Gastric Cancer最新文献

{"title":"Updated Asian consensus guidelines for the diagnosis and management of gastrointestinal stromal tumor (2025).","authors":"Hidekazu Hirano, Yoichi Naito, Tsuyoshi Takahashi, Seiichi Hirota, Kyoung-Mee Kim, Min-Hee Ryu, Jian Wang, Hui Cao, Jian Li, Chien-Feng Li, Chueh-Chuan Yen, Han-Kwang Yang, Hwoon-Yong Jung, Chun-Nan Yeh, Hsiu-Po Wang, Li-Tzong Chen, Lin Shen, Yoon-Koo Kang, Toshirou Nishida","doi":"10.1007/s10120-026-01773-4","DOIUrl":"10.1007/s10120-026-01773-4","url":null,"abstract":"<p><p>Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor arising from the gastrointestinal tract. Accurate pathological diagnosis and appropriate treatment for this malignancy require a multidisciplinary approach. In consideration of the differences in clinical practice between Asian and Western countries, the Asian Consensus Guidelines for the Diagnosis and Management of GISTs were published in 2016 by multidisciplinary experts in Asian countries (Japan, Korea, China, and Taiwan). Given the accumulation of new evidence since the previous publication, a multidisciplinary expert panel consisting of pathologists, surgical oncologists, and medical oncologists revised the Asian consensus guidelines. This narrative review provides updated consensus recommendations reflecting available evidence, expert opinion, and current clinical practice for the diagnosis and management of GIST in Asian countries.</p>","PeriodicalId":12684,"journal":{"name":"Gastric Cancer","volume":" ","pages":"887-903"},"PeriodicalIF":6.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13525072/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148445776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinicopathological characteristics of gastric papillary adenocarcinoma compared with tubular adenocarcinoma.","authors":"Taku Hattori, Masanori Terashima, Atsushi Ochiai, Tadakazu Shimoda, Yusuke Koseki, Kenichiro Furukawa, Keiichi Fujiya, Yutaka Tanizawa, Etsuro Bando","doi":"10.1007/s10120-026-01774-3","DOIUrl":"10.1007/s10120-026-01774-3","url":null,"abstract":"<p><strong>Background: </strong>Papillary adenocarcinoma (Pap) is a relatively rare histological subtype of differentiated adenocarcinoma, and its biological behavior has not been fully elucidated. The present study aimed to clarify the clinicopathological characteristics of Pap.</p><p><strong>Methods: </strong>This study retrospectively included 1701 patients with differentiated-type gastric cancer who underwent gastrectomy at our institution between 2009 and 2021. Clinicopathological characteristics, recurrence patterns, and survival outcomes were compared between the two groups.</p><p><strong>Results: </strong>Patients in the Pap group were older and showed higher rates of venous-and lymphatic invasion, as well as more advanced clinical and pathological stages. In the multivariate analysis of cumulative recurrence, histological type was identified as an independent predictor (HR 2.051, p = 0.037). The most common initial site of recurrence was the liver in both groups, with a significantly higher incidence observed in the Pap group (p < 0.001). In the multivariate analysis of overall survival, histological type was also identified as an independent prognostic factor (HR 1.962, p = 0.044).</p><p><strong>Conclusions: </strong>Pap showed poorer survival than the Tub group, with a particularly higher incidence of liver metastasis recurrence.</p>","PeriodicalId":12684,"journal":{"name":"Gastric Cancer","volume":" ","pages":"1015-1023"},"PeriodicalIF":6.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148307971","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}

{"title":"A systematic review of factors associated with the patient and diagnostic intervals in gastric cancer.","authors":"John A Queenan, Noor Breik, Shaila J Merchant, Monica Yuen, Ekaterina Kosyachkova, Colleen Webber, Amanda Ross-White, Biniam Kidane, Safiya Karim, Natalie Coburn, Alyson L Mahar","doi":"10.1007/s10120-026-01775-2","DOIUrl":"10.1007/s10120-026-01775-2","url":null,"abstract":"<p><strong>Introduction: </strong>Many patients with gastric cancer in low-incidence countries are diagnosed at advanced stages, underscoring the need for earlier detection to enable curative treatment. This systematic review aimed to summarize risk factors affecting the patient interval (symptom recognition to first contact with a healthcare professional) and the diagnostic interval (first contact to diagnosis).