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2024年,免疫治疗领域取得了一系列重要进展,为疾病治疗提供了新的思路和方法。综述了肿瘤免疫治疗的新策略、嵌合抗原受体T细胞疗法(chimeric antigen receptor T-cell immunotherapy, CAR-T)治疗自身免疫性疾病的突破,以及肿瘤浸润性淋巴细胞(tumor infiltrating lymphocytes,TIL)和CAR-T在实体癌症治疗中的应用进展。在肿瘤免疫治疗方面,研究发现靶向肿瘤微环境中的T细胞代谢,如乳酸代谢和氨代谢,能够显著增强抗肿瘤免疫效应,为提高治疗效果提供了新的方向。此外,CAR-T在治疗自身免疫性疾病中展现出巨大潜力,通过基因编辑和优化CAR结构,实现了对难治性疾病的治疗突破,为自身免疫性疾病的治疗提供了新的解决方案。在实体癌症治疗中,TIL和CAR-T的优化策略,如代谢调控和个性化设计,进一步提升了其抗肿瘤活性,为实体瘤治疗开辟了新的道路。建议未来研究应加强对免疫代谢机制的深入探索,并结合纳米技术等新兴手段,以提高治疗的精准性和有效性。综上所述,免疫治疗在不断取得新的突破,为未来疾病治疗提供了更多可能性和新思路,有望为患者带来更好的治疗效果和生活质量。

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黄波,教授,研究方向为肿瘤免疫,电子信箱:

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2024年免疫治疗研究热点回眸
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黄波
科技导报 | 特色专题:2024年科技热点回眸 2025,43(1): 96-101
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科技导报 | 特色专题:2024年科技热点回眸 2025, 43(1): 96-101
2024年免疫治疗研究热点回眸
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黄波
作者信息
  • 中国医学科学院基础医学研究所, 北京 100730
  • 黄波,教授,研究方向为肿瘤免疫,电子信箱:

Hotspots of immunotherapy in 2024
Bo HUANG
Affiliations
  • Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing 100730, China
出版时间: 2025-01-13 doi: 10.3981/j.issn.1000-7857.2025.01.00036
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2024年,免疫治疗领域取得了一系列重要进展,为疾病治疗提供了新的思路和方法。综述了肿瘤免疫治疗的新策略、嵌合抗原受体T细胞疗法(chimeric antigen receptor T-cell immunotherapy, CAR-T)治疗自身免疫性疾病的突破,以及肿瘤浸润性淋巴细胞(tumor infiltrating lymphocytes,TIL)和CAR-T在实体癌症治疗中的应用进展。在肿瘤免疫治疗方面,研究发现靶向肿瘤微环境中的T细胞代谢,如乳酸代谢和氨代谢,能够显著增强抗肿瘤免疫效应,为提高治疗效果提供了新的方向。此外,CAR-T在治疗自身免疫性疾病中展现出巨大潜力,通过基因编辑和优化CAR结构,实现了对难治性疾病的治疗突破,为自身免疫性疾病的治疗提供了新的解决方案。在实体癌症治疗中,TIL和CAR-T的优化策略,如代谢调控和个性化设计,进一步提升了其抗肿瘤活性,为实体瘤治疗开辟了新的道路。建议未来研究应加强对免疫代谢机制的深入探索,并结合纳米技术等新兴手段,以提高治疗的精准性和有效性。综上所述,免疫治疗在不断取得新的突破,为未来疾病治疗提供了更多可能性和新思路,有望为患者带来更好的治疗效果和生活质量。

免疫代谢  /  嵌合抗原受体T细胞疗法  /  肿瘤浸润性淋巴细胞  /  生物机械力
