The RAC1 tripartite hub: coupling metabolic plasticity and immune evasion to dictate breast cancer cell fate.

For decades, the Ras-related C3 botulinum toxin substrate 1 (RAC1) has been classically defined merely as a cytoskeletal motor driving cancer cell motility and metastasis. However, emerging spatial and metabolic evidence suggests a broader role for this GTPase. This Review proposes the "3C Tripartite Convergence Model," presenting RAC1 as a central integrative node that couples Cellular metabolic plasticity (C1), Cross-cellular symbiosis (C2), and Cold microenvironment sculpting (C3). Rather than a simple signaling relay, accumulating evidence indicates RAC1 may contribute to coordinated metabolic and immune adaptations associated with therapy resistance. We examine evidence linking RAC1 to the glycolysis-oxidative phosphorylation (OXPHOS) switch, facilitates intercellular mitochondrial transfer via tunneling nanotubes, and contributes to lactate-mediated immune evasion. Recognizing that targeted therapy resistance involves spatial and metabolic reprogramming is important for future clinical strategies. While the toxicity of pan-RAC1 inhibitors highlights significant challenges, the development of next-generation strategies-including targeted degraders and the exploitation of synthetic lethal metabolic vulnerabilities-provides a potential roadmap for overcoming immune evasion and metabolic adaptation in refractory breast cancers.