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
Discussion on KRAS G12D from Dr.
@danieltanmd
at #AACR26 shows considerable interest from the field in this subset - should we examine these cancers differently in patients with or without a smoking history?
Heat 65 · 51 likes · 1 reply · 13 reposts
Kayla Tyskiewicz, Markus Hippich, Tristan Cates, Gervaise Henry, Gilad Silberberg, Nicole Spanburg, Madeline Westcott, Daniel Ciznadija, Michael Boice, Paul Heverly, Frank Smith, Marianna Zipeto, Stefano Cairo, Sebastian Brabetz
Read the abstract →Seema nadir, Sumaiya Binte Hamid, Mati Ur Rehman, Azhar Hussain Rajabali, Kulsoom K. Ghias, Arooj Shafiq
Read the abstract →Silvia Coma, Ian Smith, Cristina Caffarra Malvezzi, Clint A. Stalnecker, Emilia Berardelli, Enrico Patrucco, Fusheng Zhou, Channing Der, Chiara Ambrogio, David G. DeNardo, Jonathan A. Pachter
Read the abstract →Ahmad A. Tarhini, Monica Chen, Jia Liu, Varun Monga, Victoria Atkinson, Sarina A. Piha-Paul, Bartosz Chmielowski, Benjamin Herzberg, Charlotte Lemech, Prachi Bhave, Ganessan Kichenadasse, Gerald Falchook, Janice Mehnert, Andrae Vandross, Mohamad Salkeni, Meredith McKean, David Wages, Ann Marie Kennedy, Meagan B. Ryan, John Clark, Abdulaziz Nanah, Michael J. Fossler, Philip Komarnitsky, Igor Puzanov
Read the abstract →Kanwal Pratap Raghav, Jun Zhang, Myung-Ah Lee, Jingdong Zhang, John Park, Yanqiao Zhang, Susana Rosello Keranen, Byoung Chul Cho, Herbert Ho Fung Loong, Cheng Chen, Huan Li, Shaonan Wang, Yandong Shen, Zifei Fan, Qian Chen, Hui Wang, Jing Zhang, George Zhi Jian Chen, Jayesh Desai, Antoine Hollebecque
Read the abstract →Source: Stephen V Liu, MD · x.com