immune metabolism  /  CAR-T  /  TIL  /  biomechanical forces
黄波. 2024年免疫治疗研究热点回眸. 科技导报, 2025 , 43 (1) : 96 -101 . DOI: 10.3981/j.issn.1000-7857.2025.01.00036
Bo HUANG. Hotspots of immunotherapy in 2024[J]. Science & Technology Review, 2025 , 43 (1) : 96 -101 . DOI: 10.3981/j.issn.1000-7857.2025.01.00036
免疫治疗是利用人体免疫系统,采用主动或被动手段以调节人体的免疫反应的强弱和模式,达到对疾病产生治疗效果的新兴疗法[1];但其历史可追溯到汉代,运用以毒攻毒的思想,治疗感染性疾病。肿瘤免疫疗法作为当前免疫治疗的主流,已在临床上广泛开展应用。2018年度的诺贝尔生理学或医学奖颁给了美国的James P. Allision和日本的Tasuku Honjo教授,以表彰他们在肿瘤免疫治疗领域所做出的突出贡献。现如今,嵌合抗原受体T细胞疗法(chimeric antigen receptor T-cell immunotherapy, CAR-T)、免疫检查点抑制剂疗法等新兴免疫疗法接踵而至,每年新增获批上市的产品正不断地为肿瘤免疫治疗提供新的思路和工具[2]。此外,CAR-T等技术手段用于自身免疫疾病的免疫治疗策略也正跨进临床应用的大门。当前以肿瘤免疫治疗为前沿先导的研究,其所回答的关键性问题,不仅进一步推动了新型免疫疗法的出现,同时也大大提升了我们对免疫学基本理论知识的认知,并在T细胞代谢以及T细胞机械力生物学方向有了新的突破。本文对免疫治疗领域在2024年取得的突破进行回顾性综述和总结。
在肿瘤微环境(tumor mircroenviroment,TME)中,营养物质如葡萄糖、谷氨酰胺等被肿瘤细胞大量攫取利用,并产生大量如乳酸、色氨酸以及氨等代谢副产物,营造一个以“营养物剥夺”与“代谢废物堆积”为主要特征的肿瘤代谢微环境。抗肿瘤T细胞长期处于营养缺乏状态,导致其抗肿瘤免疫效应低下。不仅如此,肿瘤细胞通过代谢重编程塑造的肿瘤免疫抑制代谢微环境,是导致抗肿瘤T细胞效应能力低下的重要因素。因此,探究肿瘤微环境中抗肿瘤T细胞的代谢规律以及分子机制,开发靶向肿瘤微环境T细胞代谢的免疫治疗策略迫在眉睫。
中国医学科学院基础医学研究所黄波团队[3]发现了CD8+ T细胞激活的过程中细胞内氨逐渐积累并最终导致T细胞死亡,揭示了这一独特死亡方式的分子机制,为异己抗原清除后效应T细胞快速死亡这一基本免疫学现象提供了全新解释,同时为靶向氨代谢的T细胞免疫代谢治疗策略提供了新的思路与机制基础。2024年2月,上海交通大学医学院上海市免疫学研究所邹强团队[4]等合作在《Immunity》发表研究论文,发现乳酸通过上调转录因子Foxp3表达调控肿瘤浸润Treg细胞中RNA剪接过程影响CTLA-4单抗疗效的作用机制,阐述了乳酸-Foxp3-USP39-CT⁃ LA-4信号轴在维持肿瘤浸润Treg细胞免疫抑制功能中的重要作用,提示靶向Treg细胞RNA剪接增强抗肿瘤免疫治疗的应用前景。同年8月,郑州大学第一附属医院生物细胞治疗中心的张毅团队发现,肿瘤内PD-1信号可通过Akt-GATA1通路抑制磷脂代谢关键酶磷脂磷酸酶1(Plpp1)的表达,进而导致不饱和脂肪酸累积,驱动CD8+ T细胞铁死亡,损害抗肿瘤免疫[5]。而通过PD-1检查点阻断治疗可挽救CD8+ T细胞铁死亡。该研究揭示了磷脂代谢在调控肿瘤浸润CD8+ T细胞抗肿瘤功能的关键作用,明确了肿瘤浸润CD8+ T细胞中PLPP1介导的磷脂代谢有利于T细胞抵抗铁死亡,从而增强其抗肿瘤功能及其在免疫治疗中的重要角色。
