Radiotherapy-induced ferroptosis is accompanied by an adaptive response of tumor cells to ferroptosis-inhibiting gene expression. In this study, a degradable, in situ generated silicon-manganese composite system was constructed, loaded with a carbonic anhydrase (CA IX) inhibitor (4-(2-aminoethyl)benzenesulfonamide (ABS)) to form a DSiMn-ABS nanosystem to enhance the ferroptosis sensitivity of hypoxic tumor cells and improve the effect of radiotherapy. The system can continuously degrade in the tumor environment and X-rays to release manganese dioxide (MnO2) and ABS; thereby inhibiting CA IX activity, inducing intracellular acidification in tumor cells, regulating the AMP-activated protein kinase (AMPK)/acetyl-CoA carboxylase (ACC) axis to increase the sensitivity of tumor cells to ferroptosis, and affecting the activity of glutathione peroxidase 4 (GPX4) through MnO2 to consume glutathione (GSH), further inhibiting the ferroptosis defense system of tumor cells, and ultimately effectively improving the efficiency of radiotherapy. Studies have shown that the system can effectively inhibit tumor growth and provide a new dual sensitization strategy for tumor radiotherapy.

Innovations:
1. For the first time, carbonic anhydrase IX inhibition was combined with the ferroptosis mechanism to develop a new radiosensitization strategy, which achieved an enhancement of ferroptosis by regulating the acidity of the tumor microenvironment.
2. In terms of material design, a degradable silicon-manganese composite nanosystem with X-ray responsiveness was developed to achieve intelligent drug delivery and controllable release, providing new ideas for the application of nanomaterials in tumor treatment.
3. The key role of the AMPK/ACC signaling axis in regulating ferroptosis was deeply revealed, providing an important theoretical basis for understanding the ferroptosis mechanism and developing new treatment strategies.
Inspiration from scientific research:
1. When conducting tumor treatment research, the complexity of the tumor microenvironment should be fully considered, and the treatment effect should be improved through the synergistic effect of multiple mechanisms.
2. The design of nanomaterials should focus on multifunctional integration, combining therapeutic functions with environmental responsiveness to achieve intelligent and precise treatment.
3. Mechanism research has important guiding significance for the development of new treatment strategies, and in-depth exploration of cell signaling pathways should be strengthened.
Extension of ideas:
1. Further explore other types of microenvironment regulation strategies, such as pH, oxygen concentration, etc., to enhance the therapeutic effect.
2. Study the synergistic effect of ferroptosis and other cell death modes to develop more effective combined treatment plans.
3. Optimize the design of nanomaterials, improve their biocompatibility and targeting, and promote clinical translational research.
4. Explore the development of new radiosensitizers and establish a more complete radiotherapy sensitization system.
5. In-depth study of tumor resistance mechanisms and develop targeted strategies to overcome them.