修回日期: 2026-05-06
接受日期: 2026-05-25
在线出版日期: 2026-06-28
癌症相关成纤维细胞(cancer-associated fibroblasts, CAFs)是消化道肿瘤微环境中最主要的间质细胞, 通过形成物理屏障、分泌促肿瘤因子、代谢重编程、构建免疫抑制网络、外泌体传递及维持肿瘤干细胞特性等多维机制, 塑造耐药微环境并限制药物疗效. 本文系统综述CAFs的异质性分型及其在食管癌、胃癌、结直肠癌和胰腺癌等消化道肿瘤中的耐药机制, 并总结直接清除、功能重编程、基质正常化、联合用药及外泌体阻断等靶向CAFs的转化研究策略, 为突破消化道肿瘤治疗瓶颈提供理论依据.
核心提要: 本文系统综述癌症相关成纤维细胞(cancer-associated fibroblasts, CAFs)的异质性分型及其在食管癌、胃癌、结直肠癌和胰腺癌等消化道肿瘤中的耐药机制, 并总结直接清除、功能重编程、基质正常化、联合用药及外泌体阻断等靶向CAFs的转化研究策略, 为突破消化道肿瘤治疗瓶颈提供理论依据.
引文著录: 汪晓宇, 任刚. CAFs塑造耐药微环境: 消化道肿瘤治疗壁垒的多维机制与破解策略. 世界华人消化杂志 2026; 34(6): 433-442
Revised: May 6, 2026
Accepted: May 25, 2026
Published online: June 28, 2026
Cancer-associated fibroblasts (CAFs) are the predominant stromal cells within the tumor microenvironment of gastrointestinal malignancies. They contribute to drug resistance and tumor progression through multiple mechanisms, including the formation of physical barriers, secretion of pro-tumorigenic factors, metabolic reprogramming, establishment of immunosuppressive networks, extracellular vesicle-mediated signaling, and maintenance of cancer stem cell properties. In this review, we systematically summarize the heterogeneity and subtypes of CAFs and elucidate their roles in mediating therapy resistance in esophageal, gastric, colorectal, and pancreatic cancers. We further discuss translational strategies targeting CAFs, including direct depletion, functional reprogramming, extracellular matrix normalization, combination therapy, and inhibition of extracellular vesicle signaling. This review provides a comprehensive theoretical framework for overcoming therapeutic resistance and improving treatment outcomes in gastrointestinal tumors.
- Citation: Wang XY, Ren G. Cancer-associated fibroblasts in shaping the drug-resistant microenvironment: Mechanistic insights and therapeutic strategies for gastrointestinal cancers. Shijie Huaren Xiaohua Zazhi 2026; 34(6): 433-442
- URL: https://www.wjgnet.com/1009-3079/full/v34/i6/433.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v34.i6.433
核心提要: 本文系统综述癌症相关成纤维细胞(cancer-associated fibroblasts, CAFs)的异质性分型及其在食管癌、胃癌、结直肠癌和胰腺癌等消化道肿瘤中的耐药机制, 并总结直接清除、功能重编程、基质正常化、联合用药及外泌体阻断等靶向CAFs的转化研究策略, 为突破消化道肿瘤治疗瓶颈提供理论依据.
消化道肿瘤(例如食管癌、胃癌、结直肠癌、胰腺癌)是具有高度侵袭性的恶性肿瘤, 发病率和死亡率较高[1,2]. 目前的治疗手段主要包括手术、放疗、化疗及靶向免疫治疗, 但是由于胃肠道肿瘤的异质性及耐药情况, 导致处于晚期及转移的患者预后较差, 死亡率较高, 给临床治疗带来了挑战[3].
肿瘤微环境(tumor microenvironment, TME)是肿瘤内部的一个复杂且独特的系统, 主要是由肿瘤细胞、肿瘤相关成纤维细胞(cancer-associated fibroblasts, CAFs)、免疫细胞、间充质组织、血管及各种细胞因子等构成, 而CAFs是TME中最主要的间质细胞[4]. CAFs具有高度异质性, 其多种亚型在肿瘤的增殖、转移及免疫逃避中发挥了重要的作用, 可以通过分泌细胞因子重塑细胞外基质、形成物理及化学屏障阻止药物递送、调节免疫细胞的数量及功能抑制免疫等, 从而影响消化道肿瘤的治疗效果[5,6]. 通过直接清除、功能重编程、基质正常化、联合用药及外泌体阻断等策略靶向CAFs, 有望解除物理与免疫双重屏障、逆转治疗耐药、增强药物递送, 从而突破消化道肿瘤的治疗瓶颈, 改善患者预后[7,8].