黄波团队[6]于2024年1月在《Nature Immunolo gy》发表题为《Lithium carbonate revitalizes tumor-re active CD8+ T cells by shunting lactic acid into mito chondria》的研究论文。该研究利用细胞同位素代谢物示踪技术,从靶向乳酸代谢的角度提出了抗肿瘤治疗的新策略。研究发现,小分子药物碳酸锂可促进肿瘤微环境浸润CD8+ T细胞线粒体乳酸代谢,将肿瘤内高浓度免疫抑制性代谢废物——乳酸“变废为宝”,实现增强肿瘤反应性CD8+ T细胞的代谢适应性,以促进在高乳酸的肿瘤微环境中的杀伤活力,该研究成果为靶向T细胞乳酸代谢的抗肿瘤免疫治疗策略提供了新的思路。2024年3月,浙江大学医学院附属第二医院王良静团队和附属邵逸夫医院陈淑洁团队合作[7],利用多组学测序和生物信息分析发现共生约氏乳酸杆菌和生孢梭菌可以合作代谢色氨酸,产生一种衍生物——吲哚-3-丙酸(IPA),IPA可增强Tcf7超级增强子(SE)区域开放水平并介导H3K27乙酰化来调控“干细胞样”TCF-1+ Tpex细胞,促进效应细胞分化,增敏免疫检查点疗法。该研究有望为基于微生态的免疫治疗辅助方案提供新策略。2024年4月,中国科学院分子细胞科学卓越创新中心王红艳团队[8]研究发现胆固醇25-羟化酶(CH25H)以及25-羟基胆固醇(25-HC)是肿瘤免疫治疗的潜在代谢靶点,敲除巨噬细胞中CH25H可通过增强T细胞活性,将冷肿瘤转变为热肿瘤,并与an ti-PD1治疗协同作用,提高抗肿瘤效果。同时,进一步分析表明,CH25H缺失的巨噬细胞具有显著的表观遗传和代谢重编程,促进抗肿瘤免疫微环境的建立,为癌症治疗提供了新的研究方向和潜在靶点。2024年12月,中国医学科学院系统医学研究院/苏州系统医学研究所李贵登团队与美国Fred Hutchinson癌症中心的研究人员合作[9],发现甘露糖代谢的降低是T细胞效应功能低下的重要代谢特征,通过体内外实验回补D-甘露糖可增强过继性T细胞抗肿瘤活性,并抑制其耗竭分化,机制上,D-甘露糖处理诱导T细胞内代谢重编程,增加O-糖基-N-乙酰氨基葡萄糖转移酶(OGT)介导的β-catenin的O-糖基化,从而保持Tcf7的表达和表观遗传干性,从而促进T细胞干性。该研究的发表强调了甘露糖代谢调节在癌症免疫疗法中的潜力。
2024年,新加坡国立大学药学系唐玮、南洋理工大学蒲侃裔团队在《Chemical Society Reviews》发表综述文章《Nanomaterial-enabled metabolic reprogram ming strategies for boosting antitumor immunity》,强调了纳米技术在癌症免疫治疗中的潜力,特别是在调节肿瘤代谢和增强免疫应答方面。通过精确的纳米平台设计,可实现对肿瘤微环境中特定细胞类型的靶向,以及对代谢途径的精确调节,从而提高治疗效果并减少副作用。该研究将为如何精确靶向特定细胞代谢的肿瘤免疫治疗提供更有效可靠的手段(图 1[10]
CAR-T在治疗自身免疫性疾病方面展现了令人瞩目的潜力。最初CAR-T被设计用于治疗血液系统恶性肿瘤,但近年来,这一技术在自身免疫性疾病治疗中的应用潜力正在被逐步挖掘。2024年6月,《Cell》发表了海军军医大学长征医院徐沪济教授团队的研究成果,该研究冲破了风湿免疫病治疗的三大关卡,在荆棘密布的科学之路点亮方向[11]。其一,自身免疫性疾病是“免疫系统的错位”,自身抗体介导的持续性炎症和组织损伤使得传统疗法无法从根本上纠错。其二,传统自体CAR-T需要从患者自身采集T细胞进行体外扩增和改造,其细胞来源受限、生产周期漫长。其三,同种异体细胞疗法受限于移植物抗宿主病(GVHD)的发生,供者T细胞中保留的异体免疫识别能力可能对患者的正常组织发起攻击,从而加剧组织损伤。该研究首次通过基因编辑健康供者的外周血T细胞,制备出针对B细胞表面CD19的通用型靶向的CAR-T细胞;与此同时,团队通过CRISPR-Cas9技术敲除HLA-A、HLA-B、CIITAPD-1等基因以降低同种异体CAR-T的免疫排异。该CAR-T细胞产品TyU19重新建立了3名难治性风湿免疫疾病患者的免疫耐受,系统性随访表明TyU19治疗后患者的临床症状显著改善,包括肌肉功能恢复、抗体水平下降、纤维化逆转等。该研究为治疗顽固性自身免疫疾病提供了安全、有效且易于推广的新思路,标志着免疫细胞疗法的突破性进展。Th2细胞介导2型炎症因子(如IL-4、IL-5、IL-13)的过度分泌,使得哮喘患者的气道反应“草木皆兵”,从而导致屏障受损、气道阻塞、长期慢性炎症以及不可逆气道重塑。CAR-T的研究及运用让包括哮喘在内的慢性炎症性疾病不再“沉疴难起”。2024年5月,清华大学基础医学院彭敏团队[12]极具创新地通过敲除BCORZC3H12A基因,设计出靶向IL-5的长寿命CAR-T细胞——5TIF4;在此基础上,进一步表达IL-4 mutein以阻断IL-4和IL-13信号通路,5TIF4细胞由此诞生。结果表明,小鼠单次注射5TIF4即可显著缓解哮喘症状,持续抑制肺部炎症。利用长寿命、双效功能的CAR-T产生如此高效、持久的疗效在哮喘治疗领域尚属首次。
