2. Academic Validation
  3. Pancancer Fine-Mapping of Mutational Intolerance Identifies CHEK1 as an Immunosuppressive Driver in Lung Adenocarcinoma

Pancancer Fine-Mapping of Mutational Intolerance Identifies CHEK1 as an Immunosuppressive Driver in Lung Adenocarcinoma

  • Adv Sci (Weinh). 2026 May;13(25):e21265. doi: 10.1002/advs.202521265.
Tao Wang 1 2 3,  Hongyu Zhao 4 5 6 7,  Xiaojie Sun 8,  Yuqi Ding 9,  Zhipeng Zhu 1 2 3,  Xiaotong Yu 1 2 3,  Rongyi Zhu 10,  Dan Wang 8,  Kailong Li 10,  Yang Liu 11,  Li-Bin Wang 12,  Xiaolu Zhao 4 5 6 7,  Baojun Suo 13,  Hongsen Bi 14,  Peipei Zhang 9 15,  Tong Liu 1 2 3,  Fengbiao Mao 1 2 3
Affiliations

Affiliations

  • 1 Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China.
  • 2 Cancer Center, Peking University Third Hospital, Beijing, China.
  • 3 Beijing Key Laboratory for Interdisciplinary Research in Gastrointestinal Oncology (BLGO), Beijing, China.
  • 4 State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China.
  • 5 National Clinical Research Center for Obstetrics and Gynecology (Peking University Third Hospital), Beijing, China.
  • 6 Key Laboratory of Assisted Reproduction (Peking University), Ministry of Education, Beijing, China.
  • 7 Beijing Key Laboratory of Collaborative Innovation in Frontier Technologies for Population Quality, Beijing, China.
  • 8 Department of Pathology, Zibo Central hospital, Zibo, Shandong, China.
  • 9 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
  • 10 Department of Biochemistry and Molecular Biology, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
  • 11 Department of Medical Genetics, Center for Medical Genetics, School of Basic Medical Sciences, Peking University Health Science Center, Peking University, Beijing, China.
  • 12 Department of Cell Biology, School of Basic Medical Sciences, Peking University Stem Cell Research Center, Peking University Health Science Center, Peking University, Beijing, China.
  • 13 Department of Gastroenterology, Peking University Third Hospital, Beijing, China.
  • 14 Department of Plastic Surgery, Peking University Third Hospital, Beijing, China.
  • 15 Key Laboratory for Neuroscience, Ministry of Education/National Health and Family Planning Commission, Peking University, Beijing, China.
PMID: 41722056 DOI: 10.1002/advs.202521265
Abstract

Mutation-intolerant genes (MIGs), which are constrained in tumors yet variable in normal tissues, are critical for Cancer survival. Herein, we developed miDriver, a computational framework using pancancer-normal mutation contrasts to identify 1,020 MIGs across 8,096 tumors of 13 Cancer types. Strikingly, MIGs are highly associated with synthetic lethality, cell-cycle progression, and clinical outcome. CRISPR screening reveals MIGs, especially CHEK1, as cancer-specific vulnerabilities, whose suppression impairs tumor proliferation and migration. Single-cell transcriptomics reveals a CHEK1-high subpopulation exhibiting stem-like and immune-suppressed features, linking tumor-intrinsic fitness to microenvironment remodeling. Multiplexed immunofluorescence revealed that CHEK1 and MIF are co-expressed in tumor cells, and CHEK1-high tumor cells exhibit closer spatial proximity to M2-like macrophages. Mechanistically, CHEK1 promotes p53 phosphorylation to upregulate MIF expression and secretion, thereby driving M2-like macrophage polarization via the MIF-CD74 axis. In vivo, targeting the CHEK1-MIF axis (particularly CHEK1) broadly reverses immunosuppression. Clinically, higher tumor CHEK1 levels are associated with poorer response to anti-PD-1 therapy. Exemplified by CHEK1, these findings establish MIGs as dual therapeutic targets capable of simultaneously disrupting tumor-intrinsic fitness and remodeling the immunosuppressive niche. This work proposes a novel paradigm for selectively targeting MIGs to eliminate aggressive tumor subclones while minimizing toxicity to normal cells.

Keywords

CHEK1; CRISPR base‐editing screens; M2‐like macrophage; immunosuppression; lung adenocarcinoma; multi‐omics profiling; mutational intolerance.

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