</p><p><strong>Methodology: </strong>We reviewed the peer-reviewed literature from 2012 to 2025. The search was conducted across CINAHL, EMBASE, MEDLINE, and PsycINFO, with each title/abstract and full-text article reviewed by two team members. We extracted publication details, study methodology, variables, participant demographics, clinical descriptors, and interval-related information. We followed PRISMA reporting guidelines.</p><p><strong>Results: </strong>Of 2,848 references screened, 8 studies were included: three on patient intervals and five on diagnostic intervals. Patient-interval studies involved 31 to 187 participants, with median lengths ranging from 9 to 210 days; patient-reported intervals were typically longer than those based on health data alone. Risk factors for longer patient intervals included herbal remedy use, symptom alarm and severity, older age, and multimorbidity. Diagnostic-interval studies included 69 to 2,175 participants, with median intervals of 24 to 84 days; factors associated with longer intervals included lower family-physician density, older age, early-stage disease, female sex, and low diagnostic suspicion.</p><p><strong>Conclusion: </strong>Long intervals between symptom onset and diagnosis remain a major challenge for people diagnosed with gastric cancer in countries without screening programs. This review identifies significant methodological gaps restricting comparability. Further research with standardized definitions and equity-focused approaches is needed to inform early detection and patient education initiatives.</p>","PeriodicalId":12684,"journal":{"name":"Gastric Cancer","volume":" ","pages":"930-939"},"PeriodicalIF":6.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148404518","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}

{"title":"Clinical outcomes of endoscopic resection for remnant gastric cancer: a multicenter prospective cohort study.","authors":"Yosuke Toya, Takayuki Matsumoto, Haruhisa Suzuki, Kohei Takizawa, Toshiaki Hirasawa, Yoji Takeuchi, Kenji Ishido, Shu Hoteya, Tomonori Yano, Shinji Tanaka, Masahiro Nakagawa, Tetsuya Yoshizaki, Naohiro Yoshida, Kingo Hirasawa, Mitsuru Matsuda, Hironori Yamamoto, Tetsuya Sumiyoshi, Shinji Kitamura, Hisao Tanaka, Ryo Shimoda, Yumi Mashimo, Ryutaro Morizono, Kazutoshi Fukase, Taichi Shimazu, Hiroyuki Ono, Satoshi Tanabe, Hitoshi Kondo, Hiroyasu Iishi, Motoki Ninomiya, Ichiro Oda","doi":"10.1007/s10120-026-01759-2","DOIUrl":"10.1007/s10120-026-01759-2","url":null,"abstract":"<p><strong>Background: </strong>While the incidence of early-stage remnant gastric cancer (RGC) is increasing, evidence for the validity of endoscopic resection (ER) for RGC remains limited. We aimed to clarify outcomes of ER for RGC.</p><p><strong>Methods: </strong>This is the second analysis of a nationwide prospective cohort study of ER for early gastric cancer (EGC) at 41 Japanese centers from July 2010 to June 2012. We compared short-term and long-term outcomes of 355 patients with 369 RGCs and 8460 patients with 9394 primary EGCs in the naïve stomach. We calculated 5-year overall survival (OS) and disease-specific survival (DSS) rates. Hazard ratios (HRs) for all-cause mortality were estimated using a Cox regression model; patients with curatively resected primary EGC were the reference group.</p><p><strong>Results: </strong>For RGCs and primary EGCs, median procedure times were 87 and 77 min (p < 0.001); en-bloc resection rates were 96.7 and 99.5% (p < 0.001); R0 resection rates were 83.5 and 93.3% (p < 0.001); intraoperative perforation rates were 4.2 and 1.9% (p = 0.002); and delayed perforation rates were 1.1 and 0.3% (p = 0.018), respectively. 5-year OS (83.1% vs 89.5%, p < 0.001) and DSS (98.5% vs 99.6%, p = 0.002) were lower in RGC cases than primary EGC cases. HRs for all-cause mortality against curatively resected primary EGC were 1.19 (95% CI 0.85-1.66) for curatively resected RGC, 1.37 (1.12-1.60) for non-curatively resected primary EGC, and 1.87 (1.21-2.90) for non-curatively resected RGC.</p><p><strong>Conclusions: </strong>Although ER for RGC showed slightly inferior short-term outcomes to ER for primary EGC, long-term outcomes were comparable under the curative resection.</p>","PeriodicalId":12684,"journal":{"name":"Gastric Cancer","volume":" ","pages":"1034-1044"},"PeriodicalIF":6.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148175814","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}