癌症治疗领域一直在不断进步,而免疫疗法的兴起为患者带来新希望。在众多免疫疗法中,肿瘤浸润性淋巴细胞(tumor infiltrating lymphocytes, TIL)和CAR-T细胞作为“活着的药物”在血液肿瘤中疗效显著,但对实体肿瘤却收效甚微。如何让TIL和CAR-T细胞能够进入实体瘤内部,并且进入后保持高活性,成为领域内急需回答解决的重大科学问题(图 2)。
为了增强TIL和CAR-T细胞的抗肿瘤活性,科学家正在从代谢角度深入探究不同代谢物质对细胞功能的影响。2024年2月,斯坦福大学医学院Crys tal L. Mackall团队发现通过直接补充或过表达腺苷脱氨酶,可增加肌苷(INO)水平,并显著改变CAR-T细胞的转录组、表型和功能,并且增加CAR-T细胞的多胺代谢,改变细胞的代谢重编程和表观遗传状况,从而增强CAR-T细胞的功能和干性[13]。2024年4月,《Nature》同时发表2篇研究论文《PGE2 limits effector expansion of tumour-infiltrating stem-like CD8+ T cells》《PGE2 inhibits TIL expansion by disrupting IL- 2 signalling and mitochondrial function》[14-15]。这2项研究从不同角度揭示了肿瘤内部PGE2通过阻断IL-2信号通路,抑制TIL的扩增和效应亚群分化。这一发现不仅为理解肿瘤如何逃避免疫监视提供了新视角,也为通过干预PGE2-EP2/EP4信号通路来恢复TIL的抗肿瘤能力提供了科学依据,预示着临床治疗的新突破。在2024年11月,贝勒医学院和德克萨斯儿童癌症中心的研究人员在临床水平上证明了外源性添加IL-15有助于T细胞存活和增殖,可以提高基于CAR-T细胞的免疫疗法[16]。该研究为肿瘤浸润CAR-T细胞的进一步优化提供了独特的见解,为设计下一代更有效、毒性更低的细胞免疫疗法提供了蓝图。
研究人员通过设计个性化CAR-T治疗方案或者优化CAR-T的序列,从而提升TIL和CAR-T细胞的抗肿瘤活性。2024年7月,《Nature Medicine》发表的研究论文《Adoptive transfer of personalized neoanti gen-reactive TCR-transduced T cells in metastatic colorectal cancer: Phase 2 trial interim results》为个性化肿瘤免疫治疗开辟了新天地[17]。研究人员从癌症患者的肿瘤浸润淋巴细胞中分离出个性化新抗原反应性T细胞受体(TCRs),通过γ逆转录病毒载体将TCR α和β链导入自体外周血淋巴细胞,并将这些细胞过继转移到患者体内。这一策略在临床试验中取得了显著效果,为癌症患者提供了一种全新的个性化治疗方案。同年11月,David Baker团队与加州大学旧金山分校Kole T. Roybal团队合作,开发了一种高度可定制的工程化受体——SNIPR[18]。这种受体使得CAR-T细胞能够在特定环境中(如肿瘤附近)被激活,从而减少了对非肿瘤组织的毒性。这一创新减少了CAR-T的副作用,同时提高了治疗效果,展现了广泛的临床应用潜力。同月,中国科学院分子细胞科学卓越创新中心(生物化学与细胞生物学研究所)许琛琦研究组联合上海科技大学王皞鹏课题组,在传统28Z和BBZ CAR分子胞内段引入TCR中的CD3ε元件(E-CAR),并且通过对CD3ε进行了序列优化来提高E-CAR在细胞膜上的稳定性[19]。优化后的E-CAR T细胞比普通的CAR T细胞具有更高的抗原敏感性,以及更好的持续杀伤能力,在动物模型中显示了更好的抗肿瘤功能。
这些连续的科学突破,不仅在细胞水平取得了成功,而且在临床试验中也显示出了巨大的潜力。随着科学研究的深入和技术的突破,这些疗法正不断进化,为癌症患者带来更多样化和精准化的治疗选择。期待这些前沿疗法能够持续优化,以实现在临床上的广泛应用,并最终改善患者的治疗效果和生活质量。
