修回日期: 2026-05-23
接受日期: 2026-06-18
在线出版日期: 2026-06-28
转移性结直肠癌的治疗决策及预后与驱动基因突变类型高度相关, 其中RAS、BRAF等驱动基因突变不仅决定靶向治疗路径, 也深刻重塑肿瘤免疫微环境, 进而影响抗肿瘤治疗应答与预后. 本综述聚焦现有证据, 系统阐述常见驱动基因突变如何通过调控免疫细胞浸润、细胞因子网络与代谢重编程, 塑造转移性结直肠癌的免疫抑制生态, 并探讨其临床转化价值.
核心提要: 本综述聚焦现有证据, 系统阐述转移性结直肠癌(metastatic colorectal cancer, mCRC)常见驱动基因突变如RAS、BRAF等, 与肿瘤免疫微环境(tumor microenvironment, TME)的相关性, 阐述分子机制及临床转化意义, 并阐述mCRC不同转移部位之间的TME特点, 表明mCRC驱动基因突变通过重塑免疫微环境深刻影响疾病进程与治疗应答, 基因突变与TME之间存在复杂的双向调控网络, 未来mCRC的精准治疗策略应超越单一靶点抑制, 转向"驱动基因靶向+免疫微环境重塑"的联合模式.
引文著录: 申艳丽, 王璐娜, 李蓉, 胡凤娣, 林艳苹, 谢琳. 转移性结直肠癌驱动基因突变与肿瘤免疫微环境相关性研究进展. 世界华人消化杂志 2026; 34(6): 487-495
Revised: May 23, 2026
Accepted: June 18, 2026
Published online: June 28, 2026
The therapeutic decision-making and prognosis of metastatic colorectal cancer (mCRC) are critically influenced by the specific driver gene mutation profiles. Mutations in driver genes such as RAS and BRAF not only determine eligibility for targeted therapies but also profoundly reshape the tumor immune microenvironment, thereby modulating anti-tumor responses and affecting clinical outcomes. This review synthesizes available evidence to systematically elaborates on how common driver gene mutations-through regulation of immune cell infiltration, cytokine networks, and metabolic reprogramming-contribute to the establishment of an immunosuppressive ecosystem in mCRC. The clinical translational value of these mechanistic insights is also discussed.
- Citation: Shen YL, Wang LN, Li R, Hu FD, Lin YP, Xie L. Driver gene mutations and the tumor immune microenvironment in metastatic colorectal cancer: Current evidence and research progress. Shijie Huaren Xiaohua Zazhi 2026; 34(6): 487-495
- URL: https://www.wjgnet.com/1009-3079/full/v34/i6/487.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v34.i6.487
核心提要: 本综述聚焦现有证据, 系统阐述转移性结直肠癌(metastatic colorectal cancer, mCRC)常见驱动基因突变如RAS、BRAF等, 与肿瘤免疫微环境(tumor microenvironment, TME)的相关性, 阐述分子机制及临床转化意义, 并阐述mCRC不同转移部位之间的TME特点, 表明mCRC驱动基因突变通过重塑免疫微环境深刻影响疾病进程与治疗应答, 基因突变与TME之间存在复杂的双向调控网络, 未来mCRC的精准治疗策略应超越单一靶点抑制, 转向"驱动基因靶向+免疫微环境重塑"的联合模式.
