreatic cancer/pancreatic ductal adenocarcinoma (PC/PDAC). Research in this field has expanded from expression profiling and liquid biopsy to non-canonical translational control, metabolic adaptation, therapy resistance, immune-associated remodeling, and extracellular-vesicle (EV)-related communication. The most intensively studied and mechanistically developed area currently lies at the intracellular level. In digestive system tumors, tsRNAs can act through EIF4 displacement, AGO2/RISC-dependent silencing, direct target repression, and ribosome-associated interactions, with some of these mechanisms validated in animal models. Beyond direct regulation of gene expression, tsRNAs can also influence tumor metabolic state and thereby contribute to chemo- and radio-resistance. By contrast, studies directly examining the effects of tsRNAs on immune-cell populations remain relatively limited, and work on EV-mediated systemic propagation still largely focuses on vesicle association and biomarker value. Functional delivery and recipient-cell effects require further clarification. Among the currently summarized studies, pancreatic-derived signaling that conditions the hepatic niche represents one of the few examples approaching a cross-organ functional model. This review discusses the major functional layers of tsRNAs in digestive system tumors, beginning with the relatively mature intracellular mechanisms and then extending to emerging immune, extracellular/systemic, and host-microbe research. We also identify key unresolved problems, including nomenclature standardization, modification-aware sequencing, criteria for EV functional delivery, causal validation of microbiota-derived tsRNAs, and prospective biomarker validation against benign and inflammatory disease controls.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13435531/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148671065","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":"LMTK2 Inhibits Metastasis of Colon Cancer Cells Through p38 MAPK.","authors":"Jie Lun, Jinzhao Zhang, Jianxin Xu, Liyuan Jing, Yanqing Qin, Jing Fang, Mengchao Yu","doi":"10.1111/cas.70490","DOIUrl":"10.1111/cas.70490","url":null,"abstract":"<p><p>Metastasis is the leading cause of death in patients with colon cancer. Although Lemur tyrosine kinase 2 (LMTK2) has been implicated in cell proliferation, its role in metastasis is unclear. In this study, we found that low LMTK2 expression correlates with metastatic status (M1 stage) and a higher metastasis rate in a large colon cancer cohort. Additionally, LMTK2 expression is negatively correlated with pro-metastatic genes and positively correlated with metastasis suppressors, a pattern that was validated in 50 clinical colon cancer specimens. Functional studies demonstrated that LMTK2 potently inhibits cell migration and invasion in vitro and suppresses metastasis in a mouse model in vivo. Mechanistically, LMTK2 disrupts the interaction between p38 MAPK and its upstream kinases MKK3/6, thereby inhibiting p38 activation and subsequent cell migration and invasion. Notably, the kinase-deficient LMTK2 (K168R) mutant also suppresses p38 phosphorylation and impedes cell migration and invasion. These results uncover a novel anti-metastatic function of LMTK2, which acts through inhibition of p38 independently of its kinase activity.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13435533/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148671098","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":"Pathophysiological and Molecular Features of DXd ADC-Related Interstitial Pneumonitis in Cynomolgus Monkeys.","authors":"Kazuyoshi Kumagai, Takuma Iguchi, Kentaro Kubota, Ken Sakurai, Yoshimi Tsuchiya, Katsuyoshi Chiba","doi":"10.1111/cas.70424","DOIUrl":"10.1111/cas.70424","url":null,"abstract":"<p><p>Interstitial lung disease (ILD) is an important adverse event related to deruxtecan-based antibody-drug conjugates (DXd ADCs). Understanding mechanisms and translationally relevant preclinical models remain incompletely defined. Here, we established a reproducible cynomolgus monkey model of DXd ADC-related ILD and performed the first integration of bronchoalveolar lavage fluid (BALF) extracellular vesicle (EV) proteomics with lung single-cell RNA sequencing (scRNA-seq). Weekly intravenous administration of a target-nonbinding human IgG1 DXd ADC to cynomolgus monkeys for 12 weeks consistently induced