Ranitidine as an adjuvant regulates macrophage polarization and activates CTLs through the PI3K-Akt2 signaling pathway

Int Immunopharmacol. 2023 Mar:116:109729. doi: 10.1016/j.intimp.2023.109729. Epub 2023 Feb 16.


Adjuvants are an indispensable component of vaccines, but there are few adjuvants for human vaccines. H2 receptor blockers, inhibiting gastric acid secretion, have immune enhancement effects. Ranitidine (RAN) is a water-soluble H2 receptor blocker, and whether it has an immune-enhancing effect is still unknown. In this study, flow cytometry, western blotting, and immunofluorescence methods were used to analyze whether RAN could activate macrophage polarization to the M1 phenotype in vivo and in vitro. Here, we found that the M1 inflammatory cytokine levels and surface markers in RAW264.7 cells were upregulated by NF-κB activation, possibly through the PI3K-Akt2 signaling pathway, after RAN treatment. Endocytic function was also enhanced by feedback regulation of Akt2/GSK3β/Dynmin1 signaling. Furthermore, to evaluate the adjuvant function of RAN, we used OVA plus RAN as a vaccine to inhibit the growth of B16-OVA tumors in mice. We also found that in the RAN adjuvant group, macrophage polarization to M1, Th1 cell differentiation, and cytotoxic T lymphocyte (CTL) activation were significantly upregulated. The tumor growth of mice was inhibited, and the survival rate of mice was significantly improved. This study provides new evidence for the mechanism by which RAN activates the immune response and is expected to provide a new strategy for the research and development of tumor vaccine adjuvants.

Keywords: Adjuvant; Anticancer therapy; CTL; Macrophage polarization; PI3K-Akt2 pathway; Ranitidine.

MeSH terms

  • Adjuvants, Immunologic* / pharmacology
  • Adjuvants, Immunologic* / therapeutic use
  • Animals
  • Cancer Vaccines / immunology
  • Cancer Vaccines / therapeutic use
  • Humans
  • Macrophage Activation / drug effects
  • Macrophage Activation / immunology
  • Macrophages* / drug effects
  • Macrophages* / immunology
  • Mice
  • NF-kappa B / metabolism
  • Neoplasms* / drug therapy
  • Neoplasms* / immunology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • RAW 264.7 Cells
  • Ranitidine* / pharmacology
  • Ranitidine* / therapeutic use
  • Signal Transduction
  • T-Lymphocytes, Cytotoxic* / drug effects
  • T-Lymphocytes, Cytotoxic* / immunology
  • Vaccines


  • Adjuvants, Immunologic
  • Akt2 protein, mouse
  • NF-kappa B
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Ranitidine
  • Vaccines
  • Cancer Vaccines