结直肠癌(colorectal cancer, CRC)是全球发病率第三、死亡率第二的恶性肿瘤, 在我国发病率和死亡率分别位居第二和第四位[1], 且均呈上升趋势. 虽然癌症早筛让早期CRC预后明显改善, 但转移性CRC(metastatic colorectal cancer, mCRC)仍占20%-25%, 肝转移最常见, 其次为肺、腹膜转移, 5年生存率仅10%-15%. 驱动基因突变是mCRC发生、进展及治疗抵抗的核心因素, 主要包括RAS、BRAF突变等[2]. 这些突变通过持续激活下游信号促进肿瘤细胞增殖、侵袭和转移, 同时重塑肿瘤免疫微环境(tumor immune microenvironment, TIME)实现免疫逃逸, 后者在mCRC转移和耐药中起决定性作用. 驱动基因突变通过多种机制重塑TIME, 归纳为以下4个方面[3-5]: (1)信号通路激活上调趋化因子招募免疫抑制性细胞; (2)代谢重编程(Warburg效应、谷氨酰胺分解)造成营养剥夺和酸性低氧环境抑制效应免疫细胞; (3)外泌体递送miRNA、介导癌症相关成纤维细胞(cancer associated fibroblasts, CAFs)极化和免疫编辑; (4)表观遗传修饰(如DNA甲基化)沉默抗原呈递基因. 本综述回顾了近年来关于mCRC驱动基因突变与TIME相关研究报道, 系统严谨地梳理阐述mCRC驱动基因突变与TIME相关性、机制及转化意义, 旨在为精准免疫靶向联合治疗策略提供新思路.
KRAS突变是mCRC最常见也最重要的驱动基因突变, 其发生率为40%-50%[6], 多项研究提示RAS突变与TIME中免疫细胞谱系失衡密切相关. TIME由肿瘤细胞、浸润免疫细胞(CD8+T细胞、调节性T细胞(regulatory T cells, Tregs)、肿瘤相关巨噬细胞(tumor-associated macrophages, TAMs)等)、CAFs、血管内皮细胞、细胞外基质以及代谢产物和细胞因子网络构成. CD8+T细胞是重要的抗肿瘤效应细胞, 它的减少提示肿瘤免疫监视能力下降, 而CD163+巨噬细胞则代表M2型巨噬细胞, 具有促进肿瘤生长和免疫抑制的作用. 微卫星稳定(microsatellite stable, MSS)KRAS突变型mCRC"冷肿瘤"特征明显, 表现为低CD8/CD3比值、高Tregs/CD8比值, 提示更强的免疫抑制倾向[7]. 有研究表明, KRAS突变CRC中肿瘤浸润淋巴细胞总体减少, CD8+T细胞密度降低30%-50%, 而Tregs(Foxp3+)增加2-3倍, M2 TAMs(CD163+、CD206+)增多, 髓源性抑制细胞(myeloid-derived suppressor cells, MDSCs)(CD33+ CD11b+)浸润升高, 肿瘤相关中性粒细胞(MPO+)显著增加[8]. 此外, KRAS突变还与多种免疫抑制分子(如CTLA-4、IDO、STAT3、PD-L1)表达上调有关, 共同构成免疫逃逸屏障[9,10]. 研究显示KRAS突变, 尤其是G12D、G12V亚型, 显著诱导免疫抑制性TIME[11].
KRAS基因突变主要集中在第12、13和61密码子, 其中以G12和G13位点最为常见, 如G12D、G12V和G13D等[12]. 不同突变位点可通过改变KRAS蛋白的构象及其下游信号通路激活程度, 从而对肿瘤细胞与免疫系统之间的相互作用产生不同影响.
不同KRAS突变亚型的免疫细胞浸润可能表现出不同特征, 有研究[11]提示, G12V或G12D突变更容易形成免疫抑制性微环境, 细胞毒性T细胞浸润更少, 而免疫抑制细胞如M2型巨噬细胞更高. 因此, KRAS某些突变亚型可能通过调控免疫细胞浸润, 促进肿瘤免疫逃逸. 相比之下, G13D突变在部分研究中显示出不同的TIME特征. 有研究[13]指出, G13D突变患者的肿瘤免疫细胞浸润程度可能相对较高, 尤其是CD8+T细胞的浸润水平略高于其他KRAS突变亚型. 这种差异可能与G13D突变对下游信号通路激活程度较弱有关, 从而导致肿瘤免疫抑制作用相对减轻[14]. 但也有研究[15]提示不同KRAS突变亚型G12V、G12D、G13D, CD8+T细胞在亚型间无显著差异, 但在肿瘤组织内G12D Tregs相对G12V更高. 目前关于不同KRAS位点突变免疫微环境差异的研究仍然有限, 具体机制仍需进一步探索.