interstitial pneumonitis in all animals, with radiologic abnormalities emerging by Week 6 and progressing thereafter. Longitudinal SomaScan-based proteomic analyses revealed a pronounced and selective increase in differentially expressed proteins (DEPs) in BALF-derived EVs from Week 6 onward, exceeding changes observed in plasma or bulk BALF. Gene Ontology analysis showed enrichment of inflammatory, wound repair/regeneration, and extracellular matrix remodeling pathways within the BALF EV compartment. Integration of BALF EV proteomics with lung scRNA-seq demonstrated strong concordance between EV-associated signatures and transcriptional programs in alveolar epithelial, mesenchymal, and immune cell populations. Core injury-associated genes, including FN1, TIMP1, and COL3A1, were broadly upregulated across cell types, along with cell-type-restricted signatures including AT1 cells (BMP4, HMOX2), AT2 cells (CXCL2, SIRPA), fibroblasts (TNC, IGF1), endothelial cells (LCP1, CXCL12), neutrophils (ADAM17), and macrophages (CD84, HAVCR2, CXCL10). Together, this study defines a robust cynomolgus monkey model of DXd ADC-related ILD and identifies BALF EVs as a sensitive, lung-localized molecular readout and a promising translational source of mechanistic insights.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":"2305-2316"},"PeriodicalIF":4.3,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394137/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148018209","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":"Integrated Transcriptomic and Functional Analyses Reveal lncRNA-miRNA-mRNA Axis in AML Relapse After Allo-HSCT.","authors":"Fei Zhao, Wenhao Wang, Hongye Gao, Ping Zhu, Weihua Zhai, Yi He, Aiming Pang, Sizhou Feng, Mingzhe Han, Lina Wu, Shukai Qiao, Lei Zhang, Erlie Jiang, Xiaolei Pei, Donglin Yang","doi":"10.1111/cas.70417","DOIUrl":"10.1111/cas.70417","url":null,"abstract":"<p><p>Relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the leading cause of treatment failure in acute myeloid leukemia (AML), yet the non-coding RNA-mediated regulatory mechanisms in relapse-driving tumor clones are not fully understood. In this study, we performed transcriptomic profiling of CD34⁺ cells from the bone marrow of patients who had relapsed after allo-HSCT and from those in sustained remission, and observed that long non-coding RNAs (lncRNAs) exhibited the largest magnitude of differential expression relative to other RNA classes. To systematically elucidate their function, we integrated correlation analysis, neighborhood topology, and thermodynamic modeling to construct relapse-associated competing endogenous RNA (ceRNA) networks. These networks highlighted multiple lncRNA-miRNA-mRNA axes potentially promoting leukemic progression. Functional interrogation using CRISPR-based xenograft assays and a single-cell CRISPR screening platform (Perturb-seq-like strategy) revealed that relapse-associated lncRNAs regulate AML cell proliferation and survival. Among them, SNHG8 emerged as a representative regulator that promotes relapse through the SNHG8-miR-625-ZC3H13/15 signaling axis. SNHG8 knockdown markedly impaired AML cell growth and triggered apoptosis. Furthermore, treatment with hypomethylating agents (HMAs) such as azacitidine and decitabine differentially modulated lncRNA/ceRNA expression signatures, thereby linking clinical interventions to transcriptomic regulation. Together, our findings identify lncRNA-ceRNA networks in post-transplant relapse of AML and identify the SNHG8 axis as a potential therapeutic vulnerability, providing a rationale for further investigation of lncRNA-targeted strategies in this clinical setting.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":"2289-2304"},"PeriodicalIF":4.3,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394839/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147976638","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":"RUNX1-Driven CPXM1 Transcription Promotes Malignant Phenotypes and EMT in Gastric Cancer Cells.","authors":"Ping Jia, Fengming Xu, Tao Zhou, Pingping Wang, Huiping Chen, Jing Zhang, Xiaochen Yuan, Haoxun Xu, Yu Ouyang","doi":"10.1111/cas.70475","DOIUrl":"10.1111/cas.70475","url":null,"abstract":"<p><p>Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, with current treatment strategies largely limited to surgery, chemotherapy, and targeted therapy. Although the glycoprotein CPXM1 has been implicated