近年来, 尽管已有综述对CAFs在肿瘤耐药中的作用进行了梳理, 但多侧重于单一机制描述或泛癌种概述, 缺乏对消化道肿瘤特异性CAFs亚群基于单细胞测序的精准解析, 以及从"分型识别"到"联合干预"的系统性策略设计. 随着单细胞测序技术的成熟, CAFs的异质性图谱已被精细重构, 这为"精准基质靶向"提供了分子基础; 同时, 单一靶向CAFs策略的局限性日益凸显, 基于机制互补的联合用药逻辑成为转化研究的新焦点. 基于此, 本文系统综述CAFs在消化道肿瘤中的生物学特征、异质性分型及靶向治疗策略的最新进展, 旨在为临床转化提供理论参考.
CAFs的来源多种多样, 主要来源于驻留在肿瘤中的成纤维细胞, 其他来源包括巨噬细胞、平滑肌细胞、骨髓来源的干细胞、内皮细胞及上皮细胞等[9]. 在消化道肿瘤中, 肿瘤细胞分泌转化生长因子-β(Transforming growth factor-β, TGF-β)能够激活成纤维细胞或胰腺星状细胞(pancreatic stellate cells, PSCs), 使其具有CAFs的表型[10]. 有研究表明[11]在胰腺癌中, 脂肪细胞、周皮细胞、骨髓来源的巨噬细胞和内皮细胞也可以分化为CAFs并被招募到肿瘤部位.
基于泛癌的单细胞分析, CAFs可分为6个亚群, 在肿瘤或癌旁组织中明显富集, 其中3个主要亚群为肌成纤维细胞型CAFs(myofibroblastic CAFs, myCAFs)、炎症型CAFs(inflammatory CAFs, iCAFs)和抗原呈递型CAFs(antigen-presenting CAFs, apCAFs)[12]. 不同亚型的CAFs在肿瘤耐药中起到不同的作用. MyCAFs以α-平滑肌肌动蛋白(alpha-smooth muscle actin, α-SMA)、成纤维细胞激活蛋白(fibroblast activation protein, FAP)、骨膜蛋白(periostin, POSTN)和Ⅰ型胶原蛋白α1链高表达为特征, 能够促纤维化, 形成物理屏障, 限制药物的渗透及免疫细胞的浸润; iCAFs以白细胞介素-6(interleukin-6, IL-6)、白血病抑制因子、C-X-C基序趋化因子配体12(C-X-C motif chemokine ligand 12, CXCL12)和肾足突蛋白为标志, 能够分泌细胞因子, 形成免疫抑制微环境; apCAFs表达MHC-Ⅱ分子(如CD74、人类白细胞抗原-DR型), 虽然无法作为专业抗原呈递细胞发挥作用, 但研究表明[13-17]它可以通过诱导T-reg的形成, 在肿瘤免疫抑制中发挥作用.
消化道肿瘤在泛癌框架基础上演化出具有专属标志物、空间分布特征及治疗预测价值的CAFs亚群. 在胰腺癌中, 内皮样CAFs同时表达成纤维细胞标志物FAPα和内皮细胞标志物CD144, 具备独特的内皮样表型, 为肿瘤细胞提供转移通道, 并且分泌细胞因子促进原位肿瘤细胞的增殖与侵袭, 主动驱动肿瘤转移[18]. 在胃癌中, 基于机器学习鉴定出FA_H(高基质活化型)和FA_L(低基质活化型)两种预后亚型: FA_H表现为免疫抑制特征, 对达沙替尼敏感; FA_L则富集免疫激活信号, 更可能从免疫检查点抑制剂中获益[19]. 在结直肠癌中, THBS2+ CAFs通过分泌COL8A1激活PI3K/AKT通路诱导上皮-间充质转化(epithelial-mesenchymal transition, EMT), 特异性介导奥沙利铂耐药[20]; CTHRC1+ CAFs则通过限制胶原沉积、增强细胞外基质(extracellular matrix, ECM)可塑性促进癌细胞迁移和血管生成, 在癌前病变阶段即可被检测到, 提示早期诊断价值[21,22]. 在肝细胞癌中, CAFs主要源于活化的肝星状细胞, 其中缺氧代谢性肌成纤维细胞以POSTN、COL1A1和LOX为标志, 在肿瘤侵袭前沿形成胶原XV富集的基质带, 物理性排斥CD8+ T细胞并介导免疫检查点抑制剂耐药[23]; YAP1+ CAFs则通过上调COL1A1、COL3A1和LOX增加基质硬度, 激活自噬和GTPase通路促进肿瘤进展[24].
