撰文丨王聪 编辑丨王多鱼 排版丨水成文 溶瘤病毒 （ Oncolytic Viruse， OV） 是癌症治疗中一种很有前景的疗法。这些具有复制能力的病毒在肿瘤细胞中的优先复制和溶瘤作用，以及溶瘤后激活的免 疫反应，被认为是溶瘤病毒发挥抗肿瘤作用的主要原因。基于单纯疱疹病毒 （HSV） 的首个获美国 FDA 批准的溶瘤病毒疗法 Imlygic 瘤内注射治疗黑色素瘤已 取得了显著成功。 2023 年 10 月， Alexander L. Ling 等人在 Nature 期刊发表论文 【1】 ，报告了一项 first in human 的 1 期临床试验的安全性数据，41 名 复发性胶质母细胞 瘤 （rGBM） 患者接受了基于 单纯疱疹病毒 1 型的溶瘤病毒 （ oHSV ） 的治疗，该溶瘤病毒经过精心设计改造，其 仅在胶质母细胞瘤细胞内选择性复制，同 时不损害健康脑组织。这种肿瘤趋向性的溶瘤病毒利用了癌细胞的弱点：一旦感染，它就会劫持癌细胞的机制来自我复制，从而导致受感染癌细胞的死亡。该溶 瘤病毒不仅仅是癌细胞杀伤剂，它还能引发免疫原性级联反应，将免疫系统的多种成分招募到肿瘤中。结果显示， 瘤内注射 oHSV 治 ...

撰文丨王聪 编辑丨王多鱼 排版丨水成文 在癌症免疫治疗领域，靶向 免疫检查点 分子 PD-1/PD-L1 和 CTLA-4 的抑制剂已经取得了显著成功， 它们能够解除肿瘤对免疫系统的限制，然而，仍有相当比例的癌症患者要么对这些疗法没有影响，要么随 着治疗的进行而产生耐药性。 传统免疫疗法的局限性 因此，我们亟需发现新的免疫检查点，以帮助更广泛的癌症患者获益。 2026 年 2 月 11 日，加拿大蒙特利尔大学/ 蒙特利尔临床研究所的 André Veillette 团队 （博士后 Li Bin 为论文第一作者） ，在国际顶尖学术期刊 Nature 上发表了 题为： SLAMF6 as a drug-targetable suppressor of T cell immunity against cancer 的研究论文。 该研究发现了一种 新的免疫检查点 —— SLAMF6 ，它是 T 细胞介导的抗肿瘤免疫的关键抑制因子， 通过 一种名为" 顺式同型相互作用 " （ 同一个 T 细胞表面上的 SLAMF6 之间相互结合） 的独特方式发挥" 自 我抑制 " 作用。 通过单克隆抗体破坏 SLAMF6 的 顺式同型 ...

这提示了我们，癌症免疫治疗中可能存在着一种 内在随机性 ，这意味着，即使我们将来对所有已知的确定性机制都了如指掌，这种内在随机性为癌症免疫疗法的 成功设定了一个理论上限，导致我们无法完全预测治疗结局。 2026 年 2 月 5 日，美国国家癌症研究中心的研究人员在国际顶尖学术期刊 Cell 上发表了题为： Stochasticity in cancer immunotherapy stems from rare but 撰文丨王聪 编辑丨王多鱼 排版丨水成文 functionally critical Spark T cells 的研究论文。 癌症免疫疗法这一不断扩大的领域，很大程度上得益于过继 T 细胞疗法和/或检查点抑制疗法在一小部分传统疗法 （放疗、化疗和手术） 无效癌症患者身上取得 的成功。然而，大多数癌症患者对癌症免疫疗法仍无良好响应，这可能是由于肿瘤细胞的遗传或表观遗传改变、环境因素、缺乏适当的肿瘤特异性 T 细胞以及肿 瘤浸润淋巴细胞 （TIL） 的耗竭表型所致。所有这些因素都是决定性的，这意味着对这些机制有更深入的理解应该足以准确预测每位患者对癌症免疫疗法的响应 或抵抗情况。 该研究表明，癌症 ...

