A novel colchicine-binding site inhibitor suppresses triple-negative breast cancer growth and metastasis and synergizes with anti-PD-L1 immunotherapy in an immunogenic cancer model.

Triple-negative breast cancer (TNBC) accounts for approximately 15% of all breast cancer cases and is defined by the absence of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2) expression. Approximately 40% of patients with TNBC develop metastatic disease, reducing median survival to 13.3 months. Paclitaxel remains a standard chemotherapeutic option; however, its efficacy is often limited by ATP-driven efflux pumps and βIII-tubulin overexpression. These limitations underscore the need for agents that can overcome resistance and suppress metastasis. Colchicine-binding site inhibitors (CBSIs) target the colchicine-binding site on tubulin to induce G2/M arrest and apoptosis and can bypass taxane resistance. SP-1-39, a novel CBSI, exhibits potent anti-cancer activity in a paclitaxel-resistant prostate cancer in vivo model, confirming its capacity to overcome chemoresistance. We also discovered that SP-1-39 upregulates PD-L1 expression in vitro, suggesting synergy with immune checkpoint blockade. This study evaluates the anti-metastatic activity of SP-1-39 in metastatic TNBC and the therapeutic potential of combining SP-1-39 with anti-PD-L1 immune checkpoint inhibition in a PD-L1-responsive colon cancer model. Our findings provide preclinical evidence supporting SP-1-39 as a promising therapeutic agent for TNBC and other solid tumors, either as a single agent or in combination with immunotherapy.