CAFs是ECM的重要调控者, 它能够分泌胶原蛋白、纤连蛋白和透明质酸(hyaluronic acid, HA), 从而形成致密的纤维化间质, 这种促结缔组织增生性重塑增强了细胞基质的硬度, 从而支持肿瘤生长并推动消化道肿瘤的恶性进展[25-27]. 整合素α5主要在FAP+-CAFs中富集, 与ECM相关基因(如纤连蛋白、胶原蛋白)显著正相关, 增加肿瘤基质硬度, 从而减少CD8+ T细胞浸润并降低其细胞毒性功能[26]. 在结直肠癌中, 高表达dysadherin的癌细胞周围有更多活化的α-SMA+-CAFs, MMP9能够激活CAFs, 活化的CAFs分泌胶原等细胞外基质成分和肿瘤促进因子, 形成正反馈循环[28]. 除此之外, 有研究表明[29]CAFs既是基质硬化的主要制造者(通过分泌细胞外基质和交联酶), 也是硬化微环境的响应者(通过YAP/TAZ等转录因子感知硬度并持续活化), 这种"制造-响应"的双重角色使CAFs成为连接肿瘤机械微环境与恶性进展的关键枢纽, 为开发针对肿瘤基质的治疗策略提供了理论基础.
作为结直肠癌进展的核心推动因素, CAFs通过重塑TME并释放多种促肿瘤因子[如TGF-β、IL-6、胰岛素样生长因子2(insulin-like growth factor 2, IGF2)和血管内皮生长因子(vascular endothelial growth factor, VEGF)]来驱动恶性表型, 这些分泌因子激活癌细胞内的信号级联反应, 进而促进肿瘤细胞增殖、侵袭能力及远处转移[30-32]. 例如, CAFs通过分泌IGF2促进结直肠癌进展, IGF2随后结合癌细胞上的IGF1R, 激活PI3K/AKT和Hippo/yes相关蛋白1信号通路, 推动肿瘤增殖, CD142+-CAFs还可以通过分泌肝细胞生长因子(hepatocyte growth factor, HGF), 与结直肠癌细胞上的c-Met受体结合, 触发下游RAS、Wnt/β链蛋白和PI3K通路, 推动细胞增殖[31]. CAFs能够通过调节IL-6、WNT2及促进血管生成的促肿瘤因子(包括VEGF-α、FGF-2、CXCL 12、MMP-9和HGF)分泌, 从而促进肿瘤血管生成, 对肿瘤的耐药产生影响[30].
TME中的代谢重编程是近年来癌症研究的重要突破之一, 代谢重编程是肿瘤细胞的标志性特征, 既往研究主要关注CAFs的糖酵解(Warburg效应)和氨基酸代谢重编程. 在糖酵解方面, Pavlides等[33]和Martinez-Outschoorn等[34]首次提出"反向Warburg效应"概念, 发现CAFs在氧化应激和自噬作用下发生caveolin-1丢失, 进而驱动有氧糖酵解, 分泌乳酸和丙酮酸供肿瘤细胞进行氧化磷酸化; 后续研究进一步证实[35], 缺氧诱导的共济失调毛细血管扩张突变蛋白氧化激活可通过磷酸化GLUT1和上调PKM2促进CAFs糖酵解, 其产生的乳酸通过MCT4/MCT1转运至肿瘤细胞, 激活TGF-β1/p38 MAPK/MMP2/9信号轴促进肿瘤侵袭. 在氨基酸代谢方面, Sousa等[36]发现胰腺星状细胞通过自噬产生并分泌非必需氨基酸(特别是丙氨酸), 被肿瘤细胞摄取后用于TCA循环和脂质生物合成; 此外, 肿瘤细胞分泌的外泌体miR-105可激活CAFs中MYC信号, 诱导葡萄糖和谷氨酰胺分解代谢[37]. 除经典的糖、氨基酸代谢外, 近年研究开始揭示CAFs中脂质代谢重编程在消化道肿瘤耐药中的独特作用, 为理解代谢偶联提供了新维度. Gong等[38]首次系统分析了CAFs的脂质组学特征, 发现CAFs通过脂肪酸合酶(FASN)重编程脂肪酸代谢, 分泌长链多不饱和脂肪酸, 经结直肠癌细胞CD36介导的摄取后用于合成磷脂和甘油酯, 最终促进肿瘤细胞迁移和上皮-间质转化, 揭示了CAFs脂代谢重编程在肿瘤转移中的重要作用.
