Combination therapy with cetirizine and anti-PD-1 antibody suppresses colitis-induced colon tumor formation in mice

Eur J Pharmacol. 2025 Jul 15:999:177704. doi: 10.1016/j.ejphar.2025.177704. Epub 2025 May 2.

Abstract

Immune checkpoint inhibitors (ICIs) have transformed cancer therapy, yet their efficacy remains limited in inflammation-associated tumors, necessitating combinatorial approaches. Although combinations with cytotoxic or targeted agents are well established, the therapeutic potential of non-oncologic drugs, such as antihistamines, is less explored. In this study, we investigate whether cetirizine, a non-sedating histamine H1 receptor antagonist, enhances the antitumor effects of anti-programmed cell death protein 1 (PD-1) antibody in a murine model of colitis-associated colorectal cancer. Combination therapy, not monotherapy, significantly reduced tumor volume in vivo. Flow cytometry of splenocytes revealed increased PD-1 expression on T cells only in the combination group, suggesting systemic immune activation. Immunohistochemical analysis showed elevated CD3+ T-cell infiltration into tumors following combination treatment. Meanwhile, gene expression analysis of tumor tissues revealed downregulated Vegfa, Mmp9, Il10, and Cd80, along with upregulated Hspg2 and Fn1, suggesting a shift in the tumor microenvironment. In vitro, cetirizine suppressed Mmp9 expression in CT26 cells, Il10 in macrophages, and VEGFA in human umbilical vein endothelial cells, indicating cell-type-specific effects that partially mirror the in vivo findings. Immunohistochemistry further demonstrated a reduced frequency of FoxP3+ regulatory T cells among CD3+ T cells within the tumor stroma in the combination group. Collectively, these findings indicate that cetirizine enhances ICI efficacy by reshaping the tumor microenvironment through immunomodulatory mechanisms. Our results support the repurposing of antihistamines as a novel strategy to improve cancer immunotherapy.

Keywords: Anti-PD-1 antibodies; Histamine; Histamine H(1) receptor antagonist; Immune checkpoint inhibitors; Tumor microenvironment; Tumor-infiltrating lymphocytes.

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols* / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols* / therapeutic use
  • Cell Line, Tumor
  • Cetirizine* / pharmacology
  • Cetirizine* / therapeutic use
  • Colitis* / complications
  • Colitis* / drug therapy
  • Colitis* / immunology
  • Colitis-Associated Neoplasms* / drug therapy
  • Colitis-Associated Neoplasms* / immunology
  • Colitis-Associated Neoplasms* / pathology
  • Colonic Neoplasms* / drug therapy
  • Colonic Neoplasms* / etiology
  • Colonic Neoplasms* / immunology
  • Colonic Neoplasms* / pathology
  • Disease Models, Animal
  • Female
  • Humans
  • Immune Checkpoint Inhibitors* / pharmacology
  • Immune Checkpoint Inhibitors* / therapeutic use
  • Mice
  • Mice, Inbred BALB C
  • Programmed Cell Death 1 Receptor* / antagonists & inhibitors
  • Programmed Cell Death 1 Receptor* / immunology
  • Tumor Microenvironment / drug effects

Substances

  • Cetirizine
  • Programmed Cell Death 1 Receptor
  • Immune Checkpoint Inhibitors
  • Pdcd1 protein, mouse