Cancer immunotherapy has made significant progress in the last few decades, revolutionizing oncology. However, low patient response rates and potential immune-related adverse events continue to be major clinical challenges. Cancer nanomedicine, by virtue of its regulated delivery and modular flexibility, has shown the potential to strengthen antitumor immune responses and sensitize tumors to immunotherapy. In this study, we developed tumor microenvironment (TME) responsive nanomedicine to achieve specific and localized amplification of the immune response in tumor tissue in a safe and effective manner, while simultaneously reducing immune-related side effects. We synthesized the TME responsive prodrug by coupling MSA-2, a stimulator of interferon genes (STING) agonist, and NLG-919, an indoleamine 2,3 dioxygenase (IDO) inhibitor. The prodrug was assembled into nanoparticles to enhance the solubility and bioavailability. By synthesizing a TME responsive prodrug, we aim to explore the therapeutic efficacy of combined regimen (STING agonist and IDO inhibitor) for cancer, and reduce the unwanted side effects of STING agonism on normal tissues. Free prodrug and nanoparticles were characterized by mass spectrometry, dynamic light scattering (DLS), and transmission electron microscopy (TEM). Following that, we investigated the tumor accumulation, anti-tumor activity, and toxicity in vitro and in vivo. Prodrug nanoparticles demonstrated the ability to inhibit the tumor growth and activate antitumor immune response by modulating immune cells populations in tumor microenvironment. The TME responsive nanomedicine provided an effective tool for precise targeting, promoting antitumor immunity, and efficient tumor growth inhibition with safety. Outcomes of this study may have implications for future clinical trials.