Abstract Currently, the understanding of the cyclic GMP‐AMP synthase (cGAS)‐stimulator of interferon genes (STING) pathway's involvement in efficient immunotherapy mainly revolves around the role of mitochondria or nucleus modulation. Nonetheless, the role of endoplasmic reticulum (ER) stress in activating the cGAS‐STING mechanism to boost immunity against tumors remains essentially unexplored. Herein, novel findings demonstrating that ER stress can be used as a strategy for stimulating the cGAS‐STING pathway, thereby augmenting the immune response against cancer, are presented. To accomplish this objective, ER‐targeting p‐methylbenzene sulfonamide‐tailored IR780 (p‐780) is synthesized and it is loaded into CaO₂ nanoparticles, which are further functionalized with distearoyl phosphoethanolamine‐polyethylene glycol（DSPE‐PEG）‐biotin to form PEG/CaO₂@p‐780 NPs. The disruption of calcium homeostasis, coupled with the heightened levels of reactive oxygen species (ROS) mediated by p‐780, along with hyperpyrexia, collectively contributes to the amplification of endoplasmic reticulum (ER) stress. This cascade of events effectively triggers the cGAS‐STING pathway and, in parallel, facilitates the degradation of the programmed cell death 1 ligand 1 (PD‐L1) protein. In addition, oxygen released through CaO₂ decomposition is expected to promote p‐780–mediated phototherapy, while reversing the immunosuppressive tumor microenvironment associated with hypoxia. Furthermore, DSPE‐PEG‐biotin facilitates tumor site‐specific drug delivery through active targeting mediated by the biotin receptor. Collectively, PEG/CaO₂@p‐780 nanoparticles successfully activate systemic antitumor immunity by enhancing ER stress.