{"title":"Multimodal features and prognostic risk assessment in locally advanced gastric cancer patients following neoadjuvant therapy based on machine learning algorithms: a multicenter study.","authors":"Li Liu, Qing Zhong, Caiming Weng, Lihong Chen, Yuqin Sun, Shichao Wu, Minxian Zhuang, Wen Li, Guojun Xia, Zhixin Shangguan, Dong Wu, Chaohui Zheng, Jianwei Xie, Qiyue Chen, Lisheng Cai, Changming Huang, Ping Li","doi":"10.1007/s10120-026-01777-0","DOIUrl":"10.1007/s10120-026-01777-0","url":null,"abstract":"<p><strong>Background: </strong>Neoadjuvant therapy (NAT) is recommended for locally advanced gastric cancer (LAGC), but some patients respond poorly. We aimed to construct a multimodal model integrating CT images, transcriptomic sequencing, and clinicopathological data to assess prognosis in LAGC patients receiving NAT.</p><p><strong>Materials and methods: </strong>This multicenter study included 505 LAGC patients who underwent NAT. Radiomic features were extracted from preoperative CT images of 505 patients. RNA-seq was performed on 277 post-NAT specimens, with additional data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases (n = 804). Patients were divided into training (168 cases), internal validation (72 cases), and external validation cohorts. Machine learning algorithms identified key radiomic, molecular, and clinical features associated with NAT response, which were then integrated into a multimodal model to predict overall survival (OS) and disease-free survival (DFS).</p><p><strong>Results: </strong>Six radiomic and three molecular features significantly associated with NAT response were selected. Radiomic risk (hazard ratio [HR]: 4.0, P < 0.001) and molecular risk (HR: 7.1, P < 0.001) were independent prognostic factors. By integrating radiomic risk, molecular risk, and clinical characteristics, a multimodal model (MuMo) was constructed.The C-index results (OS, C-index = 0.855; DFS, C-index = 0.786) demonstrated that MuMo outperformed the single-modality models and ypTNM staging.Mechanistic analysis suggested that the efficacy of neoadjuvant therapy was significantly enriched in immune-inflammatory pathways.</p><p><strong>Conclusions: </strong>MuMo can effectively predict postoperative survival risk in LAGC patients receiving NAT, serving as a powerful tool for optimizing prognostic assessment.</p>","PeriodicalId":12684,"journal":{"name":"Gastric Cancer","volume":" ","pages":"1127-1139"},"PeriodicalIF":6.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148561878","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}

{"title":"Nodal burden modifies the prognostic significance of perineural invasion in stage I-III gastric cancer.","authors":"Qi Wang, Hongxue Meng, Shizheng Xiong, Xiaoyan Zhang, Midie Xu","doi":"10.1007/s10120-026-01784-1","DOIUrl":"10.1007/s10120-026-01784-1","url":null,"abstract":"<p><strong>Background: </strong>Perineural invasion (PNI) is an established adverse prognostic factor in gastric cancer, but whether its prognostic effect varies with nodal burden and first metastatic site remains unclear.</p><p><strong>Methods: </strong>We retrospectively analyzed 12,898 patients with stage I-III gastric cancer who underwent curative-intent R0 gastrectomy at Fudan University Shanghai Cancer Center between 2000 and 2022. Multivariable Cox models with a pre-specified PNI-by-positive-node interaction estimated associations with overall survival (OS) and progression-free survival (PFS). First distant metastatic site was evaluated using Fine-Gray and Firth logistic site-contrast models. The PNI-nodal-burden association was assessed in an independent pathology cohort and the ACRG cohort.</p><p><strong>Results: </strong>Each additional positive lymph node attenuated the PNI-associated hazard ratio for OS (interaction HR, 0.976) and PFS (interaction HR, 0.977; both interaction P < 0.001). PNI was independently associated with poorer OS (HR, 1.38; 95% CI 1.20-1.59) and PFS (HR, 1.32; 95% CI 1.15-1.51) in N0-N1 disease, but the associations were attenuated in N2-N3 disease (OS: HR, 1.12; 95% CI 1.00-1.24; PFS: HR, 1.09; 95% CI 0.99-1.21). Among N0-N1 patients with pT3-pT4 disease and liver-only or peritoneal-only first metastasis, PNI was associated with peritoneal rather than hepatic dissemination (OR, 3.87; 95% CI 1.54-10.63).</p><p><strong>Conclusions: </strong>The prognostic association of PNI was modified by nodal burden and was most evident in N0-N1 gastric cancer. These site-specific findings support prospective evaluation of PNI-informed, peritoneum-directed surveillance.</p>","PeriodicalId":12684,"journal":{"name":"Gastric Cancer","volume":" ","pages":"1024-1033"},"PeriodicalIF":6.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148591139","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}

