癌症免疫治疗的效果受到干扰素基因激动剂(STING)信号通路不足激活和免疫抑制微环境的严重限制。在这里，我们利用肿瘤微环境响应性纳米颗粒(PMM NPs)，同时利用STING和Toll样受体4 (TLR4)，通过TLR4介导的核因子-κB信号通路刺激增大STING激活，从而提高I型干扰素(即上调4.0倍的IFN-β)和促炎细胞因子的分泌，以促进特异性T细胞免疫应答。此外，PMM NPs通过降低Tregs的比例和极化M2巨噬细胞到M1型的方式减轻了肿瘤微环境的免疫抑制，从而创造出一个有利于免疫的肿瘤微环境，引发级联的适应性免疫应答。结合抗PD-1抗体，这种协同效应在受炎性结直肠癌和非炎性转移乳腺肿瘤模型中得到实现。此外，用低渗细胞再次挑战无肿瘤的动物引起完全的肿瘤排斥，表明系统性抗肿瘤记忆的产生。这种肿瘤微环境响应性纳米颗粒可能为实现STING激活的时空协调开辟了一条新途径，为下一代癌症免疫治疗提供了有前途的临床候选药物。本文受版权保护，版权所有。

Insufficient activation of the stimulator of interferon genes (STING) signaling pathway and profoundly immunosuppressive microenvironment largely limits the effect of cancer immunotherapy. Herein, we exploited tumor microenvironment (TME)-responsive nanoparticles (PMM NPs) 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 relieved the immunosuppression of the TME by decreasing the percentage of Tregs, 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 was achieved in both inflamed colorectal cancer and non-inflamed metastatic breast tumor models. Moreover, rechallenging tumor-free animals with hypotonic 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. This article is protected by copyright. All rights reserved.This article is protected by copyright. All rights reserved.