A dual-responsive supramolecular polymeric nanomedicine (NCSNPs) was developed for self-cascade amplified cancer immunotherapy. This nanomedicine combines a nitric oxide (NO) donor and an indoleamine 2,3-dioxygenase (IDO) inhibitor, NLG919, to induce pyroptosis and reverse immunosuppressive tumor microenvironments. NCSNPs are self-assembled through host-guest molecular recognition and hydrophobic interactions, enabling efficient tumor accumulation and bioavailability. The NO donor triggers pyroptosis, leading to the release of immune-stimulatory cytokines and enhancing the inflammatory response, while NLG919 inhibits IDO, blocking immunosuppressive pathways and promoting cytotoxic T lymphocyte (CTL) infiltration. The combination of these effects significantly inhibits tumor growth. In vitro and in vivo studies demonstrated that NCSNPs effectively induce pyroptosis, enhance immune responses, and reduce tumor size. The nanomedicine showed high antitumor activity with low systemic toxicity, making it a promising strategy for cancer immunotherapy. The study highlights the potential of supramolecular chemistry and nanotechnology in developing novel nanomedicines for cancer treatment.A dual-responsive supramolecular polymeric nanomedicine (NCSNPs) was developed for self-cascade amplified cancer immunotherapy. This nanomedicine combines a nitric oxide (NO) donor and an indoleamine 2,3-dioxygenase (IDO) inhibitor, NLG919, to induce pyroptosis and reverse immunosuppressive tumor microenvironments. NCSNPs are self-assembled through host-guest molecular recognition and hydrophobic interactions, enabling efficient tumor accumulation and bioavailability. The NO donor triggers pyroptosis, leading to the release of immune-stimulatory cytokines and enhancing the inflammatory response, while NLG919 inhibits IDO, blocking immunosuppressive pathways and promoting cytotoxic T lymphocyte (CTL) infiltration. The combination of these effects significantly inhibits tumor growth. In vitro and in vivo studies demonstrated that NCSNPs effectively induce pyroptosis, enhance immune responses, and reduce tumor size. The nanomedicine showed high antitumor activity with low systemic toxicity, making it a promising strategy for cancer immunotherapy. The study highlights the potential of supramolecular chemistry and nanotechnology in developing novel nanomedicines for cancer treatment.