此外, 有研究提示KRAS突变肿瘤中免疫抑制性细胞因子及TAMs水平较高, 导致免疫治疗效果不佳[16], 但不同突变位点是否对免疫治疗反应产生不同影响, 目前仍缺乏系统研究. 综上所述, KRAS不同位点突变不仅在肿瘤生物学行为上存在差异, 也可能通过调控CD8+T细胞和CD163+巨噬细胞等免疫细胞的浸润, 影响mCRC免疫微环境. 深入研究KRAS突变亚型与TIME之间的关系, 有助于揭示肿瘤免疫逃逸的分子机制, 并为mCRC个体化免疫治疗策略提供新的理论依据.
1.3.1 信号通路激活上调趋化因子招募抑制性细胞: KRAS激活抑制干扰素调节因子2, 转录上调CXC基序趋化因子配体(CXCL1、CXCL2、CXCL3), 通过CXCR2招募MDSCs和中性粒细胞, MDSCs产生活性氧(reactive oxygen species, ROS)、精氨酸酶1、诱导型一氧化氮合酶耗竭L-精氨酸, 抑制T细胞增殖. Xu[17]等研究提示, KRAS突变通过阻碍有效T细胞浸润和招募抑制性免疫细胞(包括MDSCs、Tregs、CAFs)来塑造免疫抑制微环境, 强调KRAS通过下游效应子和抑制性细胞因子、趋化因子塑造抑制性TIME. 同时KRAS突变可持续激活MAPK和PI3K等信号通路, 促进炎症因子和趋化因子的表达, 上调转化生长因子β(transforming growth factor β, TGF-β)、白介素-10(interleukin-10, IL-10)、IL-6、血管内皮生长因子(vascular endothelial growth factor, VEGF), 促进Tregs扩增、M2极化、血管异常, 这些因子能够调控免疫细胞募集和分化, 进而影响TIME状态. Cheng[18]等指出KRAS G12D突变通过MEK/ERK通路上调IL-10与TGF-β, 促进常规CD4+T细胞向Tregs转化, 敲低IL-10或TGF-β后Tregs比例下降, MEK抑制剂亦可降低IL-10、TGF-β并减少Tregs转化. Boumelha[19]等也证实, 肿瘤细胞KRAS信号通过ERK-MAPK通路直接诱导IL-10、TGF-β表达及分泌, 从而促进常规Th1 CD4+T细胞向免疫抑制性Tregs转化, 并具有其他免疫抑制功能. 此外KRAS突变肿瘤细胞外泌体携miR-1246等诱导CAFs向炎症型CAF(iCAF)转化, 可激活肝星状细胞, 后者释放包括IL-6、IL-11、VEGFA、血小板源性生长因子A、CXCL12在内的多种促肿瘤因子, 共同塑造促转移微环境, 进一步放大免疫抑制[20].
1.3.2 代谢重编程造成酸性低氧环境抑制效应免疫细胞: KRAS驱动Warburg效应, 糖酵解增强、乳酸分泌增加、谷氨酰胺分解加强, 造成营养剥夺和酸性低氧微环境, 乳酸通过单羧酸转运蛋白家族1、MCT4转运抑制NK细胞及CD8+T细胞功能, 诱导Tregs, 低氧激活缺氧诱导因子-1α排除B细胞, 促进CAFs分泌CXCL12捕获T细胞, 谷氨酰胺竞争剥夺效应T细胞[21,22].
1.3.3 PD-L1调控: KRAS信号可通过MAPK通路(如p-ERK)上调PD-L1表达. KRAS与TP53共突变与更高PD-L1水平及更强CD8+T细胞浸润相关, 提示两者协同影响肿瘤免疫原性, 但整体TMB较低, 新抗原负荷低, 导致免疫检查点抑制剂(immune checkpoint inhibitor, ICI)耐药[9](见图1).
