Tumor Microenvironment‐Responsive Nanoparticles Amplifying STING Signaling Pathway for Cancer Immunotherapy

Abstract Insufficient activation of the stimulator of interferon genes (STING) signaling pathway and profoundly immunosuppressive microenvironment largely limits the effect of cancer immunotherapy. Herein, tumor microenvironment (TME)‐responsive nanoparticles (PMM NPs) are exploited that simultaneously harness STING and Toll‐like receptor 4 (TLR4) to augment STING activation via TLR4‐mediated nuclear factor‐kappa B signaling pathway stimulation, leading to the increased secretion of type I interferons (i.e., 4.0‐fold enhancement of IFN‐β) and pro‐inflammatory cytokines to promote a specific T cell immune response. Moreover, PMM NPs relieve the immunosuppression of the TME by decreasing the percentage of regulatory T cells, and polarizing M2 macrophages to the M1 type, thus creating an immune‐supportive TME to unleash a cascade adaptive immune response. Combined with an anti‐PD‐1 antibody, synergistic efficacy is achieved in both inflamed colorectal cancer and noninflamed metastatic breast tumor models. Moreover, rechallenging tumor‐free animals with homotypic cells induced complete tumor rejection, indicating the generation of systemic antitumor memory. These TME‐responsive nanoparticles may open a new avenue to achieve the spatiotemporal orchestration of STING activation, providing a promising clinical candidate for next‐generation cancer immunotherapy.