<p>Immunogenic cell death (ICD) can activate immune cells and potentiate the response to immunotherapy. The mitogen-activated protein kinase (MAPK) signaling pathway regulates the immune response and mediates T-cell receptor signaling. Activation of the MAPK signaling pathway decreases the levels of tumor-infiltrating lymphocytes in triple-negative breast cancer (TNBC) and is associated with worse survival. Here, we investigated the potential of the MEK inhibitor cobimetinib as an ICD inducer in TNBC. We demonstrated that cobimetinib elicited hallmarks of ICD, including elevated levels of damage-associated molecular patterns. Ectopic ERK expression attenuated cobimetinib-induced CRT. Cobimetinib also evoked caspase-8 activation with increased Bax and Bak expression, while caspase inhibitor suppressed cobimetinib-induced CRT expression and apoptosis. In immunocompetent (BALB/c) mice bearing 4T1 tumors, cobimetinib exhibited stronger tumor growth inhibition than in immunodeficient (nude) mice, suggesting an immune-dependent antitumor effect. Furthermore, cobimetinib treatment increased the proportions of naïve CD8⁺ T cells and effector CD4⁺ T cells and decreases the proportion of myeloid-derived suppressor cells in immunocompetent mice bearing 4T1 tumors. Notably, we observed differential immunomodulatory effects of cobimetinib in tumor-bearing mice compared to non–tumor-bearing immunocompetent mice. Our findings indicate that MEK inhibition is associated with ICD-related molecular alterations, and that cobimetinib may contribute to immune modulation in TNBC.</p>