西替利嗪与抗 PD-1 抗体联合治疗抑制小鼠结肠炎诱导的结肠肿瘤形成

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 H 1 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.