Tumor-activated dual metabolic nanomodulator turns over tolerogenic tumor control and unleashes systemic immune responses

Temporary amelioration of immunosuppression following extrinsic stress-induced immunogenic signal release provides opportunities for immunotherapy improvement. However, therapeutics that fail to translate local stimulatory clues into ongoing systemic antitumor responses would in turn hijack the alleviated immune status toward tolerance, instead of immunity. Here, we constructed a tumor-activated precise dual-metabolic nanomodulator (RAISE) that induced extensive tumor cell death while supporting DCs functions, thus synergistically turning over tolerogenic tumor control and skewing an antitumor immunity. Sequentially responsive to tumor-overexpressing enzymes and high intracellular GSH, RAISE disintegrated in a self-destructive manner, which facilitated drug release and produced immunogenic tumor cell death associated with immunosuppression relief. Then, the regression of tolerogenic metabolism by RAISE replenished intratumoral CD103⁺ DCs, which further amplified T cell activation by enhancing antigen cross-presentation. Moreover, the blockade of indoleamine 2,3-dioxygenase activity restored the sensitivity of tumors to T cell immunity. Consequently, the cascade of immune activation helped to escape from the fate of tolerance and evolved into durable immune memory. RAISE exhibited efficient tumor control, and when combined with anti-PD-1 immunotherapy, RAISE inhibited lung metastasis, generated systemic immune responses, and induced immune memory. Taken together, RAISE can be utilized to trigger long-term systemic antitumor immunity for improving tumor immunotherapy.