大多数KRAS突变mCRC属于MSS型, 对ICI单药治疗无效, KRAS G12C抑制剂在临床前研究中已被证实可通过重塑肿瘤微环境来逆转免疫抑制状态[23,24]. KRAS G12C突变亚型的研究揭示了更精细的免疫逃逸通路. 在CRC肝转移模型中, AKR1B10在KRAS G12C突变肿瘤中高表达并与不良预后相关, 其机制涉及激活NF-κB通路上调CXCL8表达, 通过CXCL8/CXCR2轴招募中性粒细胞, 并通过增强糖酵解导致乳酸累积, 乳酸诱导中性粒细胞发生组蛋白乳酸化修饰, 促进PD-L1转录, 最终将中性粒细胞重编程为免疫抑制表型, 实现免疫逃逸[25]. 该发现提示, KRAS G12C突变通过AKR1B10-乳酸-中性粒细胞乳酸化轴建立免疫抑制屏障, 提示联合靶向KRAS G12C与阻断乳酸代谢或中性粒细胞招募可能逆转免疫逃逸. KRAS G12C抑制剂可以恢复抑制性TIME, 为与ICI组合创造机会. 然而, KRAS抑制剂不可避免的挑战是耐药性[26]. 作为KRAS上游的信号节点, 蛋白酪氨酸磷酸酶(src homology region 2 domain-containing phosphatase 2, SHP2)在阻断裂性耐药相关的RTK反馈激活中发挥核心作用, 其免疫调节作用, 值得进一步探索[27]. 临床前研究显示, SHP2抑制剂能够增强KRAS抑制剂的抗肿瘤活性, 目前多项临床试验正在进行中[28]. KRAS G12D抑制剂(MRTX1133)联合ICI也正在进行临床试验.
mCRC中BRAF突变最重要、最有意义的突变是BRAF V600E突变, 其发生率为8%-10%[6], 常与微卫星高度不稳定性(microsatellite instability, MSI-H)状态共存(约60%), 其TIME特征较KRAS更为复杂, 尤其在dMMR/MSI-H背景下表现出显著异质性[29]. 总体上BRAF V600E常伴随更高免疫浸润与免疫检查点表达, 但同时存在T细胞功能耗竭、抑制信号增强[30]. 其免疫表型受MSI状态主导, 在MSI-H背景下BRAF突变对T细胞介导抗肿瘤免疫的影响可能有限, 而在MSS背景下更易形成免疫抑制基质富集、三级淋巴结构成熟受损的微环境, 并与免疫治疗抵抗密切相关[31].
BRAF V600E突变与KRAS突变呈"相反"的免疫浸润模式, 在CRC队列中, BRAF V600E突变型较野生型表现为更高的细胞毒性T细胞与Th1细胞浸润[31]. BRAF V600E突变在mCRC整体可见更多间质成分、更高免疫细胞浸润, 尤其CD8+T细胞、M0及M1巨噬细胞增多, 且PD-1、PD-L1、CTLA-4、LAG-3、TIM-3等免疫治疗靶点表达上调, 常见中性粒细胞与M1巨噬细胞比例升高, 而初始CD4+T细胞、静息树突状细胞、浆细胞比例降低, 但同时出现T细胞耗竭评分、T细胞调控评分及免疫检查点阻断耐药评分升高, 提示"浸润多≠有效杀伤"[32].
MSI-H背景下BRAF V600E突变, 在既往研究中观察到PD-L1表达升高、CD45 RO+细胞密度增加、Th1炎症特征增强等, 但多因素分析提示部分关联可能由MSI-H本身即"免疫活跃"表型所致[32]. MSI-H中BRAF V600E突变对T细胞浸润的增量贡献有限, 多组学研究显示, 在MSI-H肿瘤内部, BRAF V600E突变对T细胞浸润差异并不显著, 且MSI-H患者接受ICI疗效相对稳定, 提示BRAF V600E突变未必进一步改变MSI-H固有的强免疫反应基础[33]. 有研究显示RAS突变相较BRAF V600E突变型与野生型表现出更低新抗原负荷与更低PD-L1表达, 且免疫炎症水平与CD8+T细胞浸润更少, BRAF V600E与野生型相比免疫炎症程度相近, 但更具"高增殖/代谢重编程"特征[34].