该研究以： Sensitized mast cells for targeted drug delivery and augmented cancer immunotherapy （ 致敏肥大细胞 用于靶向药物递送和增强癌症免疫治疗 ） 为题，发表于 国际顶尖学术期刊 Cell ，浙江 大学 药学院 顾臻 教授、 俞计成 教授及中国医科大学附属第一医院 刘福囝 教授为论文共同通讯作者 ， 浙江大学 博士后 徐妍 为论文第一作者。该论文还被选为最新一期 Cell 封面论文 。 撰文丨王聪 编辑丨王多鱼 排版丨水成文 有些人一吃海鲜会起荨麻疹，一到花粉季节就喷嚏打不停，这些常见反应都源自人体最快、最强烈的防御 机制之一 —— 过敏反应 。 而 Cell 期刊近期发表的一项研究，将这种强大的免疫反应重新定向——不再是对抗花粉或食物，而是用来 对抗癌症 。 该研究报道了一个基于 工程化肥大细胞 的靶向治疗平台， 让这些平时在 过敏反应 中扮演重要角色的细 胞，化身为对抗癌症的"快递员"，在动物模型上验证了利用 肿瘤相关抗原 作为" 过敏原 "，驱动装载 抗肿 瘤药物 （例如 溶瘤病毒 ） 的肥大细胞在体内主动聚集至肿 ...

Group 1 - The core announcement is that Jiangsu Hengrui Medicine Co., Ltd. has received a confirmation letter from the FDA regarding the acceptance of its Biologics License Application (BLA) for injection of Carrelizumab combined with Apatinib for first-line treatment of unresectable or metastatic hepatocellular carcinoma [1] - The target review date set by the FDA for the BLA is July 23, 2026, under the Prescription Drug User Fee Act (PDUFA) [1] - The drug Carrelizumab is a humanized anti-PD-1 monoclonal antibody that restores the body's anti-tumor immunity by blocking the PD-1/PD-L1 pathway [5] Group 2 - The clinical trial for Carrelizumab combined with Apatinib was approved in December 2018 and achieved orphan drug designation from the FDA in April 2021 [2] - The Phase III clinical trial (SHR-1210-III-310) demonstrated significant survival benefits, with a median progression-free survival (PFS) of 5.6 months and a median overall survival (OS) of 22.1 months, which was later updated to 23.8 months [3] - The study involved 543 participants and compared the efficacy and safety of Carrelizumab combined with Apatinib against Sorafenib, marking it as the first successful Phase III trial of immunotherapy combined with a small molecule tyrosine kinase inhibitor for advanced hepatocellular carcinoma [3] Group 3 - The total research and development investment for Carrelizumab has reached approximately 319.74 million yuan (unaudited) [5] - The global sales of anti-PD-1 antibodies are projected to be around 41.546 billion USD in 2024 [5] - The company plans to continue advancing the project and will fulfill its information disclosure obligations regarding subsequent developments [1]

Core Viewpoint - Jiangsu Hengrui Medicine Co., Ltd. has received a confirmation letter from the FDA regarding the acceptance of its Biologics License Application (BLA) for injection of Carrelizumab combined with Apatinib for first-line treatment of unresectable or metastatic hepatocellular carcinoma patients, with a target review date set for July 23, 2026 [1][2]. Group 1: Drug Information - Drug Name: Injection of Carrelizumab [1] - Dosage Form: Injection [1] - Applicant: Jiangsu Hengrui Medicine Co., Ltd. [1] - Indication: First-line treatment for unresectable or metastatic hepatocellular carcinoma in combination with Apatinib [1]. Group 2: Clinical Trial Information - The international multicenter Phase III clinical trial (Study No. SHR-1210-III-310) for Carrelizumab combined with Apatinib was approved in December 2018 [2]. - The trial demonstrated that Carrelizumab combined with Apatinib significantly extended progression-free survival (PFS) and overall survival (OS) compared to Sorafenib [2][3]. - The study enrolled 543 participants and showed a median PFS of 5.6 months and a median OS of 22.1 months, with the final analysis indicating an OS extension to 23.8 months [3]. Group 3: Market Context - Carrelizumab is a humanized anti-PD-1 monoclonal antibody that restores the body's anti-tumor immunity [5]. - The global sales of anti-PD-1 antibodies are projected to reach approximately $41.546 billion in 2024 [5]. - Cumulative R&D investment for Carrelizumab has reached approximately 319.74 million yuan (unaudited) [5].

撰文丨王聪 编辑丨王多鱼 排版丨水成文 在细胞免疫中，细胞毒性淋巴细胞利用 颗粒酶 A （ Granzyme A， GZMA） 切割并激活成孔蛋白 GSDMB，从而对靶细胞进行焦亡性杀伤。然而，GZMA 是如何识别并切割 GSDMB 的，目前仍不清楚。 2026 年 1 月 26 日，北京生命科学研究院 邵峰 院士团队、中国科学院生物物理研究所 丁璟珒 研究员团 队合作，在 Immunity 期刊 发表了题为： Exosite-mediated targeting of GSDMB by dimeric granzyme A in lymphocyte pyroptotic killing 的研究论文。 该研究表明， 颗粒酶 A （ Granzyme A， GZMA） ，通过独特的"二聚体"结构，像一把精准的钥匙，解 锁了对 GSDMB 蛋白的切割，从而引发"细胞焦亡"。这不仅揭示了淋巴细胞来源的颗粒酶用于杀伤靶细胞 的一种底物靶向机制，还为癌症免疫治疗提供了新思路。 GZMA 的二聚体结构：一把双刃钥匙 在这项新研究中，研究团队通过高精度的晶体结构分析，发现 GZMA 有一个独特之处：它是以"二聚体"形 式 ...