CAFs通过多种机制构建免疫抑制微环境, 促进肿瘤免疫逃逸和治疗抵抗. 在调节性T细胞(regulatory T cells, Tregs)招募方面, CAF-S1亚群通过分泌CXCL12β及表达OX40L、PD-L2和JAM2等膜蛋白招募并保留Tregs[39]; 同时, α-SMA+ CAFs可与Tregs形成免疫突触, 通过自噬依赖机制促进Treg激活和增殖, 导致免疫治疗抵抗[40]. 在巨噬细胞极化方面, CAFs通过分泌CXCL12、IL-6和GM-CSF等因子诱导肿瘤相关巨噬细胞向M2型极化(CD163+、CD206+), 并促进PAI-1分泌增强肿瘤侵袭[41,42]. 在CD8+ T细胞抑制方面, FAP+ CAFs产生致密胶原基质形成物理屏障阻止T细胞浸润[43]; 有研究表明[44], 在食管癌的免疫治疗中, 由于位于肿瘤边界的LAMC2+肿瘤细胞亚群能够分泌Semaphorin 3C激活COL11A1+CAFs, 形成物理屏障, 限制T细胞浸润, 使得肿瘤周围CD8+ T细胞富集, 肿瘤内CD8+ T细胞耗竭, 诱导肿瘤形成"免疫豁免生态位", 从而发生耐药; Endo180+肌成纤维细胞CAFs可限制CD8+ T细胞浸润, 其敲除后T细胞浸润增加且免疫检查点治疗敏感性增强[45]; 此外, CAFs通过表达PD-L1/PD-L2与T细胞PD-1结合直接抑制T细胞增殖, 或分泌TGF-β抑制树突状细胞功能, 减少T细胞激活[43]. 在NK细胞毒性方面, 胃癌中CAFs来源的滤泡抑制子样蛋白1可以通过DIP2A-P38途径上调NK细胞的NCOA4表达, 导致肿瘤内NK细胞的细胞毒性功能受损, 诱导肿瘤对化疗的耐药[46]. 这些免疫抑制机制共同构成了CAFs介导的肿瘤免疫逃逸网络.
Hu等[47]首次通过研究证实了CAFs来源的外泌体可能通过激活WNT/β-catenin信号通路促进癌症干细胞(cancer stem cells, CSCs)的特性, 并且外泌体携带的特定miRNA可能参与调控干细胞基因表达, 从而促进结直肠癌的化疗耐药性. 通过进一步研究, 源自CAFs的外泌体Wnt可能诱导结直肠癌细胞的去分化, 诱导非干性的结直肠癌细胞获得/转化为CSCs表型和功能, 促进结直肠癌的化疗耐药[48]. 后续关于外泌体的研究进一步增多, CAFs来源外泌体将circ_0067557转移至结直肠癌细胞, 直接与Lin28A和Lin28B蛋白结合, 稳定并上调Lin28A/B表达, 抑制let-7 miRNA家族, 解除对肿瘤抑制基因的抑制, 促进结直肠癌的进展[49]. CAFs的外泌体LINC00355通过抑制miR-34b-5p表达, 提高了CRKL的表达, 因此通过调控miR-34b-5p/CRKL轴, 从而增强了结直肠癌的化疗耐药性[50]. 除此之外, 在胃癌的联合治疗中, 顺铂和紫杉醇通过激活USP7/hnRNPA1轴, 促进CAFs中外泌体miR-522的分泌, 进而抑制ALOX15, 减少癌细胞中的脂质-ROS积累, 使肿瘤的化疗敏感性降低[51].