MSS背景下BRAF V600E突变表现为免疫抑制. 其抑制机制有以下几个方面: (1)致癌性MAPK通路激活被认为可在肿瘤-免疫循环多个环节促进免疫逃逸, 被认为是在MSS BRAF V600E中, PD-L1可通过c-Jun与YAP转录上调, 补体经典通路基因高表达与不良预后及抑制性TIME相关[33]; (2)BRAF突变可显著影响肿瘤相关淋巴结构的数量与成熟度, 并与预后负相关, 同时伴随T细胞亚群改变及B细胞功能缺陷, 推动免疫微环境重塑[35]; (3)多数MSS BRAF V600E突变CRC属于免疫抑制的间充质亚型, 富含肌成纤维细胞与SPP1+巨噬细胞, 构成免疫治疗抵抗的重要基质屏障[31].
在小鼠模型中, D594A突变较V600E与G469V恶性度更低, 并呈现MHC-I与PD-L1上调及CD8+T细胞浸润显著增高, 机制上与ATF3-THBS1轴促进CXCL9/CXCL10产生, 进而驱动功能性CD8+T细胞浸润相关, 提示其具备更强的"免疫可激活"潜力[36].
临床前与临床转化证据提示, BRAF/MEK抑制可诱导肿瘤细胞内在的Ⅰ/Ⅱ型干扰素反应、抗原提呈相关基因及T细胞趋化因子程序, 从而免疫启动微环境, 在MSS BRAF V600E的mCRC中, PD-1+BRAF+MEK抑制剂三联方案相较历史对照显示出更高的缓解率与一定持久性改善[37]. 在接受ICI治疗的MSI-H mCRC人群中, BRAF V600E突变的男性患者的生存结局更差, 转录组学分析提示其TIME呈"免疫耗竭/免疫冷肿瘤"状态, 并伴随雄激素受体信号富集[34]. 这表明BRAF突变的免疫学效应受到性别与转移阶段等多重因素调制. 在BRAF突变MSI-H mCRC中, 男性患者出现更"冷"的TIME并伴随更差ICI疗效, 提示未来临床试验需将性别与BRAF状态纳入分层设计, 并探索联合抗CTLA-4等强化免疫策略[38].
PIK3CA突变发生率为10%-20%, 约35%-60%的PIK3CA突变伴随KRAS突变[39], 激活PI3K/AKT/mTOR促进代谢重编程和生存信号[40]. PIK3CA突变/PI3K通路激活的肠癌免疫微环境总体呈免疫抑制表型, 以抑制性髓系细胞(MDSC、M2样巨噬细胞)富集、CD8+T细胞浸润相对不足、炎症因子/效应分子表达偏低为特征, 并可通过CCL2-CCR2轴局部招募抑制性髓系细胞从而介导免疫逃逸[41]. PIK3CA突变(如H1047R)除直接影响肿瘤细胞外, 还可通过外泌体介导的"远程通讯"重塑转移微环境[42,43]. CRC细胞来源的外泌体携带PIK3CAH1047R突变DNA, 可被成纤维细胞摄取并在受体细胞内转录翻译, 通过与PI3K通路P85亚基互作激活成纤维细胞向CAF转化, 活化的CAF分泌大量IL-6, 一方面促进原发灶EMT与迁移, 另一方面在远端器官激活巨噬细胞, 形成有利于转移的微环境. 该机制提示驱动基因突变可通过非细胞自主方式, 提前为转移"铺路".
在753例CRC队列中[44], PTEN缺失与更高CD274(PD-L1)表达独立相关, PIK3CA突变合并PTEN缺失与PD-L1阳性率更高相关(82% vs 70% vs 50%), 提示PI3K通路双重激活可能进一步上调PD-L1. 另一项224例CRC研究亦报道PIK3CA突变与PD-L1表达显著相关(P<0.001), 且外显子9突变更突出[45].
PIK3CA突变通过外泌体-DNA远程激活CAF/IL-6轴促进转移, 提示血清外泌体PIK3CA突变与IL-6可能成为监测转移风险的液体活检组合指标, 并为"靶向PIK3CA+抗IL-6"联合干预提供理论依据[42].
