This study demonstrates that tetrasulfide bonds significantly enhance the anti-tumor efficacy of dimeric prodrug nanoassemblies (DPNAs). Tetrasulfide bonds provide superior self-assembly stability, prolonged blood circulation, and high tumor accumulation compared to trisulfide and disulfide bonds. The γ-4S-2CTX nanoparticles (NPs) exhibit high tumor selectivity and can be activated by endogenous reducing agents in tumor cells, acting as a "tumor bomb." An "add fuel to the flames" strategy was developed to further enhance the reductive stress at tumor sites by replenishing exogenous reducing agents, significantly improving therapeutic efficacy and tumor selectivity. The study highlights the crucial role of tetrasulfide bonds in constructing intelligent DPNAs and provides a promising platform for cancer therapy. The results show that γ-4S-2CTX NPs effectively inhibit tumor growth with high efficacy and good safety profiles. The study also addresses the limitations of current detection methods and suggests future research directions for further improving the safety and efficacy of DPNAs.This study demonstrates that tetrasulfide bonds significantly enhance the anti-tumor efficacy of dimeric prodrug nanoassemblies (DPNAs). Tetrasulfide bonds provide superior self-assembly stability, prolonged blood circulation, and high tumor accumulation compared to trisulfide and disulfide bonds. The γ-4S-2CTX nanoparticles (NPs) exhibit high tumor selectivity and can be activated by endogenous reducing agents in tumor cells, acting as a "tumor bomb." An "add fuel to the flames" strategy was developed to further enhance the reductive stress at tumor sites by replenishing exogenous reducing agents, significantly improving therapeutic efficacy and tumor selectivity. The study highlights the crucial role of tetrasulfide bonds in constructing intelligent DPNAs and provides a promising platform for cancer therapy. The results show that γ-4S-2CTX NPs effectively inhibit tumor growth with high efficacy and good safety profiles. The study also addresses the limitations of current detection methods and suggests future research directions for further improving the safety and efficacy of DPNAs.