in tumorigenesis, its functional role and underlying molecular mechanisms in GC remain unclear. In this study, we demonstrated that CPXM1 is significantly upregulated in GC tissues, and that elevated CPXM1 expression is associated with an unfavorable prognosis in GC patients. Both in vitro and in vivo functional assays revealed that CPXM1 significantly promotes GC cell proliferation, invasion, and metastasis. Mechanistically, CPXM1 was found to facilitate epithelial-mesenchymal transition (EMT), a critical process driving cancer progression. Furthermore, we identified the transcription factor RUNX1 as a direct upstream regulator of CPXM1, which binds to the CPXM1 promoter and transcriptionally activates its expression. Collectively, these findings delineate a previously unrecognized RUNX1/CPXM1/EMT axis that contributes to GC malignant progression, highlighting CPXM1 as a potential diagnostic biomarker and therapeutic target.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2026-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13425543/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148632026","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":"Adipocyte-Derived Palmitic Acid Promotes Breast Cancer Malignancy via ZDHHC15-Mediated S-Palmitoylation of PPARγ.","authors":"Geon Ho Moon, Min Young Lee, Jiwon Koh, Ki Yong Hong, Junji Fukuda, Sung Joon Kim, Yang-Sook Chun","doi":"10.1111/cas.70487","DOIUrl":"10.1111/cas.70487","url":null,"abstract":"<p><p>Peroxisome proliferator-activated receptor gamma (PPARγ), a well-characterized regulator of adipogenesis, also functions as a tumor suppressor in breast cancer. However, the PPARγ agonist rosiglitazone has shown limited clinical efficacy, highlighting the importance of understanding PPARγ regulation within the tumor microenvironment. Here, we demonstrate that adipocyte-derived palmitic acid promotes PPARγ S-palmitoylation via zinc finger DHHC-domain containing protein 15 (ZDHHC15), as confirmed by acyl-biotin exchange (ABE) assay. Immunoblot, RT-qPCR, and immunoprecipitation further revealed that this modification leads to ubiquitin-mediated proteasomal degradation of PPARγ. Functional studies using adipocyte-conditioned media and an oxygen-permeable 3D spheroid culture system showed that PPARγ palmitoylation promotes breast cancer malignancy and confers resistance to rosiglitazone. Notably, the palmitoylation inhibitor 2-bromopalmitate (2-BP) stabilizes PPARγ, suppressing breast cancer malignancy. Furthermore, 2-BP synergistically enhances the therapeutic efficacy of rosiglitazone, suggesting that targeting PPARγ S-palmitoylation represents a promising therapeutic strategy in breast cancer.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2026-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13424263/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148631921","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":"Nicotinic Acid Restriction Enhances the Therapeutic Benefit of NAMPT Inhibition in Small-Cell Lung Cancer Models.","authors":"Kyoji Tsurumi, Miyuki Nomura, Mai Ouchi, Shigehiro Yagishita, Naohiko Kikuchi, Taku Sato, Mami Morita, Yoji Yamashita, Kayoko Hayashi, Tomoyoshi Soga, Akinobu Hamada, Tatsuro Fukuhara, Nobuhiro Tanuma","doi":"10.1111/cas.70486","DOIUrl":"10.1111/cas.70486","url":null,"abstract":"<p><p>Small-cell lung cancer (SCLC) is an aggressive malignancy with limited therapeutic options. We previously showed that nicotinic acid riboside (NAR) sustains NAD biosynthesis in vivo and compensates for NAMPT inhibition in SCLC models. Here, we evaluated combining NAMPT inhibition with dietary nicotinic acid (NA) restriction to suppress NAR-dependent NAD biosynthesis. This combination showed enhanced antitumor activity consistent with synthetic lethality in SCLC CDX models and showed robust efficacy in PDX models, including those derived from chemotherapy-refractory tumors. In most CDX models examined, combination therapy showed greater antitumor activity than standard chemotherapy with cisplatin and etoposide. Although we did observe transient leukopenia, the treatment was otherwise better tolerated than chemotherapy, with less impact on body weight and platelet counts. These findings support NAD metabolism-targeted therapy as a promising strategy to treat SCLC.