Immunotherapy has transformed cancer treatment by harnessing the immune system, yet its clinical efficacy remains limited by the immunosuppressive tumor microenvironment (TME), which blocks immune recognition and suppresses effector cells. To address this, we developed nanomedicine-based strategies that deliver immune stimulators with spatial, temporal, and molecular precision. pH-sensitive polymeric micelles selectively accumulated in tumors and triggered IL-12 release, safely eradicating resistant tumors. By co-delivering IL-15 and IL-15R? as a nanosuperagonist, micelles enhanced cytotoxic T cell and NK cell activity, while their modular design also enabled mRNA delivery for transient local cytokine production. To further refine control, photoactivatable micelles precisely induced IL-2 expression, amplifying local immunity while reducing systemic toxicity. Together, these approaches show that nanomedicine can actively reprogram the TME, integrate with checkpoint inhibitors or cell therapies, and expand the therapeutic reach of immunotherapy against resistant cancers.