机械力在肿瘤免疫中的作用日益受到关注。肿瘤微环境中的机械特性(如基质刚度、流体剪切力、压力变化)显著影响免疫细胞的功能和抗肿瘤反应。作为肿瘤微环境的重要组成部分,机械力通过调控免疫细胞的迁移、激活、耗竭及免疫逃逸等多种过程,在肿瘤免疫调控中具有重要作用。2024年6月,在发表于《Cell》的题为《Osr2 functions as a biome chanical checkpoint to aggravate CD8+ T cell exhaus tion in tumor》的研究论文中,作者探讨了机械力通过调控Osr2表达加剧CD8+ T细胞耗竭的机制[20]。文章使用单细胞RNA测序、ATAC-seq及小鼠模型,系统验证了Osr2在肿瘤免疫逃逸中的关键作用,并提出靶向Osr2有望增强CAR-T在实体肿瘤中的疗效。该研究首次揭示了机械力作为实体肿瘤微环境中调控T细胞功能的关键因素,拓展了对传统耗竭机制的理解。该工作为开发靶向机械力调控的肿瘤免疫治疗提供了新的理论基础和潜在方向。2024年3月,《Nature Communications》发表了题为《Cell softness renders cytotoxic T lymphocytes and T leukemic cells resistant to perforin-mediated killing》的研究论文,探讨了细胞力学特性在肿瘤免疫调控中的核心作用,揭示了机械力如何影响细胞毒性T淋巴细胞(CTLs)的功能和T细胞白血病的免疫逃逸[21]。该研究首次明确细胞硬度不仅是肿瘤细胞的特征,也是CTLs避免自溶的重要策略。这一发现拓展了免疫细胞与肿瘤细胞在力学微环境中相互作用的认知,为机械力如何介导免疫功能提供了新视角。更重要的是,文章提出靶向调控肿瘤细胞力学特性的策略,如使用YAP抑制剂增强穿孔素介导的抗肿瘤免疫效应,开辟了新型肿瘤免疫治疗的方向。这些研究不仅为理解免疫逃逸机制提供了新的理论基础,还为力学调控在肿瘤免疫中的潜在应用奠定了实践依据。这为未来开发基于力学特性的肿瘤免疫治疗策略提供了重要参考。
综上所述,免疫治疗和免疫学基础研究正齐头并进、同步发展,这是未来疾病治疗手段的核心来源。基础研究为因、治疗技术为果的研究模式为科学家提供了丰沛的灵感和思路。由果寻因,籍因至果,在认识世界的同时开发出改造世界的工具,这种科学研究上的良性循环在免疫学领域得到了充分的体现。不难预料,免疫学理论研究和免疫治疗技术开发将在未来不断取得新的突破,为患者提供对抗疾病的有力武器。
  • 国家自然科学基金项目(82388201)
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2025年第43卷第1期
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doi: 10.3981/j.issn.1000-7857.2025.01.00036
  • 接收时间:2024-12-31
  • 首发时间:2025-07-31
  • 出版时间:2025-01-13
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  • 收稿日期:2024-12-31
  • 修回日期:2025-01-06
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国家自然科学基金项目(82388201)
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    中国医学科学院基础医学研究所, 北京 100730
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2种不同金属材料的力学参数

Family
属数
Number of
genus
种数
Number of
species
占总种数比例
Percentage of
total species (%)

Genus
种数
Number of
species
占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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