Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, 310003, P. R. China.
Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, 310003, P. R. China.
Adv Sci (Weinh). 2022 Oct;9(29):e2202914. doi: 10.1002/advs.202202914. Epub 2022 Aug 18.
Immunotherapy, the most promising strategy of cancer treatment, has achieved promising outcomes, but its clinical efficacy in pancreatic cancer is limited mainly due to the complicated tumor immunosuppressive microenvironment. As a highly inflammatory form of immunogenic cell death (ICD), pyroptosis provides a great opportunity to alleviate immunosuppression and promote systemic immune responses in solid tumors. Herein, membrane-targeted photosensitizer TBD-3C with aggregation-induced emission (AIE) feature to trigger pyroptosis-aroused cancer immunotherapy via photodynamic therapy (PDT) is applied. The results reveal that pyroptotic cells induced by TBD-3C could stimulate M1-polarization of macrophages, cause maturation of dendritic cells (DCs), and activation of CD8 cytotoxic T-lymphocytes (CTLs). Pyroptosis-aroused immunological responses could convert immunosuppressive "cold" tumor microenvironment (TME) to immunogenic "hot" TME, which not only inhibits primary pancreatic cancer growth but also attacks the distant tumor. This work establishes a platform with high biocompatibility for light-controlled antitumor immunity and solid tumor immunotherapy aroused by cell pyroptosis.
免疫疗法是癌症治疗中最有前途的策略，已经取得了令人瞩目的成果，但它在胰腺癌中的临床疗效有限，主要是由于肿瘤免疫抑制微环境复杂。细胞焦亡作为一种高度炎症性的免疫原性细胞死亡（ICD）形式，为缓解实体肿瘤中的免疫抑制和促进全身免疫反应提供了巨大机会。本文应用具有聚集诱导发射（AIE）特性的膜靶向光敏剂 TBD-3C 通过光动力疗法（PDT）引发细胞焦亡来触发癌症免疫治疗。结果表明，TBD-3C 诱导的细胞焦亡可刺激巨噬细胞 M1 极化，导致树突状细胞（DCs）成熟和 CD8 细胞毒性 T 淋巴细胞（CTLs）激活。细胞焦亡引发的免疫反应可以将免疫抑制的“冷”肿瘤微环境（TME）转化为免疫原性的“热”TME，不仅抑制原发性胰腺癌的生长，还能攻击远处的肿瘤。这项工作为光控抗肿瘤免疫和由细胞焦亡引起的实体肿瘤免疫治疗建立了一个具有高生物相容性的平台。
