<?xml version='1.0' encoding='UTF-8'?><xml><records><record><source-app name="HighWire" version="7.x">Drupal-HighWire</source-app><ref-type name="Journal Article">17</ref-type><contributors><authors><author><style face="normal" font="default" size="100%">Tian, Ruoxi</style></author><author><style face="normal" font="default" size="100%">Sha, Ziyue</style></author><author><style face="normal" font="default" size="100%">Zhang, Shasha</style></author><author><style face="normal" font="default" size="100%">Gong, Miao</style></author><author><style face="normal" font="default" size="100%">Wu, Jianhua</style></author><author><style face="normal" font="default" size="100%">Lu, Juntao</style></author><author><style face="normal" font="default" size="100%">Guo, Wei</style></author><author><style face="normal" font="default" size="100%">Zheng, Zhaoxu</style></author><author><style face="normal" font="default" size="100%">Guo, Zhanjun</style></author></authors><secondary-authors></secondary-authors></contributors><titles><title><style face="normal" font="default" size="100%">Apatinib enhances targeted immunotherapy &lt;em&gt;via&lt;/em&gt; the IL-6-gp130-PI3K pathway in HER2-positive gastric cancer</style></title><secondary-title><style face="normal" font="default" size="100%">Cancer Biology &amp;amp; Medicine</style></secondary-title></titles><dates><year><style  face="normal" font="default" size="100%">2026</style></year><pub-dates><date><style  face="normal" font="default" size="100%">2026-07-20 00:00:00</style></date></pub-dates></dates><elocation-id><style  face="normal" font="default" size="100%">20250687</style></elocation-id><doi><style  face="normal" font="default" size="100%">10.20892/j.issn.2095-3941.2025.0687</style></doi><volume><style face="normal" font="default" size="100%"></style></volume><issue><style face="normal" font="default" size="100%"></style></issue><abstract><style  face="normal" font="default" size="100%">Objective: We aimed to evaluate chemotherapy-free apatinib-based immunotherapy regimens for patients with human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC) who were chemotherapy-intolerant or declined chemotherapy.Methods: Enriched the Kyoto Encyclopedia of Genes and Genomes/Gene Ontology (KEGG/GO) pathway analyses were used to identify pathways modulated by apatinib treatment and those associated with trastuzumab sensitivity. RNA-seq data from The Cancer Genome Atlas (TCGA) were used to evaluate interleukin-6 (IL-6)’s role in HER2-positive GC. The efficacy of combination therapy was validated in HER2-positive GC cell lines, humanized hematopoietic stem cells, tumor cell line-derived xenografts (hHSC-CDXs), and 3 patients with stage IV GC. Mechanistic studies involved co-immunoprecipitation, western blot, immunohistochemistry, and immunofluorescence assays.Results: Apatinib enhanced the trastuzumab-induced inhibition of HER2-positive GC by blocking the IL-6/glycoprotein 130 (gp130)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/signal transducer and activator of transcription 3 (STAT3) signaling pathway in vitro, as validated through bioinformatics analysis. We confirmed the synergistic effects of apatinib with the targeted immunotherapy combination in inhibiting HER2-positive GC in both hHSC-CDXs and patients with HER2-positive GC. Given that apatinib suppressed HER2-positive GC via IL-6, we also confirmed that tocilizumab (a monoclonal antibody targeting IL-6R) significantly potentiated apatinib’s efficacy with targeted immunotherapy in hHSC-CDXs. Potential mechanisms of immunotherapy enhancement with apatinib and tocilizumab included decreased angiogenesis, M2-like tumor-associated macrophages (M2-TAMs), and regulatory T cells (Tregs), as well as increased cytotoxic CD8+ T cell infiltration in the tumor microenvironment.Conclusion: Our data support the potential application value of tocilizumab and apatinib for targeted immunotherapy in patients with HER2-positive GC, particularly in older patients who cannot tolerate chemotherapy.The GSE129221, GSE185783, and GSE220917 datasets were obtained from the GEO database. The RNA-seq data for STAD were retrieved from TCGA database. Datasets analyzed during the current study are available from Zhanjun Guo on reasonable request.</style></abstract></record></records></xml>