<p>Nanoparticle-based therapeutics have been intensively explored for tumor treatment. However, developing convenient and specific strategy that does not rely on exogenous energy guided activation remains challenging. Herein, an ion-exchange-driven chemodynamic therapy is proposed based on taking advantage of TME K⁺-mediated cation exchangeability of layered ferrous silicate (LFSs). LFSs was prepared by a facile “<i>in situ</i> 3D-to-2D structural transformation” strategy through valence bond transition from SiO–H–OSi to Fe–O, providing extensive convenience compared to those conventional exfoliation methods. The structure-activity relationship and mechanism between surrounding TME ions and the cation exchange behavior of LFSs was revealed by both experimental investigation of the cation-exchange process and DFT calculations of the adsorption hydration behavior. As a result, the interlayered Fe ions were selectively and preferentially exchanged by TME K⁺ rather than surrounding TME Na⁺, Mg²⁺, Ca²⁺, or Cl⁻, thereafter activating specific Fenton reaction together with TME H⁺, H₂O₂, and glutathione, demonstrating highly precise catalytic therapeutic efficacy both <i>in vitro</i> and <i>in vivo</i>. This study proposes an original tumor specific therapy modality with high precision and safety through taking advantage of ionic exchangeability of layered silicate, and provides enlightenment to reverse the TME K⁺ disorder.</p>