Potential treatment benefits of a GLP‑1R antagonist in combination with immune checkpoint inhibitors in colorectal cancer

The clinical efficacy of immune checkpoint inhibitors (ICIs) in colorectal cancer (CRC) remains limited. Modulation of the glucagon‑like peptide‑1 receptor (GLP‑1R) may enhance T‑cell‑mediated antitumor responses. The present study aimed to evaluate the antitumor effects of the GLP‑1R antagonist Exendin 9‑39 (Exe‑9) combined with anti‑programmed cell death protein‑1 (PD‑1) treatment in preclinical CRC models. Using in vitro co‑culture assays, ELISA and in vivo murine models, alongside immunohistochemical and molecular analyses of clinical samples, HT‑29 and MC38‑OVA colon cancer cell lines were co‑cultured in vitro with activated T cells in the presence of Exe‑9. In vivo, male BALB/c mice were injected with MC38 to establish a CRC model and nude mice were used to assess T‑cell dependency. To evaluate this synergistic effect, BALB/c mice with CRC were treated with Exe‑9, anti‑PD‑1 or a combination. Additionally, clinical CRC samples were analyzed to assess the association of GLP‑1R expression with the immunotherapy response. Exe‑9 significantly enhanced T‑cell‑mediated cytotoxicity in CRC cell lines and reduced tumor growth in immunocompetent CRC mice; however, this effect was not observed in nude mice. Furthermore, combination therapy with the GLP‑1R antagonist and anti‑PD‑1 yielded an improved antitumor effect compared with either treatment alone, and high GLP‑1R expression in clinical samples correlated with poor ICI response. These findings suggest that GLP‑1R antagonism potentiates T‑cell‑mediated antitumor immunity and may provide a promising adjunctive therapeutic strategy for patients with CRC when combined with ICIs in the future.