CAFs通过Wnt和Notch信号通路维持CSCs干性, 导致肿瘤复发和耐药. 在Wnt信号方面, CAFs分泌Wnt配体(如Wnt2、Wnt5a)或外泌体Wnts, 激活经典Wnt/β-catenin通路或非经典ROR2/PKC通路, 维持CSCs自我更新能力[52,53]; 在胃癌中, CAFs来源的Wnt5a通过调控HK2增强胃癌干细胞特性和糖酵解[54]; 在胰腺癌中, CAFs是形成支持胰腺癌干细胞干性的关键因素, CAFs分泌Wnt配体维持胰腺癌干细胞微环境, 促进其对化疗药物的耐药性并增强转移潜力[55]; 结直肠癌中CAFs通过分泌可溶性因子上调肿瘤细胞TIAM1表达, TIAM1激活Wnt信号通路驱动癌症干细胞自我更新, 抑制下调干细胞标志物(NANOG、OCT-4、ALDH等), 从而增强肿瘤的化疗耐药[56]; LOXL2+肌成纤维样CAFs能够激活邻近肿瘤细胞的Wnt信号通路, 靶向到Wnt5a+的肿瘤细胞亚群, 从而促进肿瘤的干细胞特性和药物抵抗[57]. 在Notch信号方面, CAFs通过IL-6/STAT3轴或直接表达Notch配体激活肿瘤细胞Notch1/3信号, 促进干性相关转录因子(Nanog、Sox2、Oct4)表达. 例如, 在肝癌中, CAFs分泌高水平IL-6, IL-6通过STAT3 Tyr705磷酸化激活Notch信号, 促进HCC细胞的干细胞样特性并导致索拉非尼耐药[58,59]. 这些机制共同构成了CAFs在消化道肿瘤中通过Wnt/Notch信号维持干细胞特性、促进复发耐药的网络.
上述六种机制并非孤立运作, 而是相互交织、协同放大, 共同构成CAFs驱动消化道肿瘤耐药的立体化调控网络. 首先, 物理屏障与免疫抑制及代谢重编程存在紧密的交叉对话. FAP+CAFs分泌的致密胶原基质不仅直接形成物理屏障限制药物渗透, 同时阻碍CD8+ T细胞浸润, 而基质硬度通过YAP/TAZ机械感知通路进一步维持CAFs活化状态, 形成"分泌-硬化-持续激活"的正反馈. 其次, 生化信号、代谢重编程与干细胞维持构成级联放大环路. IL-6作为关键节点因子, 一方面作为生化信号激活PI3K/AKT等促生存通路, 另一方面诱导巨噬细胞M2极化构建免疫抑制微环境, 同时通过STAT3激活Notch信号维持CSCs干性. Wnt信号同样贯穿多个维度, CAFs分泌的Wnt配体及外泌体Wnt不仅直接激活癌细胞Wnt/β-catenin通路维持CSCs自我更新, 且与HGF/c-Met信号存在交叉. 尤为重要的是, 代谢重编程与干性维持相互偶联, CAFs通过反向Warburg效应产生的乳酸和氨基酸为肿瘤细胞提供能量和生物合成原料, 而Wnt5a+ CAFs可上调HK2增强糖酵解, 提示生化信号可直接重塑代谢表型. 脂代谢方面, CAFs来源的脂肪酸不仅促进EMT, 且外泌体miR-522通过抑制ALOX15减少脂质-ROS积累, 将外泌体调控与脂代谢及化疗耐药直接关联. 再者, 外泌体作为信息整合枢纽, 桥接局部信号传递与系统性耐药调控. CAFs外泌体携带的Wnt、miRNA及circRNA可同时激活干细胞信号、调控代谢酶表达及干预免疫微环境, 实现多维度协同. 综上所述, CAFs通过"基质硬化-代谢偶联-旁分泌/外泌体信号-免疫逃逸-干性维持"的多层交叉对话, 构建了一个自我强化的耐药生态系统.
