State Key Laboratory for Organic Electronics and Information Displays & Jiangsu Key Laboratory for Biosensors, Institute of Advanced Materials (IAM), Jiangsu National Synergetic Innovation Center for Advanced Materials (SICAM), Nanjing University of Posts and Telecommunications, Nanjing 210023, P. R. China.
Nanoscale. 2024 Oct 10;16(39):18570-18583. doi: 10.1039/d4nr01497a.
The challenges posed by low immunogenicity and the immunosuppressive tumor microenvironment (TME) significantly hinder the efficacy of cancer immunotherapy. Pyroptosis, characterized as a pro-inflammatory cell death pathway, emerges as a promising approach to augment immunotherapy by promoting immunogenic cell death (ICD). The predominance of M2 phenotype tumor-associated macrophages (TAMs) in the TME underscores the critical need for TAM reprogramming to mitigate this immunosuppression. Herein, we introduce a calcium-based, intelligent-responsive nanoinducer (CaZCH NPs), designed to concurrently initiate pyroptosis and remodel TAMs, thereby amplifying antitumor immunotherapy effects. Modified with hyaluronic acid, CaZCH NPs can target tumor cells. Once internalized, CaZCH NPs respond to the acidic environment, releasing Ca, curcumin and HO to induce mitochondrial Ca overload and oxidation stress, leading to caspase-3/GSDME-mediated cell pyroptosis. Concurrently, O produced by CaZCH and pro-inflammatory cytokines from pyroptotic cells work together to shift TAM polarization towards the M1 phenotype, effectively countering TME's immunosuppressive effect. Notably, the synergistic effect of Ca-mediated pyroptosis and TAM remodeling demonstrates superior antitumor efficiency in colorectal cancer models. The induced ICD, coupled with M1-type TAMs, effectively enhances immunogenicity and mitigates immunosuppression, promoting dendritic cell maturation and activating CD8 T cell-dependent systemic antitumor immunity. Our study presents a promising synergistic strategy for achieving highly efficient immunotherapy using a simple calcium-based nanoinducer.
低免疫原性和免疫抑制性肿瘤微环境（TME）带来的挑战极大地限制了癌症免疫疗法的疗效。细胞焦亡作为一种促炎的细胞死亡途径，被认为是一种很有前途的方法，可以通过促进免疫原性细胞死亡（ICD）来增强免疫疗法。M2 表型肿瘤相关巨噬细胞（TAMs）在 TME 中的优势突显了 TAM 重编程以减轻这种免疫抑制的迫切需要。在此，我们引入了一种基于钙的智能响应纳米诱导剂（CaZCH NPs），旨在同时引发细胞焦亡和重塑 TAMs，从而放大抗肿瘤免疫治疗效果。通过透明质酸修饰，CaZCH NPs 可以靶向肿瘤细胞。一旦被内化，CaZCH NPs 会响应酸性环境，释放 Ca、姜黄素和 HO，导致 caspase-3/GSDME 介导的细胞焦亡。同时，CaZCH 产生的 O 和来自焦亡细胞的促炎细胞因子共同作用，将 TAM 极化向 M1 表型转变，有效抵抗 TME 的免疫抑制作用。值得注意的是，Ca 介导的细胞焦亡和 TAM 重塑的协同作用在结直肠癌模型中表现出卓越的抗肿瘤效率。诱导的 ICD 加上 M1 型 TAMs，有效地增强了免疫原性，减轻了免疫抑制，促进了树突状细胞成熟并激活了 CD8 T 细胞依赖性全身抗肿瘤免疫。我们的研究提出了一种使用简单的基于钙的纳米诱导剂实现高效免疫治疗的有前途的协同策略。