{"title":"Comparison of minimally invasive surgery and open surgery following chemotherapy for cStage IVb gastric cancer: a multicenter retrospective cohort study.","authors":"Yusuke Fujii, Shigeo Hisamori, Nobuaki Hoshino, Seiichiro Kanaya, Eiji Tanaka, Yoshito Yamashita, Akira Miki, Kosuke Toda, Michihiro Yamamoto, Yosuke Kinjo, Dai Manaka, Hiroaki Hata, Hironori Kawada, Shotaro Matsuda, Atsushi Itami, Kyoichi Hashimoto, Kenjiro Hirai, Sanae Nakajima, Hiroshi Okabe, Masazumi Sakaguchi, Yuichiro Kawamura, Takashi Sakamoto, Shintaro Okumura, Tatsuto Nishigori, Shigeru Tsunoda, Kazutaka Obama","doi":"10.1007/s10120-026-01779-y","DOIUrl":"10.1007/s10120-026-01779-y","url":null,"abstract":"<p><strong>Background: </strong>The standard treatment for stage IV gastric cancer (GC) is chemotherapy, but advances in systemic therapy have rendered curative surgery a viable option. However, the role of minimally invasive surgery (MIS) in this context remains unclear. This multicenter retrospective cohort study aimed to evaluate safety and effectiveness of MIS post-chemotherapy for patients with cStage IVb GC.</p><p><strong>Methods: </strong>Patients with cStage IVb GC who underwent curative-intent MIS or open surgery post-chemotherapy at 19 institutions between 2011 and 2022 were reviewed. Propensity score-matching was performed to adjust for confounding variables. The primary outcome was postoperative complications. Secondary outcomes were perioperative outcomes and long-term survival.</p><p><strong>Results: </strong>Among 237 eligible patients (MIS, 130; open surgery, 107), 64 matched pairs were analysed. The incidence of Clavien-Dindo grade ≥ II complications was 31.2% in the MIS group and 46.9% in the open group, with no significant difference (risk ratio 0.67, 95% confidence interval [CI] 0.41-1.08). MIS was associated with a longer operative time (mean difference [MD] 98 min, 95% CI 53-143) but reduced blood loss (MD, - 550 g; 95% CI, - 738 to - 362). The MIS group achieved R0 resections more often (92% vs. 78%). The 3-year overall survival rates were 56.5% and 44.6%, respectively (hazard ratio 0.83, 95% CI 0.51-1.36).</p><p><strong>Conclusions: </strong>In curative-intent gastrectomy following chemotherapy for cStage IVb gastric cancer, MIS was not associated with worse perioperative outcomes or long-term survival compared with open surgery. Given its less invasive nature, MIS could be considered a feasible option for these patients when performed by experienced surgeons.</p>","PeriodicalId":12684,"journal":{"name":"Gastric Cancer","volume":" ","pages":"1150-1165"},"PeriodicalIF":6.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13525005/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148520163","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Feasibility study of cap-assisted endoscopic mucosal resection for gastric adenocarcinoma of fundic gland type.","authors":"Risa Ashizaki, Tetsuya Yoshizaki, Yuta Higasa, Hiroshi Tanabe, Eri Nishikawa, Shinya Hoki, Ryosuke Ishida, Hitomi Hori, Tatsuya Nakai, Chise Ueda, Satoshi Urakami, Hirofumi Abe, Madoka Takao, Toshitatsu Takao, Masakyo Asahara, Yoshinori Morita, Takashi Toyonaga, Yuzo Kodama","doi":"10.1007/s10120-026-01762-7","DOIUrl":"10.1007/s10120-026-01762-7","url":null,"abstract":"<p><strong>Background: </strong>Gastric adenocarcinoma of fundic gland type (GA-FG) is a rare subtype that typically arises in the upper stomach, making endoscopic submucosal dissection (ESD) technically challenging. Cap-assisted endoscopic mucosal resection (EMRC) is widely used for early gastric cancer due to its shorter procedure time and improved safety profile. We evaluated its efficacy and safety for GA-FG.