The signal hijacker: How tumors co-opt chemical, electrical, and mechanical cues to thrive

To survive within hostile microenvironments, tumors exploit a coordinated, tri-dimensional signaling network encompassing chemical, electrical, and mechanical communication. This enables them to reshape the tumor ecosystem into a supportive niche. This review introduces a unified "signal hijacking" framework to decipher this process. First, chemical hijacking redirects metabolites through mechanisms like lactate shuttling and nucleotide theft via tunneling nanotubes and extracellular vesicles while subverting cytokine networks through TGFβ-dependent immunosuppression. Second, bioelectrical hijacking capitalizes on ion gradient alterations via V-ATPase-driven depolarization and intercellular communication through gap junction-transmitted calcium waves. Third, mechanical hijacking involves ECM restructuring through LOXL2-mediated fibrosis and cadherin tension modulation via β-catenin liberation during cellular force competitions. The hijacking of these signals reprograms the genetic and protein landscape of cells within the tumor microenvironment, fostering an environment suitable for tumor survival. Accordingly, therapeutic strategies targeting these vulnerabilities aim to disrupt tumor communication through three primary modalities: chemical interception (e.g., LDHA and MCT1 inhibitors), bioelectrical recalibration (e.g., Kv1.3 activators and TRPV1 antagonists), and mechanical intervention (e.g., LOXL2 antibodies and Piezo1 inhibitors). This "signal hijacking "paradigm recasts cancer as a battle for communicative control within the ecosystem. We thus propose that reestablishing system-wide signaling homeostasis, rather than pursuing pure cytoreduction, represents a fundamental strategy to overcome therapy resistance.