Tumor microenvironment-modulated multiple nanotherapeutic system for potent cancer immunotherapy and metastasis inhibition

The hypoxic and immunosuppressive tumor microenvironment (TME) generally weaken the efficacy of immunotherapy in solid tumors. However, reversing TME remains a formidable challenge. Here, an elaborately multitasking nanotherapeutic system ([email protected]) is demonstrated to forceful remodel TME. This nanotherapeutic system could validly relieve tumor hypoxia and induce M2 to M1 polarization of tumor-associated macrophages (TAMs) to reverse immunosuppression, serving for TME reprogramming. Furthermore, [email protected] stimulates dendritic cells maturation, thereby initiating T-cell-mediated anti-tumor immune response. Of note, the nanotherapeutic system eliminates primary tumor that established by 4T1 tumor models in mice and efficiently inhibits B16F10 melanoma metastasis without obvious adverse effects. Importantly, [email protected] combined with anti-PD-L1 immune checkpoint inhibitor achieves superior synergistic cancer immunotherapy. Collectively, our work offers a reliable and safe strategy to fabricate a multitasking nanotherapeutic system for comprehensively modulating TME to achieve effective cancer immunotherapy and metastasis inhibition.