Breast cancer stem cells (CSCs) are responsible for the occurrence, resistance, recurrence, invasion, and metastasis of tumors. However, even trace amounts of CSCs may lead to tumor resistance and recurrence, which fundamentally reduces the therapeutic efficiency of numerous anticancer drugs. Thus, the development of a therapeutic agent that can reduce the tumorigenicity of CSCs and overcome tumor resistance and recurrence is essential. Here a novel multifunctional prodrug T‐P is reported as a photosensitizer, which links phenothiazine drug with the synthesized aggregation‐induced emission photosensitizer T‐C via an ester bond. Importantly, this photosensitizer is found to be able to induce the pyroptosis of breast CSCs as well as to activate their death pathway protein phosphatase 2A to inhibit CSCs and systemic anti‐tumor effects. T‐P can rapidly target mitochondria and overlap with lysosomes after mitochondrial escape, and it can cause mitochondrial and lysosomal dysfunction. It releases reactive oxygen species through photoactivation, triggering pyroptosis‐mediated strong anti‐tumor immune response. On the 5th day of in vivo therapy of breast cancer, the primary tumor is eliminated and the growth of distant tumors is also inhibited. This research would provide an impetus as well as a new strategy for CSCs‐targeted cancer photoimmunotherapy and beyond.

中文翻译：

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多功能前药光敏剂促进乳腺癌干细胞焦亡和免疫激活

乳腺癌干细胞（CSC）负责肿瘤的发生、耐药、复发、侵袭和转移。然而，即使是微量的CSC也可能导致肿瘤耐药和复发，这从根本上降低了众多抗癌药物的治疗效率。因此，开发一种能够降低CSC致瘤性并克服肿瘤耐药性和复发的治疗剂至关重要。这里报道了一种新型多功能前药 T-P 作为光敏剂，它通过酯键将吩噻嗪药物与合成的聚集诱导发射光敏剂 T-C 连接起来。重要的是，这种光敏剂被发现能够诱导乳腺 CSC 焦亡，并激活其死亡途径蛋白磷酸酶 2A，从而抑制 CSC 和全身抗肿瘤作用。 T-P在线粒体逃逸后能快速靶向线粒体并与溶酶体重叠，导致线粒体和溶酶体功能障碍。它通过光活化释放活性氧，引发细胞焦亡介导的强烈抗肿瘤免疫反应。乳腺癌体内治疗第5天，原发肿瘤被消除，远处肿瘤的生长也受到抑制。这项研究将为癌症干细胞靶向癌症光免疫疗法等提供动力和新策略。