PT - JOURNAL ARTICLE AU - Tian, Ruoxi AU - Sha, Ziyue AU - Zhang, Shasha AU - Gong, Miao AU - Wu, Jianhua AU - Lu, Juntao AU - Guo, Wei AU - Zheng, Zhaoxu AU - Guo, Zhanjun TI - Apatinib enhances targeted immunotherapy <em>via</em> the IL-6-gp130-PI3K pathway in HER2-positive gastric cancer AID - 10.20892/j.issn.2095-3941.2025.0687 DP - 2026 Jul 20 TA - Cancer Biology &amp; Medicine PG - 20250687 4099 - http://www.cancerbiomed.org/content/early/2026/07/30/j.issn.2095-3941.2025.0687.short 4100 - http://www.cancerbiomed.org/content/early/2026/07/30/j.issn.2095-3941.2025.0687.full 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.