Endoplasmic reticulum (ER)‐targeted photosensitizers enable precise induction of pyroptosis, a highly immunogenic form of cell death that can convert immunosuppressive tumors into inflammatory hot lesions. Phototherapy (photodynamic therapy, PDT, and photothermal therapy, PTT) uniquely provides spatially confined, on/off light control while generating reactive oxygen species or localized hyperthermia; when coupled with ER‐directed delivery, they trigger ER‐stress‐mediated gasdermin activation, releasing damage‐associated molecular patterns (DAMPs) and proinflammatory cytokines that stimulate dendritic cell maturation and CD8 + T‐cell priming. Over the past 5 years, rational design of ER‐targeted photosensitizers has yielded agents with tunable phototoxicity and selective pyroptotic induction, leading to robust tumor ablation and durable adaptive antitumor immunity in mouse tumor models. This concept summarizes recent advances, elucidates rational molecular design and synthesis of ER‐targeted photosensitizers that trigger pyroptosis through PDT or PTT mechanisms, and proposes future directions for developing ER‐targeted pyroptotic phototherapy as a precision cancer immunotherapy platform.
Zhang et al. (Sun,) studied this question.