Journal Publication

Apatinib plus trastuzumab curbs IL-6 signaling in HER2-positive gastric cancer

Preclinical and case data show apatinib blocks IL-6/gp130/PI3K/STAT3 signaling to boost trastuzumab-based immunotherapy, and adding tocilizumab strengthens the effect further.

A study reported that apatinib strengthens trastuzumab-based immunotherapy against HER2-positive gastric cancer by blocking IL-6/gp130/PI3K/AKT/STAT3 signaling, with the combination validated in cell lines, humanized-mouse xenografts, and three patients.

By AppliedXLJuly 21, 2026

Executive Summary

Researchers examined whether apatinib, an oral kinase inhibitor, could improve trastuzumab-based immunotherapy for HER2-positive gastric cancer by acting on interleukin-6 signaling, using cell lines, humanized mouse models, and a small set of patients who could not tolerate or declined chemotherapy.
Apatinib blocked a specific signaling cascade that normally helps tumor cells resist trastuzumab, and combining it with immunotherapy shrank tumors more than either approach alone, with the effect reproduced in patients as well as in laboratory models.
Directly targeting the interleukin-6 receptor with a second antibody strengthened the combination further, pointing to the same pathway as the shared mechanism across both interventions rather than a coincidental effect.
The results support a chemotherapy-free treatment strategy for a subgroup of HER2-positive gastric cancer patients, mainly older adults, who currently have few options beyond standard cytotoxic chemotherapy regimens.

The question

HER2-positive gastric cancer is typically treated with trastuzumab combined with chemotherapy, but some patients, particularly older adults, cannot tolerate chemotherapy or decline it. The study asked whether apatinib, an oral VEGFR2 tyrosine kinase inhibitor, could substitute for chemotherapy's role by making trastuzumab-based immunotherapy more effective on its own, without added cytotoxic drugs. Apatinib

How it was done

The investigators combined bioinformatics analysis of KEGG and GO pathway enrichment with RNA-sequencing data from The Cancer Genome Atlas to identify how apatinib affects trastuzumab sensitivity. They then tested the apatinib-immunotherapy combination in HER2-positive gastric cancer cell lines, humanized hematopoietic stem cell tumor xenograft models (hHSC-CDXs), and three patients with stage IV gastric cancer. Mechanistic work used co-immunoprecipitation, western blotting, immunohistochemistry, and immunofluorescence to trace the signaling pathway involved. Apatinib

The mechanism

Apatinib enhanced trastuzumab's tumor-inhibiting effect by blocking the IL-6/gp130/PI3K/AKT/STAT3 signaling pathway, a cascade tumor cells can use to blunt trastuzumab's action. Bioinformatics analysis of TCGA data corroborated interleukin-6's role in HER2-positive gastric cancer, and the synergy between apatinib and targeted immunotherapy held across the xenograft models and the three treated patients. Apatinib

The reinforcing signal

Because apatinib worked through interleukin-6, the researchers tested tocilizumab, a monoclonal antibody against the interleukin-6 receptor, alongside apatinib and immunotherapy. Tocilizumab further potentiated the combination's efficacy in the xenograft models, a result that lands as one of the study's more informative findings: two different ways of hitting the same pathway, a kinase inhibitor and a receptor-blocking antibody, both amplified the same treatment effect. Apatinib

Tumor microenvironment changes

The combination altered the tumor microenvironment in ways consistent with a stronger anti-tumor immune response: decreased angiogenesis (new blood vessel formation), fewer M2-like tumor-associated macrophages and regulatory T cells (both of which normally suppress immune attack on tumors), and increased infiltration of cytotoxic CD8-positive T cells, the immune cells that directly kill tumor cells. Apatinib

What it changes

The authors concluded the data support using tocilizumab and apatinib alongside targeted immunotherapy as a chemotherapy-free option for HER2-positive gastric cancer, especially in older patients unable to tolerate chemotherapy. The clinical component rests on three patients, a case-level signal rather than a trial result, so it establishes proof of mechanism rather than a comparative efficacy finding. Apatinib

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