{"id":530,"title":"Engineered T cell–agonist chimera for logic-gated STING activation and augmented cancer immunotherapy","title_zh":"工程化T细胞-激动剂嵌合体实现逻辑门控STING激活并增强肿瘤免疫治疗","url":"https://doi.org/10.1073/pnas.2617384123","doi":"10.1073/pnas.2617384123","pmid":null,"journal":"Proceedings of the National Academy of Sciences","kind":"paper","lang":"en","published_at":"2026-11-03T00:00:00+00:00","fetched_at":"2026-11-08T03:45:22+00:00","authors":["Fangmin Chen","Mengfan Li","Siyuan Ren","Lujia Huang","Wenyue Lan","Qilong Wu","Bo Hou","Chang Chen","Zhiai Xu","Haijun Yu"],"primary_topic":"repro-immunology","topics":[{"slug":"repro-immunology","score":3.0,"hits":["immunotherapy"]}],"topic_score":3.0,"preference_score":0.0,"preference_labels":[],"llm_score":32.0,"final_score":38.0,"score_dims":{"novelty":78,"rigor":72,"impact":12,"relevance":8,"translation":10},"recommend_reason":"逻辑门控的T细胞-纳米激动剂嵌合体设计在肿瘤免疫治疗中颇具新意，但研究对象为黑色素瘤与胰腺癌模型，与生殖医学、辅助生殖及胚胎多组学无实质关联，对本领域读者参考价值很低。","keywords":["STING激动剂","过继T细胞治疗","肿瘤相关巨噬细胞","逻辑门控纳米药物","肿瘤免疫微环境"],"selected":0,"story_id":null,"llm_provider":"deepseek","llm_model":"deepseek-flash","llm_effort":"low","source_key":"crossref-cns","source_name":"Crossref · CNS 与大子刊新上线（领域过滤）","source_tier":1,"mention_count":1,"has_interpretation":false,"journal_key":"pnas","journal_tier":"general-top","journal_if":9.4,"is_mock":false,"summary_zh":"该研究针对实体瘤免疫抑制微环境限制过继T细胞疗效的问题，先证实激活肿瘤相关巨噬细胞（TAM）中的STING可增强过继T细胞的瘤内浸润与细胞毒性；进而设计TAM靶向纳米激动剂，并通过共价表面锚定构建T细胞-激动剂嵌合体（SNTC），使STING激动剂与过继T细胞同步分布。纳米激动剂响应T细胞表面升高的还原电位在瘤内局部释放，再经胞内谷胱甘肽介导在TAM中恢复STING激动剂，实现AND逻辑门控激活。SNTC重塑肿瘤基质与免疫抑制微环境，并增强TAM抗原提呈以激活内源T细胞；黑色素瘤小鼠中60天以上生存率超过40%，与免疫检查点阻断联用可使原位胰腺癌模型肿瘤持续消退。","summary":"The efficacy of adoptive T cell therapy against solid tumors is markedly hindered by the immunosuppressive microenvironment. Here, we demonstrate that stimulator of interferon genes (STING) activation in tumor-associated macrophages (TAM) enhances the intratumoral infiltration and cytotoxicity of adoptive T cells. We next design a TAM-targeted nanoagonist and engineer a T cell – agonist chimera (SNTC) via covalent surface anchoring, to achieve synchronized biodistribution of STING agonist with adoptive T cells. The nanoagonist is locally released in tumor tissue in response to the elevated reduction potential on T cell surface, followed by intracellular glutathione-mediated restoration of STING agonist in TAM, thereby enabling AND logic-gated STING activation. SNTC not only reshapes tumor stroma and immunosuppressive tumor microenvironment to augment adoptive T cell function but also enhances the antigen presentation ability of TAM to activate endogenous T cells. SNTC elicits robust antitumor efficacy in melanoma tumor-bearing mice, resulting in over 40% survival beyond 60 d. Moreover, combining tumor-infiltrating T lymphocyte (TIL)-based SNTC with immune checkpoint blockade therapy leads to sustained tumor regression in mouse model of orthotopic pancreatic tumor. Collectively, SNTC holds translational potential to optimize STING activation for adoptive T cell therapy of cancer.","interpretation_basis":null,"fulltext_status":null,"interpretation":null,"fulltext":{"available":false,"status":null,"reason":"尚未抓取全文（未入选、分数未达阈值，或还没跑 fulltext 步骤）","pmcid":null,"license":null,"chars":0,"source":null,"fetched_at":null}}