RT Journal Article SR Electronic T1 Apatinib enhances targeted immunotherapy via the IL-6-gp130-PI3K pathway in HER2-positive gastric cancer JF Cancer Biology & Medicine JO Cancer Biology & Medicine FD China Anti-Cancer Association SP 20250687 DO 10.20892/j.issn.2095-3941.2025.0687 A1 Tian, Ruoxi A1 Sha, Ziyue A1 Zhang, Shasha A1 Gong, Miao A1 Wu, Jianhua A1 Lu, Juntao A1 Guo, Wei A1 Zheng, Zhaoxu A1 Guo, Zhanjun YR 2026 UL http://www.cancerbiomed.org/content/early/2026/07/30/j.issn.2095-3941.2025.0687.abstract AB 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.