The emergence of immunotherapy has significantly transformed cancer therapy, and achieved promising outcomes. However, low patient response rates and the potential immune-related adverse events remain critical challenges, warranting extensive research. In this study, we developed an albumin-prodrug injection formulation (PIF) to enhance cancer immunotherapy. The stimulator of interferon genes (STING) agonist MSA-2 was esterified with the Indoleamine 2,3-dioxygenase (IDO) inhibitor NLG919 to synthesize the prodrug MSA-NLG. Subsequently, bovine serum albumin (BSA) was employed to prepare the anti-tumor injection formulation MSA-NLG@BSA, which effectively prolonged the circulation time of the prodrug, improved pharmacokinetic properties, and promoted tumor aggregation and penetration. This strategy ensures that the drug remains inactive in normal tissues, thereby reducing immune activation-induced damage. The prodrug was dissociated into MSA-2 and NLG919 within tumor cells overexpressing esterase. The MSA-2 molecule stimulates immune cells to secrete cytotoxic cytokines, triggering an anti-tumor immune response and reshaping immune cell population. Meanwhile, NLG919 regulates the recognition and killing of tumor cells by immune cells, effectively blocking the immunosuppression caused by IDO overexpression. This study highlights the potential of a tumor environment-responsive prodrug strategy to enhance the efficacy of immunotherapy, demonstrating the promising clinical translation of the novel MSA-NLG@BSA (PIF) formulation.