尽管免疫治疗取得了显著的临床突破，但激活免疫原性和打破免疫抑制的肿瘤微环境(ITME)仍然具有诱人而具有挑战性。在这里，我们设计了一种定制的免疫刺激剂，用于减轻ITME并引发免疫应答，以应对这一挑战。该免疫刺激剂采用双层硅涂覆上转换纳米颗粒(UCNPs)作为纳米载体，通过修饰N-对甲苯磺酸甘氨酸 (N-p-Tosylglycine)，其中密集的二氧化硅用于叶绿素e6 (Ce6)，而谷胱甘肽 (GSH) 响应性可降解二氧化硅用于装载白藜芦醇 (RES) (UCNPs@SiO2 -Ce6@MON(RES)@ER (UCSMRER )）。一方面，UCSMRER 通过靶向内质网(ER)分子N-p-Tosylglycine 的精确定位，精确靶向到内质网(ER)。这种精确的内质网(ER)定位光动力疗法(PDT)能够在980 nm 激光照射下原位产生活性氧 (ROS)，既直接诱导严重的细胞死亡，又引起基于内质网(ER)应激的免疫原性细胞死亡 (ICD) 效应，从而触发肿瘤免疫应答。另一方面，PDT 过程加重的肿瘤缺氧可以通过按需释放的RES 得到有效缓解，RES 通过受损线粒体电子传递链 (ETC) 降低氧耗，从而实现缺氧的减轻。这种整合的精确ER 定位和氧补偿策略最大化了PDT 效果并增强了ICD 相关的免疫治疗作用，有助于减轻ITME，激活肿瘤的免疫原性并进一步放大抗肿瘤效果。这种关于PDT 和免疫疗法的创新理念为与癌症相关的临床应用提供了新的思路。本文受版权保护，所有权利已被保留。

Notwithstanding that immunotherapy has made eminent clinical breakthroughs, activating the immunogenicity and breaking the immunosuppressive tumor microenvironment (ITME) remains tempting yet challenging. Herein, a customized-designed immunostimulant was engineered for attenuating ITME and eliciting an immune response to address this challenge head-on. This immunostimulant was equipped with dual silica layers coated upconversion nanoparticles (UCNPs) as nanocarriers modified with N-p-Tosylglycine, in which the dense silica for chlorin e6 (Ce6) and the glutathione (GSH)-responsive degradable silica for loading resveratrol (RES) (UCNPs@SiO2 -Ce6@MON(RES)@ER (UCSMRER )). On the one hand, UCSMRER was positioned accurately in the endoplasmic reticulum (ER) guided by the ER-targeted molecular N-p-Tosylglycine. This precise ER-targeted photodynamic therapy (PDT) could generate reactive oxygen species (ROS) in situ under the 980 nm laser irradiation, which not only induced severe cell death directly but also caused intense ER stress-based immunogenic cell death (ICD) effects, triggering a tumor immune response. On the other hand, tumor hypoxia aggravated by the PDT process was effectively alleviated by RES released on-demand, which reduced oxygen consumption by impairing the mitochondrial electron transport chain (ETC). This integrated precise ER-targeted and oxygen-compensated strategy maximized the PDT effect and potentiated ICD-associated immunotherapy, which availed to attenuate ITME, activate tumor immunogenicity and further magnify anti-tumor effect. This innovative concept about PDT and immunotherapy sheds light on the cancer-related clinical application. This article is protected by copyright. All rights reserved.This article is protected by copyright. All rights reserved.