</p><p><strong>Methods: </strong>We retrospectively analyzed patients with GA-FG who underwent EMRC or ESD between April 2013 and September 2024. Outcomes included en bloc, complete, and curative resection rates; procedure time; and adverse events. Odds ratios (ORs) were estimated using logistic regression, and inverse probability of treatment weighting was applied for adjustment.</p><p><strong>Results: </strong>We enrolled 70 patients with 77 lesions that were treated by EMRC (n = 57) or ESD (n = 20). En bloc resection was achieved in 100% of both groups. Complete resection rates were 96.5% for EMRC and 100% for ESD (P = 1.00). The EMRC group had significantly shorter median procedure time (6 vs. 46 min, P < 0.001) and fewer adverse events (OR 0.05, 95% CI 0.003-0.36; P = 0.002). No significant differences were found in curative resection (OR 3.47, 95% CI 0.86-14.08; P = 0.08) and intraoperative perforation (10% in the ESD group, 0% in the EMRC group; P = 0.06).</p><p><strong>Conclusions: </strong>Our findings suggest that EMRC is a safe and effective treatment for GA-FG, offering shorter procedure times and a lower risk of complications compared with ESD.</p>","PeriodicalId":12684,"journal":{"name":"Gastric Cancer","volume":" ","pages":"1045-1052"},"PeriodicalIF":6.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13524992/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148015205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long-term acid suppression after gastric cancer treatment: clarifying denominators and time-dependent exposure.","authors":"Xiaohe Zhang, Chaochi Yue","doi":"10.1007/s10120-026-01771-6","DOIUrl":"10.1007/s10120-026-01771-6","url":null,"abstract":"","PeriodicalId":12684,"journal":{"name":"Gastric Cancer","volume":" ","pages":"1177-1178"},"PeriodicalIF":6.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148251319","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}

{"title":"CXCL12 upregulates PD-L1 expression and promotes M2 polarisation of tumour-associated macrophages to confer anti-PD-1 resistance in gastric cancer.","authors":"Chao Wu, Boya Li, Huiling Li, Panjie Zhu, Yichen Wang, Xiaoxi Li, Yingnan Feng, Li Zhang, Zizhao Cheng, Dan Gao, Lan Zhang, Xianzhe Dong","doi":"10.1007/s10120-026-01769-0","DOIUrl":"10.1007/s10120-026-01769-0","url":null,"abstract":"<p><strong>Objective: </strong>Immunotherapy offers promise for gastric cancer (GC) patients, yet its efficacy is substantially limited by high rates of treatment resistance, the mechanisms of which remain incompletely characterised. We aimed to delineate the role and mechanistic basis of CXCL12 in conferring anti-PD-1 resistance in GC.</p><p><strong>Methods: </strong>An anti-PD-1-resistant GC mouse model was established through chronic anti-PD-1 induction and in vivo tumour tissue passaging. Human and murine GC cell lines stably overexpressing CXCL12 (OE-CXCL12) were generated via lentiviral transduction to construct corresponding OE-CXCL12 GC mouse models. Single-cell transcriptomics analysed the tumour microenvironment (TME) in anti-PD-1-resistant GC. Molecular docking and Drug Affinity Responsive Target Stability (DARTS) assays predicted and validated ligand-receptor binding, respectively. RNA or protein expression of specific molecules was quantified by RT-qPCR, ELISA, immunofluorescence, and western blotting.</p><p><strong>Results: </strong>Anti-PD-1-resistant GC models showed upregulated CXCL12, PD-L1, and CD206 expression with unchanged PD-1. OE-CXCL12 reduced anti-PD-1 sensitivity, elevated M2-TAM infiltration and TGF-β, IL-10, IL-4 levels in TME, reduced M1-TAM and CD8⁺ T cell infiltration and IL-12 level, with differentially expressed genes enriched in HIF-1, PD-L1/PD-1 checkpoint, and PI3K/AKT signalling pathways. M2-TAM-conditioned medium elevated SOX2, OCT-4, NANOG in GC cells. Mechanistically, CXCL12 binds CXCR4 to activate PI3K/AKT/HIF-1α, promoting PD-L1 expression and M2-TAM polarisation. CXCL12 inhibition recovered anti-PD-1 efficacy.</p><p><strong>Conclusions: </strong>This identifies CXCL12 as a novel anti-PD-1 resistance gene in GC, with the CXCL12/CXCR4/PI3K/AKT/HIF-1α axis induces anti-PD-1 tolerance through a dual-pathway mechanism of promoting PD-L1 expression and M2-TAM polarisation, providing potential therapeutic strategies to prevent and reverse anti-PD-1 resistance in GC.</p>","PeriodicalId":12684,"journal":{"name":"Gastric Cancer","volume":" ","pages":"972-986"},"PeriodicalIF":6.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148271254","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}