The study introduces a dual-responsive supramolecular polymeric nanomedicine (NCSNPs) designed to enhance cancer immunotherapy by self-cascading the benefits of pyroptosis and IDO inhibition. Pyroptosis, a form of programmed cell death, can induce immunogenic cell death and long-term immune activation. The NCSNPs are formulated by coupling β-cyclodextrin with a nitric oxide (NO) donor and an indoleamine 2,3-dioxygenase (IDO) inhibitor, NLG919, through host-guest molecular recognition and hydrophobic interactions. These nanoparticles exhibit excellent tumor accumulation and bioavailability due to their supramolecular engineering. The study confirms the occurrence of NO-triggered pyroptosis in tumors and demonstrates that the IDO inhibitor NLG919 can reverse the immunosuppressive microenvironment by enhancing the infiltration of cytotoxic T lymphocytes, leading to significant tumor inhibition. This novel strategy provides a promising approach for cancer immunotherapy by synergistically inducing pyroptosis and blocking immune suppression.The study introduces a dual-responsive supramolecular polymeric nanomedicine (NCSNPs) designed to enhance cancer immunotherapy by self-cascading the benefits of pyroptosis and IDO inhibition. Pyroptosis, a form of programmed cell death, can induce immunogenic cell death and long-term immune activation. The NCSNPs are formulated by coupling β-cyclodextrin with a nitric oxide (NO) donor and an indoleamine 2,3-dioxygenase (IDO) inhibitor, NLG919, through host-guest molecular recognition and hydrophobic interactions. These nanoparticles exhibit excellent tumor accumulation and bioavailability due to their supramolecular engineering. The study confirms the occurrence of NO-triggered pyroptosis in tumors and demonstrates that the IDO inhibitor NLG919 can reverse the immunosuppressive microenvironment by enhancing the infiltration of cytotoxic T lymphocytes, leading to significant tumor inhibition. This novel strategy provides a promising approach for cancer immunotherapy by synergistically inducing pyroptosis and blocking immune suppression.