TP53突变发生率为67%-72%. TP53突变可见肿瘤间质中存在较多的NK细胞[46], CD4+T细胞比例升高, 且CD4+T亚群中Treg、Th17、中央记忆T细胞增加. p53功能失调可重塑微环境向免疫抑制方向发展, 包括促进TAM等抑制性髓系细胞作用, 削弱CD8+T细胞抗肿瘤活性[47]. KRAS、TP53双突变可显著降低免疫细胞(尤其T细胞)能量代谢功能, 损害抗肿瘤免疫[48]. TP53突变可通过上调肿瘤细胞CEBPB, 促进T细胞CTLA-4表达并降低T细胞浸润, 加剧免疫抑制[49].
APC突变发生率为66%-74%. 在mCRC中, APC突变与几乎所有免疫细胞浸润下降相关, 这可能是多数mCRC由APC突变起始并伴随免疫排斥的潜在机制之一[50]. 也有研究[51]提示, APC状态与CD4+T、CD8+T、NK细胞及巨噬细胞浸润呈正相关, 但该结论来自相关性分析, 需结合样本分层与混杂因素谨慎解读. APC多为失活突变, 直接产生强免疫原性新抗原能力受限, 但可通过Wnt/β-catenin通路异常导致下游蛋白(如Ascl2)过表达, 间接成为免疫干预靶点[52].
NRAS突变少见, 亚洲人群发生率约为3%-5%[53,54], 其免疫微环境特点与RAS家族整体趋势一致(与KRAS类似). 现有证据主要来自KRAS与NRAS合并后RAS突变的mCRC数据, 由于NRAS突变本身病例数较少, 其作为独立因素对免疫微环境的贡献仍需更多大样本研究确认. 分析NRAS突变肿瘤中I型干扰素反应下调, 并与cGAS-STING通路被阻断有关, 敲低突变NRAS可增强cGAS-STING激活[55]. NRAS突变可激活IL-1、NF-κB等促炎通路, 并与免疫抑制微环境形成相关[56]. 在MSI-H/dMMR mCRC中, RAS突变/包括NRAS突变, 表现为新抗原负担与PD-L1表达更低, 整体炎症水平与CD8+T细胞浸润更少[34]. NRAS、PIK3CA、TP53、APC、SMAD4等共突变组合进一步塑造异质性, 未来mCRC精准治疗将以"驱动突变-免疫微环境轴"指导分层治疗.
mCRC的TIME并非由单一驱动突变决定, 而是多通路协同的结果. 一项针对mCRC的多组学研究发现[57], 转移灶普遍存在RTK-RAS、NOTCH与WNT通路突变, 并构建了一个以细胞黏附失调与免疫耗竭为核心的16基因枢纽网络, 其中CXCR2、CCR7、CXCL13等趋化因子/受体与CD19等标志物共同指向TME的免疫耗竭特征. 同时, 磷酸化的核糖体蛋白S6在mCRC组织中显著上调, 并与上皮间质转化蛋白及不良预后相关, 提示mTORC1下游信号可能参与维持转移灶的侵袭与免疫抑制表型[57]. 在CRC中, 远处转移是影响患者预后的主要因素, 其中最常见的转移部位包括肝、肺以及腹膜. 近年来研究表明, 不同转移部位不仅在临床表现和预后方面存在差异, 其TIME也具有明显的异质性, 不同器官特有的免疫系统会影响肿瘤细胞的生长、免疫逃逸以及对免疫治疗的反应.
肝脏是CRC最常见的转移器官. 由于肝脏具有特殊的免疫耐受环境, 其免疫微环境往往呈现明显的免疫抑制特性, 细胞毒性T细胞(如CD8+T细胞)的浸润水平相对较低, 而免疫抑制细胞如M2型巨噬细胞、Tregs及MDSCs则明显增多[58,59]. Zhu[60]等指出, 肝转移瘤免疫微环境中M2巨噬细胞比例显着升高, 活化肥大细胞比例显着降低, 关键信号通路涉及胆固醇代谢和血小板活化. 肝脏内的Kupffer细胞和肝窦内皮细胞能够分泌多种免疫抑制性因子, 如IL-10和TGF-β, 从而促进TAM的极化并抑制效应T细胞的功能[61]. 这种免疫抑制环境有利于肿瘤细胞在肝脏定植和生长, 也可能导致肝转移病灶对免疫治疗的反应较差.
