KRAS / RAS 靶向 — 从平台化到 Ph3 验证
第一代 G12C 药（sotorasib、adagrasib）结合关闭态 KRAS。治疗后受体酪氨酸激酶反馈把 KRAS 重新推到开启态，单药缓解大约 30–40%、无进展约半年，远低于 EGFR / ALK。AACR 2024 还在讨论「G12C 单药耐药」；2026 的讨论已经是「整个 RAS 家族怎么被一套平台打」。
KRAS是人类最早发现的癌基因之一，长期被视为“不可成药”，在非小细胞肺癌、结直肠癌和胰腺导管腺癌中高频突变；它不仅驱动致癌信号，还塑造免疫抑制性微环境——升高PD-L1与肿瘤突变负荷、阻碍效应T细胞浸润并招募MDSC、Treg等抑制性细胞[1]。临床疗效则存在亚型差异，一项74例患者的队列提示KRAS-G12D突变与PD-1/PD-L1抑制剂的原发耐药相关[2]。机制上，既往研究多聚焦趋化因子轴：胰腺癌中突变Kras经NF-κB上调CXCL5、借CXCR2募集肿瘤相关中性粒细胞并阻碍T细胞浸润[3]；结直肠癌中KRAS经SLC25A22-天冬酰胺信号驱动CXCL1转录以招募MDSC，阻断后可与抗PD-1治疗协同[4]；KRAS突变CRC还伴Treg增多、M1巨噬细胞与活化CD4记忆T细胞减少[5]，RNF43缺失等共突变亦可重塑免疫微环境[6]。这些认识基本停留在“招募谁、排斥谁”的细胞构成与趋化因子层面，对免疫激活更上游的环节，上述文献着墨甚少。
正在AACR 2026年会late-breaking壁报环节以同步发表形式报告的这项研究来自Di Cao及同事：论文于2026年4月19日在线发表于Cancer Research[7]（DOI: 10.1158/0008-5472.CAN-25-4447），题为“Mutant KRAS Suppresses DNA Sensing by Remodeling Membrane Tension to Clear Extracellular Tumor DNA”。按推文的概括，它回答的是KRAS如何调控肿瘤免疫微环境，而给出的解释落在胞外肿瘤DNA上——突变KRAS通过重塑膜张力将其清除，从而抑制DNA感知。
与以CXCL5/CXCL1-CXCR2轴募集中性粒细胞和MDSC为核心的既有机制[3][4]、以及以浸润细胞构成变化为落脚点的描述[1][5]相比，该工作把KRAS的免疫效应前移到肿瘤DNA能否被感知这一更上游的环节，并把膜张力这一生物物理性质引入机制链条。换言之，KRAS塑造免疫微环境的方式不止于改变浸润细胞的“名单”，还可能从源头减少可供感知的肿瘤DNA，这与既往趋化因子机制处在不同的解释层面。
当然，目前可及的信息仅到标题与发表层面，具体瘤种、样本量与体内验证方式均未见披露；该机制是否适用于KRAS的不同变异（如G12D[2]）及不同共突变背景[1][6]，能否转化为与免疫检查点抑制或CXCR2通路阻断联用的干预策略[3][4]，都还是悬而未决的问题，有待完整论文数据给出答案。
- 1.Unveiling the role of KRAS in tumor immune microenvironment · Biomed Pharmacother 2024
- 2.KRAS-G12D mutation drives immune suppression and the primary resistance of anti-PD-1/PD-L1 immunotherapy in non-small cell lung cancer · Cancer Commun (Lond) 2022
- 3.CXCR2-Dependent Accumulation of Tumor-Associated Neutrophils Regulates T-cell Immunity in Pancreatic Ductal Adenocarcinoma · Cancer Immunol Res 2016
- 4.Targeting of SLC25A22 boosts the immunotherapeutic response in KRAS-mutant colorectal cancer · Nat Commun 2023
- 5.Immune landscape and prognostic immune-related genes in KRAS-mutant colorectal cancer patients · J Transl Med 2021
- 6.Loss of Rnf43 Accelerates Kras-Mediated Neoplasia and Remodels the Tumor Immune Microenvironment in Pancreatic Adenocarcinoma · Gastroenterology 2022
- 7.Mutant KRAS Suppresses DNA Sensing by Remodeling ... · pubmed.ncbi.nlm.nih.gov 2026
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@pmcancercentre
answers a key question - "Does the world need another KRAS G12C OFF inhibitor?" #AACR26
Key benchmarks for any new G12Ci:
Primary resistance & ORR
Durability of response
Toxicity profile (autoimmune hepatotoxicity!)
Activity in hard-to-treat
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