As a specific inhibitor of Polo-like kinase 1 (PLK1), BI2536 synergizes with diverse chemotherapies (e.g., microtubule-targeting agents, alkylators, platinum drugs) across multiple preclinical cancer models, enhancing tumor suppression and overcoming chemoresistance by inducing G2/M arrest, activating apoptosis via BAX/caspase-3 pathways and pyroptosis via GSDME, and modulating critical signaling cascades (Wnt/β-catenin, MEK/ERK). Here, GSDME is linked to neoplasm.