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2026-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13413092/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148609160","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":"Real-World Safety and Efficacy of Pola-R-CHP in Previously Untreated DLBCL: POLASTAR Interim Analysis of 500 Patients.","authors":"Takahiro Kumode, Hitomi Sawa, Kohta Miyawaki, Atsushi Satake, Nobuhiro Kanemura, Ritsuro Suzuki, Yuki Fujiwara, Yasuhiro Nagate, Shuichi Ota, Takahiro Fujino, Hideki Goto, Noriko Fukuhara, Mamiko Sakata-Yanagimoto, Koji Izutsu, Momoko Nishikori, Hirohiko Shibayama, Daisuke Ennishi, Takayuki Shimose, Mai Asai, Itaru Matsumura, Koichi Akashi, Koji Kato","doi":"10.1111/cas.70484","DOIUrl":"10.1111/cas.70484","url":null,"abstract":"<p><p>POLASTAR (jRCT1071220082) is a multicenter, prospective observational study evaluating the real-world efficacy and safety of polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisolone (Pola-R-CHP) in Japanese patients with diffuse large B-cell lymphoma (DLBCL), addressing the limited real-world data in this setting. Patients ≥ 18 years, with previously untreated DLBCL, receiving Pola-R-CHP were enrolled. Patients excluded from POLARIX (NCT03274492), including those > 80 years, were included. Overall, 485 patients were included in the full analysis set (FAS; median age, 71 years [range 27-93]; age ≤ 80 years, 87.6%; International Prognostic Index score 2-5, 73.7%). Median relative dose intensity (RDI) for rituximab and polatuzumab vedotin was ≥ 93.0% (both FAS and patients > 80 years), and for the chemotherapy components median RDI was ≥ 87.2% in the FAS and ≥ 49.6% for patients > 80 years. Grade ≥ 3 adverse events (AEs) occurred in 47.4% of patients in the FAS and 56.7% of patients > 80 years; serious AEs occurred in 12.6% and 25.0%, respectively. The most common Grade ≥ 3 AE (FAS/> 80 years) was neutrophil count decreased (25.6%/26.7%). In the FAS, 5 (1.0%) deaths due to AEs were reported and 33 (6.8%) patients discontinued polatuzumab vedotin due to AEs. No new safety signals were observed. In the FAS, overall response rate and complete response rate (95% confidence interval [CI]) were 93.2% (90.5-95.2) and 83.3% (79.6-86.5), respectively, and were 87.3% (76.0-93.7) and 80.0% (67.6-88.4) in patients > 80 years. Safety and efficacy of Pola-R-CHP in Japanese patients, including those > 80 years, were consistent with results from POLARIX. Trial Registration: Japan Registry of Clinical Trials (jRCT1071220082).</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2026-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13397324/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148580895","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":"New Treatment Strategy and Future Research Direction for BRAF-Mutated Cancer.","authors":"Masanobu Takahashi, Sakura Hiraide Taniguchi, Yuya Yoshida","doi":"10.1111/cas.70480","DOIUrl":"10.1111/cas.70480","url":null,"abstract":"<p><p>BRAF is a key oncogene in various malignancies including malignant melanoma, thyroid cancer, colorectal cancer, and lung cancer. The protein it encodes is a constituent of the mitogen-activated protein kinase pathway that regulates cell growth. Mutations, mainly BRAF^V600E, that cause the activation of BRAF in turn induce MEK and ERK activation through their phosphorylation, which promotes the growth and survival of cancer cells. Treatment with BRAF inhibitor, and more recently, treatment with BRAF inhibitor plus MEK inhibitor was first developed in malignant melanoma. In 2022, treatment with BRAF inhibitor plus MEK inhibitor was approved tumor-agnostically for the treatment of BRAF^V600E-mutated cancer, apart from colorectal cancer, in the USA. In colorectal cancer, the combination of a BRAF inhibitor and an anti-EGFR antibody was developed in a later line setting, and more recently, the combination of a BRAF inhibitor, an anti-EGFR antibody and chemotherapy was developed. Despite the recent advances of BRAF-targeted therapies, intrinsic and/or acquired resistance to those therapies still needs to be overcome. We discuss the current status of the clinical development of BRAF-targeted therapy, clinical findings on the resistance mechanism, and new possible treatment strategies for patients with BRAF-mutated cancer.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2026-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394550/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148563447","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}