Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, 150081, China.
Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, changsha, 410008, China.
Signal Transduct Target Ther. 2022 Jun 20;7(1):196. doi: 10.1038/s41392-022-01046-3.
In recent years, immunotherapy represented by immune checkpoint inhibitors (ICIs) has led to unprecedented breakthroughs in cancer treatment. However, the fact that many tumors respond poorly or even not to ICIs, partly caused by the absence of tumor-infiltrating lymphocytes (TILs), significantly limits the application of ICIs. Converting these immune "cold" tumors into "hot" tumors that may respond to ICIs is an unsolved question in cancer immunotherapy. Since it is a general characteristic of cancers to resist apoptosis, induction of non-apoptotic regulated cell death (RCD) is emerging as a new cancer treatment strategy. Recently, several studies have revealed the interaction between non-apoptotic RCD and antitumor immunity. Specifically, autophagy, ferroptosis, pyroptosis, and necroptosis exhibit synergistic antitumor immune responses while possibly exerting inhibitory effects on antitumor immune responses. Thus, targeted therapies (inducers or inhibitors) against autophagy, ferroptosis, pyroptosis, and necroptosis in combination with immunotherapy may exert potent antitumor activity, even in tumors resistant to ICIs. This review summarizes the multilevel relationship between antitumor immunity and non-apoptotic RCD, including autophagy, ferroptosis, pyroptosis, and necroptosis, and the potential targeting application of non-apoptotic RCD to improve the efficacy of immunotherapy in malignancy.
近年来，以免疫检查点抑制剂（ICIs）为代表的免疫疗法在癌症治疗方面取得了前所未有的突破。然而，许多肿瘤对 ICI 的反应不佳甚至没有反应，部分原因是肿瘤浸润淋巴细胞（TILs）的缺乏，这极大地限制了 ICI 的应用。将这些免疫“冷”肿瘤转化为可能对 ICI 有反应的“热”肿瘤，是癌症免疫治疗中尚未解决的问题。由于癌症抵抗细胞凋亡是普遍特征，因此诱导非凋亡性调节性细胞死亡（RCD）正成为一种新的癌症治疗策略。最近，有几项研究揭示了非凋亡性 RCD 与抗肿瘤免疫之间的相互作用。具体而言，自噬、铁死亡、细胞焦亡和坏死性凋亡均表现出协同的抗肿瘤免疫反应，同时可能对抗肿瘤免疫反应产生抑制作用。因此，针对自噬、铁死亡、细胞焦亡和坏死性凋亡的靶向治疗（诱导剂或抑制剂）与免疫疗法相结合，可能会发挥强大的抗肿瘤活性，即使在对 ICI 耐药的肿瘤中也是如此。本综述总结了抗肿瘤免疫与非凋亡性 RCD（包括自噬、铁死亡、细胞焦亡和坏死性凋亡）之间的多层次关系，以及非凋亡性 RCD 的潜在靶向应用，以提高免疫疗法在恶性肿瘤中的疗效。