相比之下, CRC肺转移的免疫微环境具有不同特点. 肺组织本身富含免疫细胞, 尤其是肺泡巨噬细胞和多种淋巴细胞亚群. 有研究[62,63]显示, mCRC肺转移较肝转移具有更高的免疫细胞浸润, 肺转移病灶中CD8+T细胞和NK细胞的浸润程度相对较高. 同时肺脏微环境中的炎症反应较为活跃, 可促进抗肿瘤免疫反应的发生[64]. 然而, 在肿瘤持续存在的情况下, 肺转移灶会逐渐形成免疫抑制环境, CRC肺转移中肿瘤动员的中性粒细胞、单核细胞等可在肺内被转化为免疫抑制群体, 并伴随TAMs、MDSCs、Tregs等抑制性细胞聚集, 从而促进免疫逃逸[65].
在腹膜转移中, TIME通常呈现另一种独特模式. 腹膜腔是一个相对封闭的空间, 富含腹腔巨噬细胞、浆细胞及多种炎症因子. 研究表明, 腹膜转移病灶中常见大量巨噬细胞浸润[66], 其中以M2型巨噬细胞为主, 这些细胞可以通过分泌VEGF、IL-6等因子促进肿瘤血管生成和肿瘤生长. 同时, 腹膜转移灶中的CD8+T细胞浸润通常较低[67], 免疫细胞功能也可能受到抑制. 此外, 腹水中IL-10、VEGFA及TGF-β蛋白水平升高[66], 腹水环境中的细胞因子和外泌体也可能进一步促进免疫抑制状态, 从而加速肿瘤进展.
目前大多数研究视角侧重于原发肿瘤而忽视了转移灶的独特生物学特征, 转移灶免疫微环境特征之间的显著差异尚未被充分揭示. 总体而言, 不同转移部位的器官特异性免疫环境在很大程度上决定了肿瘤细胞的生长模式和免疫逃逸机制. 肝转移往往表现为显著的免疫抑制状态, 肺转移则可能具有相对较高的免疫活性, 而腹膜转移则呈现以巨噬细胞为主导的免疫抑制微环境. 这些差异提示, 在mCRC治疗中应充分考虑转移器官的免疫特征. 例如, 对于肝转移患者, 可能需要联合免疫调节策略以克服肝脏免疫耐受, 而对于肺转移患者, 免疫治疗或许更容易发挥作用. 因此, 深入研究不同转移部位的免疫微环境差异, 不仅有助于阐明CRC转移的免疫学机制, 也可能为未来精准免疫治疗策略的制定提供重要依据.
目前针对mCRC与TIME相关性的研究, 缺乏多组学数据整合分析, 驱动基因突变混杂类型、不同转移部位、性别激素以及肠道微生物群等在mCRC免疫微环境调控中的作用仍需更多研究结果, 来进一步促进从驱动基因突变到临床精准免疫治疗的系统性转化[68]. 且在肿瘤空间异质性与分析方法层面, 同一病灶不同区域(如肿瘤中心与浸润边缘)的免疫细胞状态存在显著差异, 而单一位点组织活检极易遗漏这些关键信息, 导致研究结果存在明显的空间采样偏差. 这些多维度局限性的叠加, 凸显了未来研究需要从单一层面的描述性分析向多组学、时间空间动态、跨学科整合的系统性研究范式转变.
mCRC驱动基因突变通过重塑免疫微环境深刻影响疾病进程与治疗应答, 基因突变与TIME之间存在复杂的双向调控网络, 未来mCRC的精准治疗策略应超越单一靶点抑制, 转向"驱动基因靶向+免疫微环境重塑"的联合模式. 本综述系统梳理上述驱动突变与mCRC免疫微环境的相关性、分子机制及临床转化意义, 为突破当前免疫治疗在多数mCRC患者中的疗效瓶颈提供理论依据.
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学科分类: 胃肠病学和肝病学
手稿来源地: 云南省
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科学编辑: 刘继红 制作编辑:张砚梁