针对CAFs的直接清除策略旨在通过特异性杀伤FAP+ CAFs, 快速重塑TME, 解除其物理屏障作用并恢复免疫浸润. 目前, 该领域最具代表性的两种策略为FAP-CAR-T细胞疗法和FAP-IL2v融合蛋白(Simlukafusp Alfa, RO6874281). FAP-CAR-T细胞疗法通过基因工程改造T细胞, 使其表达特异性识别FAP的嵌合抗原受体, 从而直接杀伤FAP+ CAFs[60]. 临床前研究表明[61], FAP-CAR-T细胞可有效减少TME中的细胞外基质沉积, 改善实体瘤的物理屏障, 增强其他免疫疗法的渗透性. Loureiro等[62]进一步开发了"开关"系统调控的通用型FAP-CAR-T细胞(UniCAR-T), 通过靶点模块实现可控的CAFs清除, 在体外3D模型及体内实验中均显示出改善的细胞毒性. 此外, Khanali等[63]设计了"AND-OR-NOT"逻辑门控T细胞, 当识别肿瘤相关抗原时触发抗FAP双特异性T细胞衔接器表达, 指导内源性T细胞清除CAFs. 然而, CAFs的显著异质性为该策略带来挑战-临床前研究提示[61], 非选择性清除肌成纤维细胞在某些情况下可能导致肿瘤侵袭性增强, 因此精确识别促肿瘤CAFs亚型是未来优化的关键方向.
FAP-IL2v融合蛋白代表了另一种创新的CAFs靶向清除策略. 该分子由抗FAP抗体与白介素-2突变蛋白(interleukin-2 variant, IL2v)融合而成, 其中IL2v通过突变 abolished与IL-2受体α的结合, 从而选择性激活NK细胞和效应T细胞, 同时避免传统IL-2治疗介导的Tregs扩增及肿瘤免疫逃逸[64,65]. 研究表明[64], Simlukafusp Alfa可通过FcRn介导的长半衰期实现持续的肿瘤基质靶向. 在临床开发方面, Koyama等[65]在日本晚期实体瘤患者中开展的I期研究显示, Simlukafusp Alfa单药或联合Atezolizumab(PD-L1抑制剂)均表现出可接受的安全性, 并在外周血中观察到NK细胞和CD8+ T细胞的扩增, 其中1例既往接受过纳武利尤单抗治疗的晚期胃癌患者达到部分缓解. 目前, 该药物联合Cetuximab治疗头颈部鳞癌的Ib期研究也在进行中, 旨在探索通过NK细胞激活增强抗体依赖性细胞毒性的协同效应[66].
与直接清除CAFs的策略不同, 功能重编程旨在通过调控特定信号通路, 将促肿瘤的CAF亚型转化为抑肿瘤或静息表型, 从而重塑TME的免疫抑制和促纤维化特性. 该策略的核心理论基础在于CAFs的高度可塑性-iCAFs和myCAFs可在特定信号刺激下相互转化, 而TGF-β信号通路是驱动这一转变的关键分子开关.
TGF-β抑制剂通过阻断TGF-β/SMAD信号通路, 可有效抑制iCAFs向myCAFs的转化, 并诱导myCAFs向iCAFs表型逆转. 在消化道肿瘤中, TGF-β信号通路在胰腺癌、结直肠癌和肝细胞癌的基质激活中发挥核心作用. Galunisertib(LY2157299)是一种口服小分子TGF-β受体I激酶抑制剂, 可特异性下调SMAD2磷酸化, 阻断经典TGF-β信号通路[67]. 临床前研究显示[67], 在胰腺癌模型中, Galunisertib可通过改善血管正常化增强化疗药物递送, 阻断肝转移, 并抑制肿瘤起始干细胞的更新. 在针对晚期胰腺癌的Ib期临床试验中, Galunisertib联合PD-L1抑制剂Durvalumab显示出可接受的安全性, 疾病控制率为25%, 中位总生存期为5.72个月[68]. 此外, TGF-β信号在结直肠癌肝转移中同样关键-肝星状细胞在TGF-β刺激下激活为肌成纤维细胞, 形成促转移前微环境. 研究表明[69], TGF-β通过诱导CAFs产生IL-6家族细胞因子(特别是IL-6和IL-11), 激活肝细胞gp130依赖的JAK/STAT信号, 促进中性粒细胞向肝脏募集, 从而形成促转移生态位. 因此, TGF-β抑制剂有望通过阻断这一级联反应抑制结直肠癌的肝转移.