Core Viewpoint - Cancer immunotherapy, particularly immune checkpoint blockade (ICB) therapy, has transformed cancer treatment, but a significant proportion of patients do not respond, highlighting the need to understand factors affecting ICB efficacy [2][3]. Group 1: Research Findings - The study published by Dan R. Littman's team indicates that gut microbiota-induced T cell plasticity enables immune-mediated tumor control, suggesting that targeting gut microbiota could enhance ICB therapy effectiveness [3][7]. - The research utilized segmented filamentous bacteria (SFB) to investigate how its colonization in the small intestine influences the efficacy of ICB therapy against tumors expressing SFB antigens [5][6]. - It was found that effective anti-PD-1 treatment in mice only occurred when SFB was present in the gut, leading to the identification of SFB-specific T H 1-like cells that produce high levels of pro-inflammatory cytokines, enhancing tumor control [6][7]. Group 2: Mechanistic Insights - The study elucidates a cellular pathway where a specific gut symbiotic bacterium enhances the efficacy of PD-1 blockade therapy by imparting T cell plasticity [7]. - Conditional removal of IL-17A+ CD4+ T cells, which are precursors to tumor-associated T H 1-like cells, completely abolished the tumor control mediated by anti-PD-1 therapy, indicating their critical role in the tumor microenvironment [6].

Core Insights - The article discusses the challenges in clinical trials targeting cancer-associated fibroblasts (CAFs), which are crucial tumor-promoting factors, due to their inherent functional plasticity and the opaque regulatory circuits behind their heterogeneous phenotypes [2] Group 1: Research Findings - A study published in Cancer Cell identified ADAM12 as a fibroblast checkpoint that impedes anti-tumor immunity, with its deletion delaying tumor progression and making tumors more sensitive to immunotherapy [3] - The research team developed a systematic screening method based on complementary CRISPR interference (CRISPRi) and CRISPR activation (CRISPRa) to screen patient-derived fibroblasts [5] - The study found that the I-type interferon (IFN-I) response program is a primary antagonistic axis against TGF-β-driven tumor-promoting myofibroblast activation, with ADAM12 mediating this relationship [5] Group 2: Implications for Treatment - Deletion of ADAM12 triggers the IFN-I response program, reconfiguring the myofibroblast population into progenitor-like states, revitalizing T-cell-based immune responses, and inducing tumor rejection in various mouse models [5] - The research positions ADAM12 as a potential target for therapeutic interventions, paving the way for future treatment strategies [5][7] - The study emphasizes the conversion of TGF-β dependent myCAF programs into IFN-I response states to exert anti-tumor activity, enhancing T-cell infiltration and sensitivity to immunotherapy [7]

Core Viewpoint - The study highlights the role of the E3 ubiquitin ligase KLHL6 as a dual negative regulator of T cell exhaustion and mitochondrial dysfunction during chronic antigen stimulation, suggesting its potential as a clinical target to enhance cancer immunotherapy effectiveness [5][7][9]. Group 1: T Cell Dysfunction and Mechanisms - T cell dysfunction, including exhaustion and mitochondrial impairment, is a major barrier in cancer immunotherapy [7]. - The research combines computational analysis with in vivo CRISPR screening to identify KLHL6 as a key factor in regulating T cell exhaustion and mitochondrial health [5][7]. - KLHL6 expression promotes the polyubiquitination and subsequent proteasomal degradation of the exhaustion core regulator TOX, inhibiting the transition from precursor exhausted T cells (Tpex) to terminal exhausted T cells (Tex-term) [7][9]. Group 2: Therapeutic Implications - Enhancing KLHL6 expression in T cells significantly improves anti-tumor and anti-viral efficacy, indicating its critical role in T cell fate and function [5][8]. - The study suggests a new therapeutic approach to restore or enhance KLHL6 expression to reverse T cell exhaustion during chronic TCR stimulation [8][9]. - The findings underscore the potential of targeting protein homeostasis and ubiquitination modifications to improve immunotherapy outcomes [9][10].