维生素A(视黄酸)通过诱导活化的PSCs恢复静息状态, 代表另一种功能重编程策略. PSCs在静息状态下储存维生素A, 而在激活为CAFs时丢失这一特性. 全反式视黄酸(all-trans retinoic acid, ATRA)作为维生素A的活性代谢物, 可通过结合核视黄酸受体调控靶基因转录, 恢复PSCs的静息表型[70]. 研究证实[71-74], ATRA可通过下调肌动球蛋白轻链2(myosin light chain 2, MLC-2)收缩性, 使PSCs恢复机械静息状态, 抑制基质重塑和癌细胞侵袭, 后续研究进一步揭示, ATRA还可通过抑制TGF-β的机械激活, 并在肝星状细胞及胰腺癌细胞中保守性调控细胞力学行为, 提示RAR-β/MLC-2轴作为跨肿瘤类型的基质重编程靶点具有广泛治疗潜力. 在结直肠癌中, ATRA同样显示出基质重编程潜力. 2024年美国癌症研究协会报道的一项研究显示[75], ATRA可特异性抑制结直肠癌患者来源的CAFs(包括肝转移CAFs)的增殖, 而不影响肿瘤类器官的生长.
基质正常化策略旨在通过重塑TME的细胞外基质和血管网络, 改善药物递送和免疫细胞浸润, 而非直接清除CAFs. 该策略的核心在于理解肿瘤基质的物理屏障作用-过度的纤维化不仅阻碍治疗药物的渗透, 还通过增加组织间质液压压缩血管, 形成缺氧和免疫抑制的恶性循环.
HA是消化道肿瘤细胞外基质的主要成分, 在胰腺癌、结直肠癌和胃癌中高度富集, 形成亲水性凝胶屏障, 限制药物扩散并促进免疫排斥. Pegvorhyaluronidase alfa(PEGPH20)是一种聚乙二醇化重组人透明质酸酶, 通过系统性降解透明质酸重塑TME, 改善化疗和免疫治疗的肿瘤内递送. HALO 109-202 Ⅱ期试验显示, PEGPH20联合化疗在HA高表达胰腺癌患者中改善无进展生存期, 确立HA作为生物标志物的价值[76]. 然而, HALO 109-301 Ⅲ期试验(n = 494)未能证实总生存期获益[77]. 提示系统性HA降解的局限性: 单纯基质消耗不足以克服肿瘤适应性反应, 且HA片段化可能加剧炎症[8]. 为克服这些挑战, 靶向性HA降解策略成为新的研究方向. 2025年研究[8]开发了抗体-酶融合蛋白(AbEn)平台, 将透明质酸酶与CAFs靶向抗体(抗FAP/LRRC15)融合, 实现肿瘤局部精准HA耗竭. 在结直肠癌和胰腺癌模型中, FAP×LRRC15×HYAL三特异性抗体较非靶向透明质酸酶显著增强肿瘤生长抑制, 并与化疗、免疫检查点抑制剂及T细胞衔接器协同增效[8].
肿瘤血管的异常结构(扭曲、渗漏、周细胞脱落)导致组织间质液压升高和缺氧, 阻碍药物和免疫细胞渗透. 抗血管生成治疗通过抑制VEGF/VEGFR信号诱导血管正常化, 恢复灌注和氧合, 创造"治疗窗口期". 在肝细胞癌中, IMbrave150 Ⅲ期试验证实阿替利珠单抗联合贝伐珠单抗较索拉非尼显著改善总生存期(overall survival, OS)和无进展生存期, 成为晚期肝细胞癌一线标准治疗[78]; 仑伐替尼亦通过靶向NRP-1-PDGFRβ复合物诱导血管正常化, 增强抗PD-1疗效[79]. 在结直肠癌中, 贝伐珠单抗、阿柏西普、瑞戈非尼等联合化疗虽为标准治疗, 但单纯血管靶向面临耐药挑战[80]. 最新研究[80]转向"免疫-血管"联合策略-通过血管正常化改善免疫检查点抑制剂浸润, 在MSI-H/dMMR结直肠癌中显示前景.
CAFs靶向与化疗/免疫检查点抑制剂的联合策略通过"基质-免疫"协同调控克服治疗抵抗. ATRA联合吉西他滨-白蛋白紫杉醇在胰腺癌STARPAC Ib期试验中显示中位OS 11.7 mo[70], STARPAC2 Ⅱ期试验正在评估手术切除转化率[3]. CXCR4拮抗剂BL-8040联合帕博利珠单抗及化疗的COMBAT IIa期试验在转移性胰腺癌中ORR 32%、DCR 77%, 机制上通过减少MDSCs/Tregs、增加CD8+ T细胞浸润实现免疫激活[81]. 2025年开发的CAsF靶向抗体-酶融合蛋白(TAVO423)联合PD-1阻断使肿瘤生长抑制率从33%提升至51%, CD8+ TILs密度增加6-9倍[8]. 此外, TGF-β抑制剂联合索拉非尼[82]、MEK/STAT3抑制剂联合PD-1抑制剂[83]、以及多靶点抑制剂zanzalintinib联合阿替利珠单抗在STELLAR-303 Ⅲ期试验中显著改善难治性结直肠癌OS(10.9 mo vs 9.4 mo)[84], 均验证了基质-免疫联合策略的临床价值. 除此之外, 针对肿瘤代谢的重编程, 可以在脂肪酸合成阶段靶向抑制限速酶, 限制脂质对肿瘤细胞的供应, 还可以针对脂肪酸转运蛋白, 如ABCA8或CD36, 抑制脂肪酸的转运, 通过联合用药抑制肿瘤的侵袭和转移, 提高治疗效果[85].
外泌体阻断策略包括"抑制分泌"和"工程化改造"两大方向. GW4869作为nSMase2抑制剂, 通过阻断神经酰胺依赖性囊泡形成抑制外泌体生物发生, 在结直肠癌和胰腺癌模型中抑制肿瘤生长并逆转化疗耐药, 且与PD-1抗体联合可通过抑制外泌体PD-L1分泌增强抗肿瘤免疫[86]. Rab27a抑制剂(如Tipifarnib)同样可减少外泌体分泌[87], 而质子泵抑制剂作为间接策略安全性更佳[88]. 工程化外泌体利用其天然靶向性实现精准干预-间充质干细胞来源外泌体负载miR-34a-5p、anti-miR-21或KRASG12D siRNA在胰腺癌中显示抗肿瘤效应[89]. 2025年最新研究[90]开发了共载抗PD-L1 scFv与STAT3 siRNA的基因工程外泌体, 实现免疫检查点阻断与致癌信号抑制双重靶向. 此外, 针对CAF外泌体特定miRNA(如miR-21、miR-196a)的反义寡核苷酸或VDR信号激活可恢复化疗敏感性[91,92].
综上所述, CAFs的高度异质性及其来源的多样性构成了消化道肿瘤靶向治疗的核心挑战: 一方面, FAP等标志物在TME与正常组织中的交叉表达, 使得特异性靶向策略面临脱靶毒性的风险; 另一方面, 治疗压力诱导下CAFs亚群(myCAFs、iCAFs、apCAFs)间的动态转化与可塑性, 导致单一靶点干预难以维持持久疗效, 极易诱发适应性耐药. 此外, CAFs通过构建物理屏障、代谢重编程、免疫抑制微环境塑造及外泌体介导的耐药信息传递等多维机制, 进一步加剧了治疗复杂性.
面对CAFs诱导耐药所带来的挑战, 未来研究可在多维度深入探索, 为开发更有效的干预策略提供依据. 首先需要精准靶向CAFs, 前提是建立可靠的生物标志物体系, 以实现获益人群的精准筛选和治疗反应的实时监测, 目前, CAFs相关生物标志物的开发主要沿三个维度推进: 液体活检标志物, 例如循环FAP+外泌体; 基于单细胞测序的CAFs分子分型标志物; 影像组学非侵入性评估CAFs驱动的基质重塑, 未来, 整合影像组学、液体活检和病理组学的多模态标志物体系, 有望实现CAFs状态的动态监测和治疗反应的实时预测, 为"基质靶向"精准治疗提供决策支持. 同时, 患者来源的类器官模型与体内成像技术相结合, 可在模拟生理微环境中动态验证靶向策略的有效性与耐药机制, 从而架起基础机制研究与临床转化之间的桥梁. 最终, 整合"直接清除-功能重编程-基质正常化"的多维度干预策略, 并探索与化疗、免疫检查点抑制剂的协同方案, 有望突破当前治疗瓶颈, 实现针对肿瘤基质微环境的个体化精准治疗, 改善消化道肿瘤患者的预后.
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学科分类: 胃肠病学和肝病学
手稿来源地: 上海市
同行评议报告学术质量分类
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科学编辑: 刘继红 制作编辑:张砚梁